Just an FYI. For any individual thinking of investing, one diligence question would be: "are any biotech/therapeutics-focused venture capital funds investing in this round?"
I agree with not investing in early-stage biotech startups unless you are a professional early-stage biotech startup investor or know your stuff to an implausible degree.
Wouldn't the risk of knowing your stuff to an implausible degree be that your decision making is likely better than that of the FDA or local equivalent, making your predictions risky due to the potential behaviours of less-informed agents?
Of course you could be expert in the mechanisms of drug regulators, but the safe bet then is surely to hire your skills out rather than gamble on startups...
If you're going to go round investing in early-stage biotech startups then the ins and outs of the FDA is probably about 50% of the "stuff" you need to know.
I used to invest in (publically traded but pre-revenue) biotech companies, I made a small profit in the end but spent way too much time stressing over trial results and FDA committee meetings etc. In terms of dollars per grey hair it was the worst way of making money that I had.
For me personally, over the past ten years, the best ways of making money have been (a) investing in just about anything you can think of that isn't a biotech company, and (b) going to work and doing my job.
With a few exceptions, seed rounds almost never work out in biotech because the later investors, especially VCs have so much leverage that seed investors almost always get diluted down to nothing. This is because the capital requirements are so great (hundreds of millions) and unlike in tech, the demand for capital is greater than the supply (though this seems to be turning)
Scott: This is important. DO NOT Post solicitations for investments. I do not know enough of your exact situation or of the nature of the solicitation to give competent legal advice to you.
But. It is generally illegal to sell securities unles you are a registered securities dealer. California's laws (and I am not a California lawyer) are very strict and they are enforced aggressively. Federal law is similar.
If I were you, I would take this information down.
I am retired. When I was in practice I was not "Big Law". I am not trying to get anybody to spend money on legal fees.
I do know a bit about securities law, a bit that grows more and more obsolete day by day. I used to teach CLE classes on the subject. But, that was in a previous millennium.
Scott is not a financial industry professional. Even professionals make mistakes. Goldman Sachs recently paid a ~3G$ fine to the SEC. And, their General Counsel just did the 21st century corporate equivalent of being a virgin who jumps into the volcano. No connection they say. And you believe them, don't you.
Scott is an uncompensated volunteer. He has no upside, but any involvement in fundraising for investment opportunities carries a downside risk. Scott no ability to control risk by contract, insurance, monitoring, or due diligence.
I am a volunteer too. I hope my advice is worth every penny you have paid for it. If you don't think I am right, you can just ignore me.
My theory is
No Control + No Monitoring + No Insurance + No Due Diligence = Big Risk. Big Risk + No Reward = Don't Do it.
Perhaps. The Federal Securities Act of 1933 defines: "the term “offer to sell”, “offer for sale”, or “offer” shall include every attempt or offer to dispose of, or solicitation of an offer to buy, a security or interest in a security, for value." The law and administrative lore are very extensive. If you had an upside in doing this, it might be worth thinking about, but if you had an upside, that would be a fact indicating legal involvement.
As you are an uncompensated volunteer, the safest thing to do is to stay far away.
Back in a previous millennium when I had hair and no belly, I worked in a law firm that was located hard by Wall Street in lower Manhattan. On a clement day, if we weren't too busy, my colleagues and I would occasionally walk over to the river, and we would lunch at Sloppy Louie's immediately adjacent to the Fulton Street Fish Market.
It was a very plain sort of place. The tables were picnic benches and the menu was fried or broiled fish, nothing fancy. We were sure that it was, like the Fish Market, run by the Mob. There was a sign over the cashier's seat imparting ageless Sicilian wisdom:
"Even a fish can't get in trouble if it keeps its mouth shut."
As I posted above, general solicitation of certain private placement offerings is legal, as of 2013, under Rule 506(c) of Regulation D, subject to various limitations, in particular that the issuer must take "reasonable steps" to verify accredited investor status.
Consider that the modal person "posting an email someone sent me saying 'our company is cool, email us if you want to invest'" who comes to the legal system's attention is less "Scott Alexander" than "author of the 'Penny Stock One Weird Trick Report.'"
I have no opinion on this, but just know that I definitely will never be able to read one of your comments without hearing it in Walter's voice and with his reasonable-then-screamy delivery. I appreciate it.
General solicitation for private placement offerings is allowed under Rule 506(c), since the 2012 JOBS Act. (However, I don't know whether there are restrictions on _who_ is allowed to perform those solicitations. And I don't know whether the company is intending to reply on 506(c), which requires them to take reasonable steps to verify the accredited investor status of their investors, or 506(b), which is more convenient because it does not require them to do that (but does not permit general solicitation.))
Thanks, Glenn. One of the nice things about being retired is that I no longer have to learn all of this dugash. I looked at the SEC pages on the JOBS act:
I think you could structure things to avoid a problem, but since Scott (and anyone else in his position) has no ability to audit the structure or monitor compliance, my advice (which is easily worth every penny you are paying for it) is still to stay away.
Your advice is certainly not unreasonable. I have kind of a pet peeve about "vetocracy by overcaution", where a valuable thing ends up prohibited-in-practice if _anybody_ near the thing believes it might be prohibited, or feels like it ought to be prohibited.
(This pet peeve brought to you mostly by software licensing, which is the absolute worst mixture of "overcautious lawyers" and "cranky software engineers who mistakenly believe themselves to be lawyers". Of course, I'm arguably in the latter category myself, so I have to be careful how much I shit-talk it.)
I think the email is supposed to be jonah@equatortherapeutics.com (you wrote puetics). Normally I wouldn’t be so pedantic but I could see somebody clicking that link and failing to send an email!
It's always an option, just vanishingly unlikely in most cases (unless you know some very sadistic people I guess...). The question with risk is not how bad is the less risky option but how horrific are the other options...
Weren't most of the "spontaneous combustion" cases people who fell asleep with a cigarette in hand, and basically turned into a human candle wick, and died of carbon monoxide poisoning before they burned up? Not sure if mitochondria would affect the frequency of that.
The Texas case sounds like a large enough sample size that you could get an idea of long-term side effects from DNP usage via a survey.
Also, doesn't most modern anti-aging thought revolve around slowing the metabolism (e.g. fasting), not speeding it up? It sounds like this stuff would make you die faster, even if you didn't have any major side effects from it.
Normally the proton gradient is used to produce ATP. With uncoupling it just makes heat and is arguably not really metabolism as it doesn’t produce anything.
Free radical production from mitochondria is partly dependent on the proton gradient. So by uncoupling you can dissipate the gradient and reduce free radical production which may be beneficial if the cell is under oxidative stress. Of course there are lots of critiques against the free radical theory of aging.
That doesn't quite make sense to me. DNP is actually making the cell pump *extra* protons over the gradient, because it still needs the same minimum number of calories to operate. The DNP is just creating a parasitic side-reaction where some of the energy consumed is wasted as heat rather than used to pump protons, creating a net caloric deficit.
If there's a certain number of free radicals generated per proton-pumping operation, I can't see how this effect would result in less free radicals generated. If anything, it might be more.
"DNP appears to mimic in part the neuroprotective and neurorestorative effects of exercise and fasting by increasing BDNF, lowering cellular stress and building cellular resiliency by mild increases in mitochondrial bioenergetics."
Basically, through slightly stressing mitochondria, you increase mitochondrial health, similar to exercise, cold exposure, and other stress related activities that have beneficial health effects.
After the proton gets pumped over the membrane the electron has to go through a series of complicated stages to get back to it, which each stage making its own ATP letting aerobic respiration be so much more efficient than anaerobic respiration. However, the high energy chemistry in a mitochondria is potentially dangerous, sometimes things break, and if one part of the chain breaks down you have lots of electrons backing up and becoming Problematic. Letting the protons bypass the normal process more easily mitigates that danger even though it causes more of the normal operation of the mitochondria.
But the same number of successful proton pumping operations are still happening, right? There's just a bunch of extra unsuccessful ones as well. It's possible that my inorganic chemistry background is letting me down here.
Right. The proton pumping setting up the potential happens just like before. It's the electron dancing down the potential ladder making ATP that fall back on to the soft proton when they trip, to strain a metaphor.
I think I get it - the theory here is that the extra protons create metastable states that trap rogue electrons without producing free radicals, right? That makes a certain amount of sense.
Thank you very much for taking the time to explain it to me.
Don't think electrons of the type you appear to be thinking are involved in making ATP. The electrons that come out of the citric acid cycle are passed along a chain of membrane-bound proteins until they reduce O2 to H2O. The reaction to create ATP from ADP is not a redox reaction and happens somewhere else.
As I understand it is the existence and magnitude of the proton gradient that increases free radical production. Thus by reducing the magnitude of the proton gradient you would get less free radical production. Cells can increase their uncoupling in response to oxidative stress. All else equal this decreases ATP production but still above minimum, well except for the lens cells for some unfortunate individuals. I also imagine that uncouplers should reduce your capacity for physical labor.
Isn't it the creating of the proton gradient by the electron transport chains that risks, well, leaking electrons? Does ATP synthesis itself even involve redox?
The electron transport chain where high energy electron goes from donor to acceptor ending up with the one of the best oxidisers (electron acceptor), oxygen creates the proton gradient. This the oxidative step. Then protons flowing back via ATP-synthase then puts a phosporyl group on ADP, making ATP. That is the phosphorylation step. Together they are oxidative phosphorylation.
I'm not a mitochondria expert but yes the electron leakage should be in the electron transport chain. But the bigger the proton gradient the more the electron chain leaks. You can read more in the introduction part of this paper: https://www.sciencedirect.com/science/article/pii/S000527281830135X#bb0060
No, the phosphorylation of ADP to create ATP is not a redox reaction. It's a thioesterification or condensation reaction. No atoms change oxidation state. I think the confusion arises because the phosphorylation is *coupled* to a redox reaction, which is the reduction of O2 to H2O. That's why it's called "oxidative phosphorylation." The reduction of O2 provides the energy for the otherwise energetically uphill phosphorylation reaction. But in mitochondria these reactions occur in different places. The reduction of O2 happens along the electron transport chain, while the phosphorylation of ADP happens in a nearby membrane-bound enzyme.
Tried getting it off Ali baba once but it was just orange died sawdust. Also my family decided I was on meth because I was involved with a seemingly mysterious substance tied to weight loss that might explode and they didn't understand my explanations...
Correction to "They pump protons across a membrane, creating pressure for electrons to travel the opposite direction." Actually they create pressure (potential) for electrons to travel in the *same* direction. When positive charge goes one way, negative charge also "wants" to go that way, following its potential energy gradient. Making electrons travel in the opposite direction would cost even more energy, defeating the purpose.
>They pump protons across a membrane, creating pressure for electrons to follow. This forms an electrical gradient...
I argue for removing "creating pressure for electrons to follow" entirely, because that misleadingly suggests that this pressure is somehow necessary or relevant for the potential difference. In reality, the proton concentration differential is enough.
Yes, that is a strange statement. In the first place, it's not true. The *electrostatic* field of H+ is very well shielded in water, that's why solvated H+ (i.e. pH < 7) is stable. So while there is a voltage across the membrane, it's not nearly enough to rip electrons loose from wherever they're bound and hustle them across the membrane. The gradient of H+ is purely in the chemical potential, as far as I know, and the same (entropic) driving force would exist even if the species in question were neutral. The only reason cells do it with charged species (H+ in the mitochondrion, Na+/K+ in neurons et cetera) is that the charge makes it difficult for these small atoms to cross back over the membrane anywhere and destroy the gradient, which they would otherwise do, because they are very polar and the membrane is nonpolar -- their solubility in the lipid bilayer is very low. Perhaps something else was meant, and I'm not understanding it.
This isn't how it works at all. The electron transport chain doesn't involve free electron movement or net electron movement across the membrane.
Electrons get transported from food (fat/carbohydrate) to oxygen via a series of reducible cofactors (the electron transport chain).
The proteins that catalyse these reactions use that energy to pump protons out of the lumen. The protons can (mostly) only come back through the FOF1 ATPase, which makes ATP when it happens.
Also, dinitrophenol doesn't "punch holes" in the membrane; it's not a pore (things that actually punch holes in membranes cause massive necrosis - I'm familiar with two examples, one of which is part of the immune system and one of which is snake venom). The trick with dinitrophenol is that it's acidic (at just the right level to be partially ionised at biological pH) and that it's lipophilic enough to pass through membranes *even while ionised* (the aromatic ring and the delocalisation of the charge over 6 atoms help with that). So, since the pH on the two sides of the membrane is different, it tends to lose its proton inside the lumen, pass out, pick it up outside and come back in.
It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!
But obviously it's not so easy in practice as human bodies are vastly complicated biochemical laboratories operating under sometimes faulty instructions.
I didn't feel like using a preexisting handle here, but couldn't come up with anything good on the spot, so I just typed the home row in order.
I've been using dvorak for 3-4 years now. I didn't have a very good reason for switching, mostly it just sounded amusing to see if I could reprogram my typing muscle memory. I've previously written a bit about it here: https://www.schlaugh.com/~/cdvhauo
Nice! I've never looked at Colemak before now. Definitely makes the right call regarding the positions of AZXCV for the keyboard shortcuts.
I'm a dvorak vim user who doesn't remap the movement keys HJKL, and it's not too bad. Colemak doesn't seem to do so well on this metric: JK (up/down) switched around and all 4 of them in the left pointer finger's domain.
Still, I would probably choose Colemak over Dvorak if I were to go do it over again.
Almost all drugs except for some newer ones are making some part of your body less efficient, though not this directly. It’s a lot easier to turn harmful machinery off than to insert useful new machinery.
That may well be, but it's hard to argue that mitochondria are harmful machinery. This is like punching a hole in your gas tank because you have a crush on the gas station attendant.
It's not about turning the whole energy-making process off, just safe ways to make it slightly less efficient since it's tuned to solve the obsolete problem of scarce calories
I've read that among a certain segment of the naturally thin population they naturally release excess calories as heat rather than storing them as fat.
I have always been on the thinner side, although I can gain weight, and I also "run hot". My appendages are frequently warmer than other people's. That could be because I have a higher core temperature or a higher peripheral temperature alone. I also have higher blood pressure so maybe there's just more convection of heat away from my core. Either way I'm shedding more heat than normal, and am more tolerant of cold temperatures and less tolerant of warm temperatures.
hm, this is interesting. i'm also on the thinner side and have been struggling to gain weight, but I definitely feel colder to the touch than average (which i always attributed to the lack of body fat to keep me warm, also im AFAB). that said, i am also more tolerant of cold temperatures than warm ones, so maybe (anecdotally ofc) there's some correlation there.
I'm thin and cold too, but I do fidget a lot - I have a tendency to twitch my leg rhythmically and such. This might contribute to excess calorie expenditure. It does seem to stop when I'm hungry, though I'm not going to claim that there's an actual energy management relationship there.
Every thin person is probably such due to a confluence of factors. I mostly attribute my thinness to the small portion sizes my mother fed me as a child.
Hey Jack, I would also fit this description - tall, hot, restless, need to jump in the river even in winter - and my wife (African, hates the cold, sleeps under 2 duvets) is worried about my blood pressure so we've been monitoring it over the past couple of weeks - it's definitely high and fluctuates wildly throughout the day, so I'm getting it checked out properly at the GP tomorrow. I like the idea of investing in big mitochondria though 🤣
> Some more evidence: people with anorexia fidget like crazy. This is the conventional wisdom among generations of psychiatrists, and has been confirmed in studies – see for example *Measurement Of Fidgeting In Patients With Anorexia Nervosa Using A Novel Shoe-Based Monitor*, which found anorexics fidget almost twice as much as healthy controls. This seems really damning to me. Consciously deciding to fidget is hard. If you don’t believe me, try to fidget as much as possible for the next two hours (the length of the study linked above) and see how well it goes. Most people just can’t do it. On the other hand, fidgeting (renamed to the more dignified “non-exercise activity thermogenesis”) is the classic strategy that the lipostat uses to maintain unconscious control over weight...
> A purely social paradigm of anorexia can’t explain the fidgeting; a biological paradigm outright predicts it.
Wow! Do you mean psychological paradigm? It's not that your conscious mind holds the mistaken belief that your fat when you're not. Or that you're attempting to control one part of your life when you can't control others. On a fundamental biological level your body thinks it's fat when it's not.
I would expect the social paradigm to explain the fidgeting as nervous movement, the logic being that it's a stressful condition or stressed people tend to develop anorexia. I don't find the idea convincing without further explanation.
Anecdotally: my friend who has low body-fat and was a sports players in his youth and early twenties used to run very hot all the time. Hot to the touch. When I was fit, more fit than usual, I also felt very warm.
On the other hand, people who are thin naturally have less insulation. This might just be one of those reverse causality situations - thin people are less insulated and so lose more heat.
Worth noting: tall people apparently have higher BMI than short people, which may well be because of the square-cube law.
First, I am disappointed that there is no "conscious uncoupling" joke in here. A missed opportunity! Second, pretty sure that instead of "all is not lost" (implying that nothing whatsoever is lost) you mean "not all is lost" (implying not everything is lost). Sincerely yours in logical pedantry,
Modern dictionaries aim to describe language as it is commonly used, not to prescribe how it should be. I think it's wrong to say they "allow" it - they observe that it gets used that way.
You'd think that, but that's because the English have an inferior practical philosophy of language. In contrast, the motto and job of the Royal Academy of Spanish (which writes the Spanish dictionary) is "to clean, make certain, and give splendor". This is why we Spaniards can have nice things, like not having spelling bees because the correspondence between the written and the spoken word is pretty much* unambiguous.
"All is not lost" is perfectly technically-correct if you just interpret it slightly differently - as "it is not the case that all is lost" ("is all lost?" "it is not"), rather than as "it is the case that all things are not-lost" ("what is not lost?" "all is")!
“All is not lost” I would formalize (well, quasi formalize; this is a comment section!) as (x) ~(Lx). “Not all is lost” as ~(x)(Lx). Those aren’t equivalent. Would you do it differently?
You can interpret "all is not lost" in one of two ways, or at least two that are clear to me at a glance. One is the way you're interpreting it; the other is the way that's equivalent to your formulation of "not all is lost". Personally, I find the latter interpretation more intuitive.
To interpret "all is not lost" as "it is not the case that all is lost", logically equivalent to "not everything is lost" or "out of all things, some are not lost", I would take it as an answer to the implicit question "is all lost?", which I think is what most people tend to mean when they use the phrase. "All is not lost" under this interpretation describes a world where we were worried that all might be lost, but then found out that this isn't true, and some things still remain. I think that's the connotation the phrase is reaching for in its standard usage.
(Equivalently to that implicit question, you could also read it as a contradiction of an implied previous statement: "All is lost!" "No it's not!")
To interpret it as "nothing is lost", I would take it as an answer to the implicit question "what is not lost?", answering with "all" i.e. "out of all things, none are lost". This interpretation feels more awkward to me, linguistically speaking. It's grammatically viable but it doesn't feel like the natural way to phrase the sentiment; an ordinary English speaker, trying to express "nothing is lost", would probably use those three words.
As for "not all is lost", I think we lose something by moving to this phrasing from "all is not lost"; specifically, it muddies the connection to the implied question or statement. Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage. "Not all is lost" is also a valid negation here, but in my opinion it's deemphasizing that implicit relief and instead putting more emphasis on the implication that although not all things are lost, some of them probably are. Less relieved, more foreboding.
“Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage.” Not when quantifiers are involved they don’t. That was my point. If I said “all tennis players own a racquet” you would not deny that by saying “all tennis players do not own a racquet.” That would be kinda dumb. You would correctly negate it as “not all tennis players own a racquet.” Same for “all is lost”.
In my experience, in ordinary colloquial English, it absolutely is the case that people will negate "X is Y" to "X is not Y" even when you could interpret the sentence as involving a logical quantifier, because most colloquial English-speakers aren't interpreting their sentences as involving logical quantifiers; and in this case, under my preferred interpretation, the word "all" is not in fact being used as a logical quantifier.
Consider the exchange: "Brown bear, brown bear, what do you see?" "ALL", as seen in a 2014 Tumblr meme, surely a valid example of colloquial English. "All" is not functioning as a logical quantifier here; it is a noun, meaning "the totality of things". That's a perfectly normal thing for the word "all" to mean.
"[The totality of things] is lost" is a sentence containing no logical quantifiers, only a noun, being linked to an adjective. Its straightforward negation is "[the totality of things] is not lost".
Or for a slightly more reputable source, Wiktionary gives an impressively detailed list of possible senses in which the word "all" can be used, and although the first one seems to be the logical-quantifier-style usage, the only examples given of that usage involve it quantifying over a specified subject; "all tennis players", in your example, or "all my friends", "all contestants", etc. in Wiktionary's. The next usage listed is as a (pro)noun, meaning "everything", with examples such as "she knows all and sees all" or "those who think they know it all". This is the usage category into which I believe "all is not lost" falls.
Exactly. Or when they say “all that glitters is not gold”, implying that even gold itself does not glitter, instead of “not all that glitters is gold.”
Mitochondria in endotherms have proteins other mitochondria don't? And they're only expressed in certain tissue types? That strike anyone else as deeply weird?
Interesting, I never knew that about pigs/boars. So they are the only animal family inside their order with a defective UCP1, and also the only ones to build nests before giving birth - nests that provide some thermal insulation to piglets. I.e. pigs are so easy to fatten because they cannot as easily convert energy to body heat.
Is that evolutionarily related? I mean that boars have somehow acquired the nesting instinct (for sows to build nests, for piglets to always return to the nest) - they are otherwise quite intelligent, whereas "nesting" can yield other advantages - and then *as consequence* lost the selection pressure on keeping a functional UCP1?
I’m guessing because they are mostly carnivore, and we’d have to provide herbivores to feed the - so it’s easier to just raise herbivores as food for us?
Production and consumption cycles have to work in tandem for something to really take off, I guess.
There are alligator farms and outlets selling alligator meat, and as far as I'm aware, it's expensive. I don't know the purely material calculus of "how much food provided for how much meat obtained" - is it more or less viable than with more conventional cattle - but the economy of scale, the efficiency of the supply chains and their ubiquitousness, is nowhere near comparable.
Today's meat industry that deals in "regular cattle" has grown upon a millenias-old production/consumption cycle where production relied on small farmers. The production-side got incredibly industrialized (to the near-extinction of small farmers, in some parts) but it was able to do so only by building upon the pre-existing consumption side of that extremely well-established cycle.
No such production/consumption cycle for alligators had taken off in past millenias, since not nearly as many "small farmers" were interested in cultivating alligators. As for smaller reptiles, they have the same disadvantage as smaller mammals. Hare farms exist, but their share of worldwide meat production is negligible; too much "processing work per kilo of meat" for it to ever spin into something significant. I suspect it'd be likewise with smaller reptiles, except that small reptiles additionally lack the appeal to consumers.
The experiments by Jules Hirsch (which found that fat people who lost weight metabolically resembled starving people, not healthy thin people) would suggest no. Metabolic syndrome is its own thing which can affect both fat and thin people, and there's at least some evidence the casuality goes the other way--some part of metabolic syndrome causes weight gain, instead of the other way around.
weight loss normalizes a ton of metabolic syndrome related issues, though.
Insulin resistance and hypertension (when it is caused by obesity) rapidly normalize with radical weight loss, as the CALERIE trials and the Biosphere experiment demonstrate.
I'm not aware of any evidence metabolic syndrome-->obesity causality. Can you post relevant papers?
"The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome" by Kitt Falk Petersen, et al
"Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance" by Kurt Højlund
"Acute postchallenge hyperinsulinemia predicts weight gain: a prospective study " by R J Sigal, et al
Research into the Dutch Hunger Winter also shows a bunch of interesting effects--individuals exposed to famine at a specific point in gestation had much higher rates of obesity, type 2 diabetes, etc, than their family history or cohort would suggest.
The CALERIE trial was specifically looking at non-obese inidividuals, so it's hard to draw conclusions from it. For one, the string of 'obesity paradoxes' show that obese individuals with hypertension, type 2 diabetes, etc, do better than normal weight individuals with those conditions, and weight cycling--repeatedly losing and gaining weight, which is the usual outcome of any dieting attempt ("Medicare's Search for Effective Obesity Treatment" by Mann et all, although every meta review will show this)--worsens outcomes. Obese type 2 diabetics who lose weight seem to die sooner than those who don't ("Mortality Risk by Body Weight and Weight Change in People with NIDDM" by Chaturvedi and Fuller). Obese people with hypertension seem to live longer than thin people with hypertension ("Is Hypertension More Benign When Associated with Obesity?" by Barrett-Connor and Khaw), and interestingly the association between obesity and hypertension, which is already relatively weak, weakens even further when you study cultures where dieting isn't common, suggesting that weight cycling as an effect of dieting might be the culprit, not weight itself ("A Cross-Cultural Perspective on Obesity and Health in Three Groups of Women" by Bindon et al, "The Prevalence of Hypertension, Obesity, and Dyslipidemia in Individuals over 30 Belonging to Minorities from the Pasture Area of Xinjiang" by Yao et al)
Thanks for the links. I agree the CALERIE trials were looking at non-obese individuals, but I don't think that makes the results harder to draw conclusions from. BMI is a continuum. Isn't it quite striking that even within the "normal" range, though at the higher end of it, weight loss through caloric restriction has beneficial effects in exactly the predicted direction?
And the VIRTA trial shows normalization of insulin resistance in diabetic patients with weight loss. I think there's a also a non-ketogenic, very low calorie diet showing similar effects but I can't find it right now.
And the GLP-1 agonists seem to work through weight loss, mediated by direction action on appetite and other assorted things (slowed gastric emptying, nausea, etc.). Though there's likely direct effects of GLP-1 agonists on insulin resistance, so that's murkier.
Re: the obesity paradoxes, some can be dismissed with the well-known phenomena of cachexia with cancer and other serious illnesses .Unexplained weight loss is a classic red-flag for a bunch of conditions. So some of that is comparing people who will die from another condition, that are experiencing weight loss because of that, and incidentally experiencing weight loss.
Regardless, while the epidemiology you cite paints a mixed picture, I think the interventional literature paints a more clear picture of excess energy intake as the primary/initial defect in most people who are obese who later get metabolic syndrome.
The obesity/hypertension stuff suggests to me that hypertension that is caused by obesity is less harmful than other types of hypertension, not that obesity per se is protective.
In terms of literal definition, no. The International Diabetes Foundation defines it as:
central obesity (i.e. large waist circumference) AND two of raised triglycerides, reduced HDL cholesterol, raised blood pressure, or raised resting fasting glucose. See Wikipedia (https://en.wikipedia.org/wiki/Metabolic_syndrome#IDF). Definitions from WHO and others are similar.
So if "metabolic syndrome is when your doctor says you have metabolic syndrome", you can be obese and not have metabolic syndrome. From the "metabolic thing is the idea that we try to approximate with the IDF definition" then that's less clear. But I think researchers focusing on metabolic syndrome (I work with some of them) do not just think of it as simply obesity and would tend towards saying they're distinct phenomena.
>Is being fat the same thing as metabolic syndrome?
No. The lipodystrophic spectrum is lean, but has metsyn, while the metabolically healthy obese are, well, obese, but don't have MetSyn. This appears to be the result of individual variation in thresholds beyond which you can't handle more energy storage.
>Does DNP causing people to lose weight necessarily mean they're getting healthier?
In areas related to energy excess pathologies? Yes, any method of weight loss - aside from chopping off your limbs or the like - will improve any issues arising from energy toxicity, if you have them. Overall? Hard to say. You could ask the same thing about using heroin to lose weight.
Not sure if I misunderstood something: how do you get from 10 000 users per death times 23 deaths to 2 300 000? Shouldn't it be 230 000, which is still more than I'd expect for the number of PED-munching bodybuilders in the UK, but at least a bit more plausible?
While shilling is in fashion, let me shill for Nick Lane's book *Power, Sex, Suicide: Mitochondria and the meaning of life* which is really interesting and gives you a better sense for why this whole *decoupling* business is really important and interesting. Seriously it's on of the 10 best non-fiction books I've read and I go through 25 or so a year.
Thanks Andrew - love that stuff and just ordered second hand from the Book barn for £6.33. Sorely tempted as I am to to invest our meagre family savings in big, hot mitochondria, I suffer from chronic financial risk-aversion (I blame my metabolism, and my parents of course)... BUT if Scott were to actually provide a link to buy shares direct from him or his friend, I'd deffo reconsider 😉
First with "Gabriel Over the White House," and now with this article, I read this piece with increasing certainty that this would turn out to be some kind of satire, which rapidly declined as no puns appeared in the last few paragraphs.
I'm excited to see this post! Low dose DNP (2-3mg/day) has been a life saver for a number of individuals that I have spoken to in the past few months, myself included. There's a few private nootropics groups that are finding great results with it. And, a bodybuilding post on low dose DNP has some great excerpts from the recent research studies.
Low dose mitochondrial uncoupling has huge potential. DNP should not be slept on.
Those "normal" doses are for fat loss. However, two recent studies have shown that low doses can have profound health benefits. I've talked to people who have experienced a wide range of effects from low dose DNP, the main ones being increased energy, lessened fatigue, higher quality sleep, less need for sleep, decreased "brain fog", etc. So, nootropic, energy, and anti-aging reasons.
If you want more info on who's using low dose DNP, and where to talk to them, etc. I could make that happen. It popped up on the radar of a few nootropics groups back in October.
Can confirm at higher low-dose—thanks for the links as was not aware of super low dose. Have been trying 50-70mg per day off and on for past couple of weeks after trying full dose for weight loss a long time ago (not tolerable). Found going much over 100mg hits energy level and mood hard.
How can I contact you? I'd rather not give out the groups publically, considering the experimental nature of them, and the potential for public scrutiny and prying eyes to negatively impact them.
Regardless of the genuine merit of mitochondria decoupling, the discussion in your link makes me a little nervous. The 'study' by Geisler (actually a single-author review. Published in Cells, not to be confused with Cell) is a sprawling, but ankle-deep overview presenting DNP as a strong, even revolutionary candidate for a dozen of the most 'interesting' diseases of our age, from Alzheimer's and ischemic stroke, to diabetes and, uh, concussions?
The intro gets us off to a strong start: "In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically". Oh.
Let's skip ahead to the COI stuff. "John G. Geisler is a founder and shareholder of Mitochon Pharmaceuticals, Inc. MP201 (DNP prodrug) [...]. ". Ah.
I'm now strapped in, and ready for the kind of stuff you see from conflicted authors in obscure journals. Neither are, of course, incompatible with good science, but let's probably not ignore the red warning lights illuminating our entire dashboard.
What follows is a sequence of strong claims on the back of a sparse constellation of mouse models, and even weaker appeals to genetic regulation patterns. The theme of 'ROS bad' does a lot of work throughout, which is Not Wrong, but as vague as mechanistic claims really get in biomedical research (is there a more widespread meme than 'take my supplement to fend off ROS/inflammation and live forever?).
Some of the highlights include a "Neuroprotection" section clocking in at 52 words (I would have thrown in a shrug emoji). Hot Takes are casually dropped throughout, like author's view that the field of dementia research have wasted their efforts on downstream symptoms rather than the Real cause of disease onset (you guessed it): the mitochondria.
My courage ran out when I went look into the 'ischemia' chapter. The author start off strong with 'A fascinating example of DNP’s capacity to become protective for the threaten tissue or penumbra was elegantly demonstrated in a rat model of cerebral stroke', then go on to boldly claim that 'In ischemic stroke, the data suggests that the first line of care would be to provide tPA back-to-back with DNP'. This is all on the back of a single study of EIGHT MICE! Maybe let's hold our horses just a little longer before we make grand allusions to patient care?
So, yeah. Bit worrying to come upon a forum passing this around uncritically as evidence for taking DNP supplements. I don't really want to get into the second 'study' (also a review, same author), except to point out I'm not wild about the claim that few people died as a result of DNP in the 1930's, and therefore the stuff can't be that bad (this is brought up in both reviews). Most deaths would not have been the obvious result of DNP intake, and this would be basically impossible to tease out using the public health surveillance infrastructure of the 1930s (it's still not easy).
(I just realized that Scott actually links to this review in his post, though only in passing to bring up Mitochon's trial evaluating DNP for Huntington Disease)
Thanks for the examination, I really appreciate that. Mediocre quality of studies / reviews aside, I can personally atest to dramatic positive effects of 2-3mg DNP a day. I've played with all kind of compounds the past 12 years, and have rarely encountered effects as profoundly positive as I have with DNP, as have others.
This is not to say that these few anecdotal reports belay any concerns of health and safety. But, when we're talking doses tens to hundreds times lower than what has been observed to cause issue, I think anecdotal evidence does become relevant in the evaluation of low dose DNP.
"This makes your body's energy production less efficient, meaning you have to burn more calories per amount of metabolism you want to do. Hence the weight loss."
Actually, I don't think so. Taube's argument has never been that caloric balance has nothing to do with weight gain or loss. His point is that it fails to explain. Like trying to explain my increasing weight by saying that I am experiencing an increased impact of gravity. Trivially true, but not the least bit useful. What I would note about this mitochondrial line of thought however, is that, though potentially beneficial, it does not address the reasons for obesity or the obesity epidemic. If I were Gary Taubes, I would make that point. Which I just did. Even though I am not Gary Taubes.
BTW, the idea of uncoupling mitochondria by changes in lifestyle and/or diet (as I recall) has been around the "keto-community" for a while. There are numerous YouTube lectures about it.
All I'll say is that I've read at least one of his books (maybe two...can't recall) and listened to a few interviews with him. If that is his argument, he doesn't make it well. To wit, quotes like this one: "The science tells us that obesity is ultimately the result of a hormonal imbalance, not a caloric one—specifically, the stimulation of insulin secretion caused by eating easily digestible, carbohydrate-rich foods"
But of course you can't literally put on mass due to the secretion of hormones. The hormones have to be acting on metabolism, either getting you to want more calories, or getting you to waste fewer.
Sometimes the fact that something can be both true and of no explanatory value is difficult to grasp and can be difficult argument to make. In the quote you provide Taubes seems to me to be saying that caloric imbalance tells us nothing about the causes of obesity. He is not saying that the first law of thermodynamics doesn't apply to humans. Of course it does. But it tells us nothing about why some of us get fat and other don't. Here is Taubes making that point:
"Why is it that from the moment you enter medical school to the moment you retire, the only disorder that you will ever diagnose with a physics textbook is obesity? This is biology folks, it's endocrinology, it's physiology - physics has nothing to do with it. The laws of thermodynamics are always true, the energy balance equation is irrelevant.
If someone's getting fatter I guarantee you they're taking more energy than they expend (as long as they're getting heavier). And if they're getting leaner I guarantee they're expending more than they're taking in. [It's] given, let's never discuss it again. And if you say it to your patients you're telling them nothing.”
Also, this:
“All those who have insisted (and still do) that overeating and/or sedentary behavior must be the cause of obesity have done so on the basis of this same fundamental error: they will observe correctly that positive caloric balance must be associated with weight gain, but then they will assume without justification that positive caloric balance is the cause of weight gain. This simple misconception has led to a century of misguided obesity research.”
That's terrible philosophy of science by Taubes. It isn't that positive caloric balance is merely "associated" with weight gain, but that is a causally necessary condition for weight gain. And if you stop it, then it prevents weight gain. Not sure if he's committing a fallacy of equivocation on "cause" or what.
I can't remember if this is specifically Taubes's argument, but he's pushing back on the notion that all bodies treat calories the same. Metabolism is complicated and poorly understood, but people believe "calories in, calories out" is a sufficient explanation for weight loss/gain. Taubes says it isn't, and that the oversimplification is absurdly unhelpful.
For example: say we have two women. Both are 5 foot even. Both are exactly 120 pounds. The common calories in/calories out explanation would say that if both of them ate exactly the same number of calories for the day and did exactly the same activities, both women's weights would be affected in the same way. This does not happen.
For one, let's say one of them used to be 200 pounds but has lost weight. This has adversely affected her metabolism--all else being equal, she's burning about a quarter fewer calories than the other, because her body has throttled her metabolism. Even if she hasn't, basal metabolic rate varies from person to person, and for women, varies depending on where they are in their menstrual cycle. Stress also causes it to go up or down. All of these are invisible processes that mean that even if our two women eat exactly the same foods in the same amounts and do exactly the same activities in the same way, their bodies will not treat these calories exactly the same way.
Taubes is basically saying that the equation isn't "in - out = weight". It's more like "(in * a bunch of variable metabolic stuff) - (out * a bunch of other variable metabolic stuff) = weight".
Taubes, I think, would say that caloric balance as the causal explanation for obesity is a hypothesis. It is based on a law of physics, but that doesn't mean that it "works". So we have to test the hypothesis against observation. He notes that the hypothesis fails to predict what we observe (e.g. children consistently run positive caloric balances but they grow taller rather than fatter, the obesity epidemic began in the late 70's in the US but people didn't start eating more or exercising less, diets based on calorie restriction don't work, etc.). In summary, he subjects the calorie balance explanation of obesity to empirical tests, finds that it consistently fails to predict and so he rejects the hypothesis. This sounds like good science.
The alternative approach has been to assert that caloric balance must be correct regardless of the evidence because it is derived from the first law of thermodynamics. This logically leads to the idea that obesity is a character problem (some combination of sloth and gluttony) rather than a medical or biological problem. As Taubes puts it, it leads to thin people telling obese people that they would be not be fat if they were as virtuous as the thin. Decades of this type of approach has completely failed to stem the tide of obesity.
Along those lines, I think that your assertions are not well supported. Gravity is necessary for weight gain, but doesn't explain the obesity epidemic. And it is not necessarily true that lowering calories results in weight loss. If you substitute a 2000 calorie/day diet 95% of which is protein and fat with a 1900 calorie/day diet of 95% carbohydrates you will not lose weight - you would likely gain weight. For that matter, I could eat 4000 calories/day of grass and I wouldn't gain weight, because, unlike cows, the human digestive system doesn't use fermentation to convert significant calories into metabolic fuel. This should be enough to prove that the simple "calories in, calories out" model is at best a gross over-simplification.
Obviously, a more-complex model is going to curve-fit better than an simpler one. But that in no way implies that calorie restriction of some sort is not a necessity for weight loss.
I am not going to go down the rathole of the diet-obsessives here, but suffice it to say that there is a lot of evidence of increased caloric intake and lower caloric outgo in the U.S. since the 19th century, when people ate candy for a meal and expended huge amounts of calories in their jobs. And there are scientists who have specifically caught Taubes out on many of his claims.
"something can be both true and of no explanatory value is difficult to grasp"
Let us try this example.
An airplane has crashed. A perfectly correct, true explanation is: "that is because the force of gravity was stronger than the lift generated by the wings".
True, but useless. It is not clear WHY that happened and it surely won't help future pilots avoid the same fate.
The standard obesity explanation "he gains weight because he eats more calories than he burn" does not really explain anything either. But once you delve into Taubes' argument about hormonal imbalances, you start to understand how the natural balance between in and out gets out of whack.
When the conclusion being drawn is that engineers should ignore lift and gravity in analyzing the causes of crashes, then the critic is making a similar mistake to what Taubes said above.
"Ignore" is one thing, "make it a central point of the investigation" another. Lift and gravity are proximate causes and are to be treated as such. In order to prevent further crashes, you need to find the ultimate cause (pilot error, construction flaws) and remedy it.
There was also recently news of a diabetes medication that causes weight-loss [1, 2]. I wonder what you think about this? The mechanism of action is allegedly loss of appetite though (and not hypercharged metabolism).
All the GLP1 analogs are very effective and have been used for a number of years in a more aggressive fashion by progressive endocrinologists for non diabetic weightloss. I have been on the 1.0 dose of semaglutide, after being on liraglutide (victoza) for a number of years to successfully prevent recurrence of metabolic syndrome. My weight still goes up and down but not as much. The GLP1 analogs work primarily by slowing stomach emptying but it turns out also improve CVD through other mechanisms and have independent central effects. My endo has had great success with the currently marketed semaglutide doses and has been telling me that the 2.4 dose was going to be a game changer for a year.
Do you have further info / reading on this? How did you find a doctor even willing to think about these things? I spent 3 years pre-covid losing about 120 lbs, and due to various shelter in place issues have put about 80 of it back on. I'm pretty convinced that I have hormonal issues but have been unable to find a doctor who will look away from the screen and actually talk to me outside of a bariatric surgery clinic, and I don't want surgery if I can avoid it. I'm pretty fucking out there on a bunch of physiological measures (6'3, about 210 lbs of lean mass according to dexa, which is so far on the right tail for people who don't use steroids I might as well be from a different planet) and mental health measures (litany of diagnoses). When the apocalypses wasn't in the air I could handle real life + weight loss + other wellness goals. Since last year, I'm barely able to handle the real life part. I would love to find a "progressive endocrinologist" that can give me more than a thyroid checkup and say "you are ok!"
My daughter used the Ozempic for a yaer and lost ~40% of her initial body weight. She start6ed at 0.25 mg, and went to 1 mg in stages. She thought the 2.4 mg was a typo.
I have started to discuss it with my doctor, and he is a bit taken aback by the dose also. Is there any way for you to off line me the name of your doctor
You'd think it would work that way - the body should have to use more energy to stay warm if it's colder - but my father (who I consider a very credible source for things) says that lowering ambient temperature actually slows metabolism and reduces net energy use unless it's actually cold enough to make you start shivering.
Depends on your individual body's reaction. Temperatures cold enough to make me start shivering and presumably burn energy result in my body raising my hunger by more than enough to compensate - I can gain weight on beans and rice. Which is not normally the case!
My experience of med students is they forgot all of this ATP stuff the moment the exam is done as they claim it’s never actually useful as a doctor. As someone interested in biology, it is also intensely boring. I wonder how much Scott had to make himself look all this stuff up again. Then again, he’s been able to write about intensely boring biology before (obviously making it interesting when he writes about it, maybe he should write a textbook)
I had never heard mitochondria described as "proton pumping" across a membrane before. That makes it sound like a fuel cell. Maybe that's a good analogy for the less bio inclined.
It is an electrochemical process that uses membranes a lot like a fuel cell. That's why we breathe oxygen: you can get a lot of energy by giving it the electrons it wants.
The names of, say, the intermediaries of the Kreb's cycle are indeed boring, and read like genealogies." Then Fumarate begat Oxaloacetate, who begat Citrate..."
But the story in broader terms is pretty cool from a logistical standpoint, with various raw materials being shuttled into the various factory like organelles and so forth.
Well, it's a YC company, and the standard YC investment terms make it worth a minimum of $2 million for the whole thing. So you're gonna have to start the bidding a bit higher.
It's pretty easy to make with simple chemistry equipment. But given that nitroaromatic compounds can have some pretty nasty toxicity, especially to liver, I would stay well away from DNP. https://link.springer.com/article/10.1007/s13181-011-0162-6
In this sentence: "Treat a hundred cases of obesity in exchange for one or two cases of cataracts (and some skin rashes, and some liver issues, and maybe a small risk of explosions) - is this obviously a bad deal?" Do you mean "*Trade* a hundred cases..." instead?
I've always found it curious that none of the easy exploits tried on the human body seem to have ever worked. Something like true nootropics, or just a good weight-loss pill, anything that would feel like cheating. As if there's some natural law preventing it. Or do we just call the working stuff medicine?
Many performance enhancing drugs banned by sports leagues do work. They tend to require unsafe doses when everyone you're competing against is also taking unsafe doses, but for people not trying to compete, there are fairly safe doses of most things that can get you a mostly free lunch, aside from the fact they're largely illegal and thus somewhat expensive and difficult to obtain.
Plain old amphetamines do a pretty good job of boosting mental acuity and causing weight loss. HGT shots will transform your body pretty dramatically. But I think we tend to ban anything that seems too easy.
Some people would say exercise and eating less *is* the "easy" hack. But nobody likes those people.
Humans at this stage of development won't continue to evolve in the same way they did before. Reproduction for us is gated behind social constraints moreso than survival constraints.
Vaccines have worked great. They're almost magical: you give the body some dead virus, and it figures out how to make a wonder drug that'll prevent you from ever getting infected? Miraculous!
Antibiotics have worked great. Who knew that penicillin could cure so many unrelated diseases in so many different organs?
If it was an easy exploit, evolution would have found it a long time ago, most likely.
Maybe long-term exposure to abundant calories might eventually find some new points of optimization, but we're likely to be engaged in mass genetic engineering long before natural selectin can have any appreciable effect.
That research was funded by Novo Nordisk. They are currently selling the drug as a Type II Diabetes treatment, under the trade name Ozempic. Some doctors are using it off label as a treatment for obesity.
Is that why YouTube keeps telling me I should ask my doctor about it? (That's the one with the jingle that's taken from the 1970s song "Magic", right?)
(I had believed that) the problem with weight loss was that the body would notice what you're doing and correct for it by making you want to eat more. Weird that this pill would get around that problem.
Why are there different endings for this post between the web version and the one that I was emailed through substack?
The email reads, "...A friend of mine works there and asked me to write a post shilling their work to potential investors. I don’t usually do this, and please don’t take this as carte blanche to ask me to shill your company. But I figured this field was interesting enough to make an exception."
While the post is "...A friend of mine works there and shilled his company hard enough to get me interested in this. He’ll probably show up in the comments section, so you can ask him if you have any questions."
Because I edited it after some commenters expressed concerns with the original version, especially that I was in violation of securities law by linking to an investment pitch.
Aaah okay. I answered your survey having NOT read the original post, and my thinking remains "go ahead and post such things and assume we (your readers) know how to think for ourselves". BUT now that I see your original wording, I can see where it blurred a line. I personally think it's fine for you to continue to tell your readers "here's a thing and some info and my opinions and you readers are thoughtful and can make choices for yourselves". At the same time, (and as a not-lawyer), I respect that you can't just ignore actual laws that don't care about your intent or your trust in your readers' abilities to think for themselves.
There are lots of animal studies. It works more or less the same way in animals as in people, although with some differences (animals don't develop cataracts unless you put a lot of work into finding the right animal model).
There are now obesity drugs that are safe and effective, so I have to quibble with the subtitle "the only diet pill that really worked". The latest trials of semaglutide report ~15% weight loss with modest side effects. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
The best one right now just as far as weight loss, last i heard, was phentarmine+ topiramate, but that works substantially less well (with the highest dose giving like 7 percent more weight loss than placebo).
Semaglutide used in the trial cited above was not a pill but an sc injection (although the pill is available as well), so the subtitle of Scott's article is still technically correct.
There is another GLP-1 agonist approved by FDA for obesity in 2014 -- liraglutide, but it is much weaker than semaglutide. In a head-to-head blind trial, liraglutide at the recommended dose gave 8% weight loss, while semaglutide at the highest dose -- 14% weight loss https://pubmed.ncbi.nlm.nih.gov/30122305/
Nothing as effective. Plenty of drugs that do result in significant weight loss, but have side-effects that make them somewhat inadvisable for the modest amount of weight you lose.
'They pump protons across a membrane, creating pressure for electrons to travel the opposite direction.' That can't be right, the electrons would have to be under pressure to travel in the same direction that the protons did.
this seems like a $20 bill laying on the ground—why doesn’t the body do this auto-regulation on its own? Or, in other words, why isn’t this a free lunch?
I think for obesity the answer is that almost no people outside a modern society are obese. It seems to be a completely new problem and evolution didn't need to come up with answers.
I'm more surprised that the body doesn't naturally use this to generate heat! There's lots of anecdotal evidence (including from the Soviet soldiers) that DNP lets you tolerate temperatures you would otherwise freeze in - how come the body just gives up and lets you die instead? I have to assume it's because we evolved in Africa and didn't need it, and actual polar animals have other better techniques they use.
There's actually been a fair amount of evolution in how easy proton bypass is in our mitochondria between arctic and equatorial populations. But people have to worry about starving to death everywhere which I assume prevents us from getting to where this drug puts you.
It seems like a pretty inefficient way to generate heat. The body already goes through a lot of calories keeping warm in the cold, so accelerating that process sounds like a good way to starve. Having a fire, fur, or clothes would be much more efficient, particularly in an environment where calories are scarce.
I'd often wondered whether 2,4-DNP could be used to combat hypothermia. I suppose the difference is that we didn't evolve in conditions where we could escape the blizzard then go to the nearest burger king the next day.
How would that function have ever evolved? The condition of long-term persistent food abundance in which it might be advantageous to become less metabolically efficient and waste food on purpose has not been widely part of any animal's environment until 50 years ago or so.
This article (https://www.mitohealth.ca/what-is-mitochondrial-uncoupling/) states that animals with naturally uncoupled mitochondria live longer and the higher rate of oxidation from uncoupled mitochondria can eliminate polyunsaturated fatty acids (industrial seed/veg oil) from tissue. Sounds great! I wonder where a person's base level of energy production settles if they are cycling a drug like this. If the mitochondria have to work less hard while on the drug, does the body reduce the reproduction of new organelles? Probably not a big deal for someone who's struggling with obesity, but efficient mitochondrial function is a hallmark of youth and a trade-off between slimmer and less energetic/youthful might not be so straightforward.
The body does auto-regulate it, same in the obese as in the lean. The problem is that the obese regulate it to a higher setting. Given that the present environment is maximally obesogenic, one might ask why everyone isn't obese yet? (Probably because people differ in resistance to obesity.)
While I don't necessarily think T-Nation is the greatest source of information, this guy lists 9 other controlled substances bodybuilders use to lose weight loss in an article explicitly saying not to use DNP: https://www.t-nation.com/pharma/how-bodybuilders-really-get-ripped
You probably shouldn't use them either unless you're in a country where they're not illegal and know what you're doing, but is there any good reason to think any of these hormone-based approaches that don't manipulate your mitochondria don't work? I'm inclined to believe anything used by pro bodybuilders who make no claim to being "natural" probably works.
I got really excited/ confused for a moment seeing DNP, as in my profession that stands for do not populate/place, then was amused/ disappointed when it was a chemical.
Moderately related: https://m.youtube.com/watch?v=kXpzp4RDGJI is a nice video that shows how a mitochondrium turns the potential difference into ATP by rotating proteins.
I ran the numbers on this back in 2017 and decided that since cataract surgery exists it was *totally worth* a ~2% risk of cataracts to be able to lose weight as much as I want (albeit with very careful dosing) via a mechanism distinct from the usual weight-loss mechanisms. So I bought some DNP, used it to lose ~20 lbs in 3 months...and then absolutely *did* get the cataracts! About 6 months after I’d stopped taking DNP my vision grew cloudy (like being in heavy fog), the effect going from “annoying” to “can barely see well enough to cross the street safely” over a couple months. I found a good surgery center and had my lenses replaced ASAP with a high-tech plastic equivalent. Then (as expected) my vision got cloudy *yet again* necessitating a followup “zap the rest of the haze with lasers” procedure. Now my vision is okay again, but it was touch-and-go for a while.
Pre-cataract me thought having had cataract surgery would *eliminate the main risk* thereby giving DNP an even BETTER risk profile but post-cataract me thinks DNP is probably scarier than I gave it credit for, so I haven’t gotten any more.
I independently calculated the <2% number based on the reported side effect levels versus estimated use levels - some of this was from medical reports written around the time the FDA banned it.
The followup eye procedure I expected to need (and in fact did need) is called a YAG Laser
Capsulotomy. Your lens sits in a capsule; both the lens *and* the back of the capsule can become cloudy. So the lens gets cloudy, you break up the lens and replace it with a plastic one, the disturbance from the surgery (or whatever) somehow makes the capsule itself go cloudy and they...zap a big hole in it with targeted lasers (while you’re hoping they remembered to change the laser setting from “bulldozer” to “eyeball”). More on the YAG procedure here: https://www.uofmhealth.org/health-library/hw36757
Pre-cataracts I had decent up-close vision *without* glasses but needed glasses to see marginally well at a distance. After multiple expensive procedures I now have good distance vision *without* glasses but (a) I now need reading glasses to focus up-close (as is appropriate to my age), (b) there is a substantial “halo” effect (worse than before) around bright lights at night.
I got “Symfony” lenses which are supposed to allow both distance and close vision without glasses. They *kind of* do that - I can read my watch without glasses. But for *comfortable* close reading I need reading glasses. My best corrected vision is now excellent in one eye and pretty good in the other.
[Cautionary note: If somebody is thinking of using DNP I strongly suggest they find a good laser eye surgeon and get their prescription taken right *before* they start DNP. The fact that the cataract comes on *so suddenly* is a problem because to correct your vision *well* with an artificial lens they need to know your exact current prescription, which requires *guesswork* if the cataracts get too bad to see or measure through by the time you’re in their office.]
I obtained 200mg DNP capsules; my typical dose level was about 2 capsules per day for no more than 2 weeks at a time.
On a re-read I notice I didn't directly answer the lens question. So: I would say the plastic lenses are on balance *probably a bit better* than my original-equipment lenses, my "night halo" griping notwithstanding. (There are tradeoffs to be made between various things a lens can be good at; I think the designers made good choices.)
Note that to get my now-satisfactory results did require a half-dozen procedures and something on the order of $10k. The procedures were: (1) replace one lens. (2) a month later, replace the other lens. (3) One of the lenses didn't end up well-centered, so go back for a "nudge" operation to reposition it better. (4) the correction level isn't great in one eye (the magnification level of the lens probably wasn't a good match to my prescription) so reshape the exterior with PRK to fix that. (5/6) then the fogging came back so do followup YAG Capsulotomy (x2) to fix that. Yay, victory!
PS: my "bulldozer" comment was an old Dave Barry line, of which I just found the original version:
'For example, in the past decade scientists have developed the laser, an electronic appliance so powerful that it can vaporize a bulldozer 2000 yards away, yet so precise that doctors can use it to perform delicate operations to the human eyeball, provided they remember to change the power setting from "Bulldozer" to "Eyeball."'
As grad student studying a lot of biochemical pathways in the body, I got curious about mitochondrial decoupling. I decided to experiment on myself with a seaweed extract which supposedly could have a mitochondrial decoupling effect in fat tissue. I didn't noticeably lose weight while taking it (maybe I just subconsciously increased my calorie intake since I wasn't actively dieting?) but I did get Really Uncomfortably Warm. Like, so warm that I was running like three or four degrees above my normal and it gave me trouble sleeping. I also noticed a sense of increased energy, but decided it wasn't worth the uncomfortable warmth after a few months and stopped taking it.
From a health perspective, how useful would this really be? I am asking a causality question. If we assume that, for example, Type 2 Diabetes is caused by being overweight then losing weight by mitochondrial decoupling would be a good thing. But my understanding is that the relationship between Type 2 Diabetes and obesity is not so simply causal. So, this drug could result in a population of people who suffer the maladies normally associated with obesity but who are not obese. Not nothing, but not great either.
*A population who suffer the maladies normally associated with obesity, and also some of them will be blind or have liver/kidney damage (never mind whatever other fun side effects we may find in the meanwhile)
Being too fat is causal in diabetes. But the absolute degree of fatness is irrelevant, you are above the threshold where it becomes a problem, or you're not. Doesn't matter if you're 50kg or 500kg.
My understanding is that Type 2 Diabetes is caused by chronic insulin resistance, which also tends to cause obesity. My simple (minded?) question was whether it is possible to lose weight by using a drug that increases basil metabolic rate while allowing you to remain insulin resistant. If you took that drug and subsisted entirely on sucrose, would you run no risk of diabetes? I don't know.
Insulin resistance is a cellular mechanism against energy excess. Cells use it to avoid being overfed until they die. This is normal and desirable. What's not desirable is when your entire system, chronically (as opposed to momentarily, after a meal), is insulin resistant, which just means that you have an energy containment problem.
Type 2 diabetes is when your energy containment capability is so wrecked that your glucose homeostasis goes, and it is one of the last things to go, being one of the most ancient parts of metabolism. IMO, diabetes should be diagnosed at the "insulin resistance" stage, not at the "hyperglycemic" stage. It's the same disease, just a different severity thereof.
If you subsisted entirely on sucrose, drug or no drug, you would probably partly or fully heal your diabetes. Check out Minger's write-up of low-fat diets, especially Kempner's rice diet.
In Texas, a century from now, going to jail for tax and insurance fraud will be as honorable and as much of a way of life as dying in a cattle raid was for the Irish.
Mitochondria uncouplers sound like they could plausibly mess with the heartbeat, in potentially dangerous ways (Specifically ventricular repolarisation, ie QT interval prolongation and the like). When you prevent ventricular myocytes from accessing the energy they need, you run the risk of delaying, or otherwise altering the fairly precise electrical patterns that keep the show running.
A (very) quick google doesn’t bring up a whole lot for me; is this a concern you ran into during your research for this post?
"Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them."
This is counterintuitive, but seems to check out. As part of their normal functioning, mitochondria generate ROS, increasing oxidative stress. If you make them less efficient, it stands to reason that they'd do more of that, but it turns out that this reduces ROS generation and oxidative stress.
I feel like I'm missing something important about the mechanism of action.
High proton gradients across the mitochondrial membrane leads to the protons of the electron transport chain being in a very reduced state, and in a reduced state they're more likely to donate an electron to an oxygen molecule to create ROS. I think of it as the ETC getting "backed up" basically, and decoupling helps deal with the backup in the absence of more demand for ATP.
This is a good excuse to plug my favorite crackpot biological theory: "mitonuclear match" which is basically how well the proteins that move protons across the mitochondrial membrane work together, plays a central role in the relationship between fertility and longevity across all species. https://nick-lane.net/wp-content/uploads/2016/12/Lane-Bioessays-mitonuclear-match.pdf
I previously competed in bodybuilding at a high level. One of the most interesting protocols that I have seen for DNP involved using it to counteract accumulated insulin resistance secondary to the usage of insulin and/or growth hormone. DNP seems to very quickly restore insulin sensitivity above and beyond the effects that one would expect from weight loss. These effects persist after the user stops use of DNP. I would be interested to see whether these new mitochondrial uncouplers have similar effects, which would make them useful for a still wider population.
Equator Therapeutics is a fantastic company and I am proud to be an Investor! That said, it is a private company and there are not always opportunities to invest in this or any cutting edge biotech startup. Lastly, as many commenters have correctly mentioned, startup investing is risky and you should consider the capital to be very much at risk. But, yes I think Jonah and his co-founders are brilliant and I am very encouraged by Equator's progress to date and their singleminded focus on getting this right for the sake of humanity - David Segura
GLP-1 agonists work. https://www.nejm.org/doi/10.1056/NEJMoa2032183 The results of this recent RCT are pretty striking, though it’s over a longer time span. It kind of blows my mind that with all these crazy new onc and rare disease breakthroughs, gene therapies, immonumodulators etc. that we don’t have have an effective, safe widely available way to interrupt/circumvent metabolism. And very few seem to be working on anything despite the country being 2/3rds overweight or obese and rising and colossal health externalities. We seem to be sticking to the good old Protestant willpower model as physicians, without even adequate tools (like prescribing food) to ensure patients actually eat healthy and exercise.
In a novelty shop when I was a lad they sold a box labeled something like "Weight loss miracle. Not a diet, not an exercise plan, not a pill." When you popped the lid, inside was a set of utensils--A fork with the tines cut off along the bias, half a butter knife, and a spoon with a hole in it.
Fascinating! I've known of dnp for some time including the dangers but never knew the backstory. Where can we invest? I can't be find the link. The story was well worth making the investment IMO
If you want to research deeper, "ephedrine thermogenesis" brings up a lot of papers.
Quick summary [*] — it seems safe under MD's supervision. Certain people should never take it under any circumstances. People who can take it should do it carefully. Because people would sometimes use it recklessly and have adverse outcomes, it got banned from being prescribed or advertised as being for weight loss. Controlled status varies tremendously worldwide — it's OTC (but you have to show valid ID) in the United States; it's outright banned in some places and completely uncontrolled in others.
[*] (Relevant disclaimers: just my reading of the medical and scientific literature, but not a physician, not giving advice, might be mistaken, everyone should do their own research and talk to your physician, etc, etc, etc.)
The low theraputic index seems almost a dealbreaker in this case. You can't beat thermodynamics, and this is a particularly brute-force thermodynamic approach to weight loss. 500 kcal of the food you ate today doesn't turn into fat because it turns into heat instead, and any bit of cleverness that makes it so you don't get the heat means that this mechanism at least doesn't spare you the fat.
If the math works out that you can safely use some variant of the leaky-mitochondria trick to lose 2 lb/week, and *maybe* 5 lb/week, but 10 lb/week puts you in heatstroke territory, then the problem is that you can't have anything with the status of an FDA-approved diet pill that won't have more than a few people thinking "I *really* need to lose 10 lbs this week to fit into my wedding dress, so I'm taking the whole month's prescription this week and I promise to eat healthy after the wedding". There was apparently some of that in the 1930s, and the British bodybuilders, but I think there's a lot more pressure to be thin now than there was in the 1930s.
I say almost a dealbreaker, because the prodrug approach has an out: if you can find a prodrug where the metabolic transformation upstream of the mitochondria is a rate-limiting factor *and* saturates well below the "cause heatstroke" level, then you might be able to make this tolerably safe. That's a pretty tall order, but as you say, for an effective counter to obesity it's worth taking a look.
1. Metformin also does something to mitochondria, right? That maybe makes them work less well? This study (https://pubmed.ncbi.nlm.nih.gov/30548390/) complained that metformin reduces how well mitochondria respond to exercise. But isn't that (at least part of) the point? Would any scientists or doctors like to explain this legibly to us social science types?
2. After I read Scott's Fussell book review, I thought, "no need to use the Greek -on to -a plural suffix for 'rhododendron.' That's a bit much for flowers. It's not like they're mitochondria." And here we are, reading about mitochondria.
2a. Rhododendrons are definitely not a high-status flower these days, at least in the DC suburbs. They are often kind of a lurid pink or red. I had them ripped out when we moved to our house and replaced with hydrangeas, which are definitely the high-status flower du jour. Something to do with the ascendancy of Mark Sikes and his mania for blue and white.
Hydrangeas are high status? Wow! They're a staple of Irish country gardens and definitely regarded as old-fashioned. They'll be white and blue if you plant them in acidic soil, pink if in alkaline soil. You can often see different coloured flowers on bushes depending on the patch of soil they grow in:
"It's aluminium sulphate which makes the petals blue, and this is only available for uptake by the plants' roots in acidic soil. If you don't have the right soil, a good way to ensure ideal conditions is by growing the plant in a container where you can use an acidic compost and occasionally top it up with aluminium sulphate.
A simple soil test from your local nursery can help determine your pH level, which will determine your hydrangea colours. Generally, soil with a pH below 6.0 (acidic soil) will produce blue hydrangea blooms, and a pH above 6.0 will produce pink hydrangea flowers. Depending on your preference, you are able to change the colour of your hydrangea blooms to fit your desired colour."
Here's someone who did a tour of Ireland and got a bit excited about the hydrangeas:
> It next shows up in history books on the Eastern Front of World War 2, where Soviet soldiers would - I can’t believe I’m writing this - take it to keep warm. There’s something quintessentially Russian about this, like a cross between the Platonic essences of AK-47s and Krokodil.
You can tell Scott has never had to survive (northern) winter without heat. :P
I absolutely would have taken DNP for warmth at the time, and I was aware of it, but had forgotten the name and couldn't find it again.
> Remember, mitochondria are the powerhouse of the cell. They pump protons across a membrane, creating pressure for electrons to follow.
It might be interesting to note that the enzyme producing ATP is quite literally a turbine (https://www.youtube.com/watch?v=kXpzp4RDGJI), although with effectively zero inertia.
I'm not sure this is a responsible post, given the tendencies of SSC/lesswrong readers to lifehack their way into trouble and wildly overestimate their competence.
The surprising part for me was hearing that bodybuilders are concerned with weight-loss.
I'm a skinny guy who knows I'll never have bulky muscles without serious weight gains. I guess I always assumed increased calorie intake was a natural perquisite for bodybuilding but in retrospect its obviously more complicated than that.
Bodybuilders that participate in competitions get their body fat % as low as 3-4% and dehydrate themselves for maximum visual effect - which is, to say the least, unhealthy. Also, caloric surplus is needed to build muscles so time and effort spent cutting is time not spent bulking, and in fact, actively wasting away.
The entire bodybuilding sport is Goodhart's Law in action, where you start with muscles as a reasonable proxy for health and fitness, and end in very weird places.
How much safer would this be if the half life were only 8 hours? Or what if we targeted the effects better? Presumably our striated muscles have to be good at thermoregulation.
But do the metabolic processes that are accelerated by these compounds produce toxins, perhaps some of the same ones causing negative consequences of obesity?
I recall some research from the past couple of years documenting that the mitochondria of ME patients ("chronic fatigue syndrome") were producing only about 50% of the energy that normal mitochondria produce. So I've been lazily guessing that an excess reliance on stress energy might be responsible for one of the most commonly expressed complaints: the all-over burning sensation beneath the surface of the skin. But this fascinating write-up of DNP gives much food for thought.
Gabapentin is one of the most common drugs used for treating the neuropathies associated with many ME patients (and most fibromyalgia patients, who tend to have varying levels of chronic fatigue) -- and gabapentin causes weight gain pretty much no matter how much you eat.
There are so many interconnected mysteries remaining, but I'm having a hard time imagining anyone intentionally wanting to cripple the main source of normal, healthy energy production. I'm no scientist, but it strikes me as akin to, say, cutting off your hands to protect you from the dangers of smoking. And it seems super weird that anyone who is interested in athletic performance would venture down the path of punching holes in their energy factories! Surely that could never be sustainable.
When I got sick about ten years ago, I was diagnosed with central neuropathy, peripheral neuropathy, small-fiber neuropathy (which IS fibromyalgia, if you believe my neurologist) -- and also an EDS-type connective tissue disorder. But I most identify with chronic fatigue syndrome (ME -- except I doubt that mine was caused by a virus) because it better captures the utterly systemic nature of the illness.
There's a good reason ME/CFS patients use the shorthand of "flu-like symptoms": because most others can imagine what a full body/mind/energy debilitation from a bad case of the flu feels like, while they tend to associate fibromyalgia, for example, with pedestrian aches and pains. I could go on and on with a list of my other symptoms (like a full year of hives/rashes upon getting sick, and of course the burning -- there's always the burning) as well as diagnoses (IBS, orthostatic hypertension), but they all seem connected at a cellular level.
So, I do hope whoever's working on this stuff for weight-loss reasons contributes to furthering the overall science (which might also apply to Long Covid). But I also hope potential consumers remain extremely wary about playing around with such a central engine of the entire body.
Can't quite shake fascination with Russia's industrial application of DNP as an antidote to freezing. One has to wonder, if DNP had been readily available in Texas last month, how many would have voluntarily tried it (rather than firing up barbecues and other CO2 producer heaters in enclosed spaces)?
Wouldn't have worked unless we already had it in our cabinets. I was not going anywhere on streets with an inch of snow covered by a quarter inch of ice covered by little bits of cars that had ventured out onto it.
We are finally understanding the biology of obesity and body weight regulation. Look at semaglutide 2.4 mg with papers in NEJM, Lancet and JAMA showing ~15% weight loss on average. Why do you want to go down the sordid trail of dangerous and stupid weight loss shams, when we have medications with an evidence base to review. Semaglutide is submitted to the FDA for review this summer for a weight indication. It is already approved for diabetes and has a cardiovascular outcome trial underway. There is no need to pursue the dangerous DNP.
My understanding is that exercise isn't great for weight loss because it makes people hungrier, canceling out the extra calories burned. Why does DNP not have the same effect?
The general rule of thumb for steady state drug concentrations in pharmacy is around 5 half lives so if DNP has a 36 hour half life it takes around a week before it hits its stable in vivo concentration which makes it no surprise people are mucking up the dose.
Scott, what's your take on CoQ10? Lot's of new supplements of CoQ10 are hitting the shelves and they say it makes your metabolism young again -ish. Thanks
When Scott mentions the relative risks of the drug verses obesity he's falling into a fallacy I see many doctors fall into. It's kind of related to goodharts law.
That is confusing a correlated marker of ill health with a cause.
Obesity does have some direct impacts on health but also is a correlate of other things that have serious impacts on health.
Insulin resistance and metabolic syndrome is probably the main one. Lack of exercise and an unhealthy diet is another. Stress and social social isolation correlate to obesity. Hypothyroidism, certain viral infections, certain psychological problems, and on.
To do a proper risk reward analysis we would need to run an experiment on at risk obese people and see what effects the pill has on overall morbidity and mortality. Short of that we would need to carefully try to tease apart the effects of obesity from correlates in obese individuals.
I also strongly suspect that obesity in many cases is actually a problematic adaptation of the body. A kind of lesser evil that has a purpose, like fever, inflammation or SAD. Targetting obesity with the drug not only presents the danger of the drug, and may not net the benefit of reducing all the correlated morbities, but also may undermine protective roles that obesity has.
I did a two-week DNP cycle last year. I tried to maintain an ingested dosage of ~500-600mg at all times, using a half-life calculator I maintained using Excel. I am 6'3", 220lb, so the dosage for my body wasn't extreme, but the experience was absolutely awful. I was barely able to sleep, I sweated through my sheets and my sweat was yellow and turned everything yellow. I also had insatiable cravings for food. I only ended up losing 3–4lb. It's not a miracle drug and the sides are, in my opinion, simply not worth it. A 500-700 calorie deficit over the course of several weeks would have resulted in a similar loss of weight.
The issue with mitochondrial uncoupling is that it acts generically across all cells, and while bodybuilding forums and old research establishes the obvious stupidity that comes with acute high usage (peripheral neuropathy, ocular damage, heat stroke), there’s indication that this has potential adverse cognitive effects.
The PNS effects come from damage to myelination of long nerves. But myelin also exists in the brain, and it’s a fair extension to assume that if DNP even has slight permeability across the BBB, this could have neurodegenerative effects long term.
Is obesity a source or a symptom? I know exercise reduces inflammation a lot, and that can look like significant weight loss.
I also know that which body types are in fashion changes mostly with which abusive partner stereotype the beauty industry is being today.
Possibly a big part of the issue is that pharmaceutical companies have a big incentive to focus on drugs rather than, say, barefoot running, and doctors usually keep up with pharmaceutical advancements more than they do with evolutionary biology and juggling and suchlike.
Mitochondria take some time to adapt to their workload, and the dose makes the poison. There's a chance it could be safe enough if one very gradually ramped up from a nanodose to a microdose, and then gradually tapered down from a microdose to a nanodose to nothing. Someone should try this on mice and see what happens before risking any humans.
I DID IT. It fucked me up and it was a year before my nerves and sense of taste began to recover. PURE FUCKING POISON. THIS IS the kind of evil p[rofitering gdamned BS that should be properly reported or completely banned from all media sources due to its' absolute manifestation of injurious affects.
I took dnp 200-400mg / each day for 9 years or so, only a few small breaks. I only stopped since I now have babies (and don't want it around the house)... It's been about a year and a half since I touched it.
I used it to maintain my weight. I'll be honest, when I was on it I never ever got I'll or sick, it was weird. Had a lot of energy too. Since being "off" I've caught a couple colds.
During and since then I had my blood work taken and everything is perfectly fine... Blood tests, Liver, kidneys, etc...all normal.
The only downside is I think I'll have cataracts soon (at age 37) since it's been difficult to drive at night (seeing starbursts since about 3 months ago but had my eyes dilated in January and eye Dr said nothing..) and about 4 years ago the eye Dr told me I had deposits on my lenses.
Another reason I stopped is that bird study saying it cut life span by 20%...
Anyway just thought I would weigh in.. never had any close calls or anything since I never went above 400mg or so.. when I saw on bodybuilding forums people doing 1g+... Just madness.
Just an FYI. For any individual thinking of investing, one diligence question would be: "are any biotech/therapeutics-focused venture capital funds investing in this round?"
I agree with not investing in early-stage biotech startups unless you are a professional early-stage biotech startup investor or know your stuff to an implausible degree.
Wouldn't the risk of knowing your stuff to an implausible degree be that your decision making is likely better than that of the FDA or local equivalent, making your predictions risky due to the potential behaviours of less-informed agents?
Of course you could be expert in the mechanisms of drug regulators, but the safe bet then is surely to hire your skills out rather than gamble on startups...
If you're going to go round investing in early-stage biotech startups then the ins and outs of the FDA is probably about 50% of the "stuff" you need to know.
I used to invest in (publically traded but pre-revenue) biotech companies, I made a small profit in the end but spent way too much time stressing over trial results and FDA committee meetings etc. In terms of dollars per grey hair it was the worst way of making money that I had.
What are the top ways of making money that you had? :D
For me personally, over the past ten years, the best ways of making money have been (a) investing in just about anything you can think of that isn't a biotech company, and (b) going to work and doing my job.
You know the joke about the foolproof method for making a small fortune in biotech?
I’ve heard that same joke applied to developing a new ski resort
With a few exceptions, seed rounds almost never work out in biotech because the later investors, especially VCs have so much leverage that seed investors almost always get diluted down to nothing. This is because the capital requirements are so great (hundreds of millions) and unlike in tech, the demand for capital is greater than the supply (though this seems to be turning)
Generally correct. Although this is becoming less true as capital comes flooding into the sector.
Presumably youre not, but If you’re an investor - direct or indirect - make sure to disclose.
I'm not.
Scott: This is important. DO NOT Post solicitations for investments. I do not know enough of your exact situation or of the nature of the solicitation to give competent legal advice to you.
But. It is generally illegal to sell securities unles you are a registered securities dealer. California's laws (and I am not a California lawyer) are very strict and they are enforced aggressively. Federal law is similar.
If I were you, I would take this information down.
Posting an email someone sent me saying "our company is cool, email us if you want to invest" is legally equivalent to selling securities?
There is a marginal risk here. I'd recommend against it too.
All right, I've deleted. Jonah can post it himself if he wants, unless someone's going to tell me even having it on the blog is a risk.
I would not let anyone solicit for investments on my blog. Substack might have a Section 230 defense, but a blogger probably does not.
I'd ask your lawyer about that.
This feels like a good example of big law selling insecurities 🤸🏾♀️
I am retired. When I was in practice I was not "Big Law". I am not trying to get anybody to spend money on legal fees.
I do know a bit about securities law, a bit that grows more and more obsolete day by day. I used to teach CLE classes on the subject. But, that was in a previous millennium.
Scott is not a financial industry professional. Even professionals make mistakes. Goldman Sachs recently paid a ~3G$ fine to the SEC. And, their General Counsel just did the 21st century corporate equivalent of being a virgin who jumps into the volcano. No connection they say. And you believe them, don't you.
Scott is an uncompensated volunteer. He has no upside, but any involvement in fundraising for investment opportunities carries a downside risk. Scott no ability to control risk by contract, insurance, monitoring, or due diligence.
I am a volunteer too. I hope my advice is worth every penny you have paid for it. If you don't think I am right, you can just ignore me.
My theory is
No Control + No Monitoring + No Insurance + No Due Diligence = Big Risk. Big Risk + No Reward = Don't Do it.
As theories go, I think that one is pretty good.
Perhaps. The Federal Securities Act of 1933 defines: "the term “offer to sell”, “offer for sale”, or “offer” shall include every attempt or offer to dispose of, or solicitation of an offer to buy, a security or interest in a security, for value." The law and administrative lore are very extensive. If you had an upside in doing this, it might be worth thinking about, but if you had an upside, that would be a fact indicating legal involvement.
As you are an uncompensated volunteer, the safest thing to do is to stay far away.
Back in a previous millennium when I had hair and no belly, I worked in a law firm that was located hard by Wall Street in lower Manhattan. On a clement day, if we weren't too busy, my colleagues and I would occasionally walk over to the river, and we would lunch at Sloppy Louie's immediately adjacent to the Fulton Street Fish Market.
It was a very plain sort of place. The tables were picnic benches and the menu was fried or broiled fish, nothing fancy. We were sure that it was, like the Fish Market, run by the Mob. There was a sign over the cashier's seat imparting ageless Sicilian wisdom:
"Even a fish can't get in trouble if it keeps its mouth shut."
As I posted above, general solicitation of certain private placement offerings is legal, as of 2013, under Rule 506(c) of Regulation D, subject to various limitations, in particular that the issuer must take "reasonable steps" to verify accredited investor status.
Every time I see that phrase my blood boils. Accredited investor? Might as well say aristocracy.
Consider that the modal person "posting an email someone sent me saying 'our company is cool, email us if you want to invest'" who comes to the legal system's attention is less "Scott Alexander" than "author of the 'Penny Stock One Weird Trick Report.'"
I have no opinion on this, but just know that I definitely will never be able to read one of your comments without hearing it in Walter's voice and with his reasonable-then-screamy delivery. I appreciate it.
Ditto and also join the chorus that exploring the edges of the securities laws is a lousy hobby.
General solicitation for private placement offerings is allowed under Rule 506(c), since the 2012 JOBS Act. (However, I don't know whether there are restrictions on _who_ is allowed to perform those solicitations. And I don't know whether the company is intending to reply on 506(c), which requires them to take reasonable steps to verify the accredited investor status of their investors, or 506(b), which is more convenient because it does not require them to do that (but does not permit general solicitation.))
"reply on" should be *"rely on", obviously.
Thanks, Glenn. One of the nice things about being retired is that I no longer have to learn all of this dugash. I looked at the SEC pages on the JOBS act:
https://www.sec.gov/spotlight/jobs-act.shtml
I think you could structure things to avoid a problem, but since Scott (and anyone else in his position) has no ability to audit the structure or monitor compliance, my advice (which is easily worth every penny you are paying for it) is still to stay away.
Your advice is certainly not unreasonable. I have kind of a pet peeve about "vetocracy by overcaution", where a valuable thing ends up prohibited-in-practice if _anybody_ near the thing believes it might be prohibited, or feels like it ought to be prohibited.
(This pet peeve brought to you mostly by software licensing, which is the absolute worst mixture of "overcautious lawyers" and "cranky software engineers who mistakenly believe themselves to be lawyers". Of course, I'm arguably in the latter category myself, so I have to be careful how much I shit-talk it.)
I think the email is supposed to be jonah@equatortherapeutics.com (you wrote puetics). Normally I wouldn’t be so pedantic but I could see somebody clicking that link and failing to send an email!
FYI, Chubbyemu recently released a video regarding a DNP overdose in a young man attempting to lose weight https://youtu.be/ChPeG19qKUo
I came here to post this.
Maybe we've gone wrong as a society if burning to death from the inside is the less risky option.
It's always an option, just vanishingly unlikely in most cases (unless you know some very sadistic people I guess...). The question with risk is not how bad is the less risky option but how horrific are the other options...
Fire Walk with Me
The candle that burns twice as fast . . . I guess some will always prefer to go out with a bang, rather than just fade away.
Alternate use: a poetic new form of political protest?
In other news, the Wikipedia page on self-immolation warns: "Self-immolation does not guarantee death for the burned."
I'm still wondering if there were more reports of spontaneous combustion back in the '30's.
Weren't most of the "spontaneous combustion" cases people who fell asleep with a cigarette in hand, and basically turned into a human candle wick, and died of carbon monoxide poisoning before they burned up? Not sure if mitochondria would affect the frequency of that.
The Texas case sounds like a large enough sample size that you could get an idea of long-term side effects from DNP usage via a survey.
Also, doesn't most modern anti-aging thought revolve around slowing the metabolism (e.g. fasting), not speeding it up? It sounds like this stuff would make you die faster, even if you didn't have any major side effects from it.
Normally the proton gradient is used to produce ATP. With uncoupling it just makes heat and is arguably not really metabolism as it doesn’t produce anything.
Free radical production from mitochondria is partly dependent on the proton gradient. So by uncoupling you can dissipate the gradient and reduce free radical production which may be beneficial if the cell is under oxidative stress. Of course there are lots of critiques against the free radical theory of aging.
Good for general health, probably, but also probably not good for male fertility though.
That doesn't quite make sense to me. DNP is actually making the cell pump *extra* protons over the gradient, because it still needs the same minimum number of calories to operate. The DNP is just creating a parasitic side-reaction where some of the energy consumed is wasted as heat rather than used to pump protons, creating a net caloric deficit.
If there's a certain number of free radicals generated per proton-pumping operation, I can't see how this effect would result in less free radicals generated. If anything, it might be more.
Regarding low dose DNP, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468406/
"DNP appears to mimic in part the neuroprotective and neurorestorative effects of exercise and fasting by increasing BDNF, lowering cellular stress and building cellular resiliency by mild increases in mitochondrial bioenergetics."
Basically, through slightly stressing mitochondria, you increase mitochondrial health, similar to exercise, cold exposure, and other stress related activities that have beneficial health effects.
After the proton gets pumped over the membrane the electron has to go through a series of complicated stages to get back to it, which each stage making its own ATP letting aerobic respiration be so much more efficient than anaerobic respiration. However, the high energy chemistry in a mitochondria is potentially dangerous, sometimes things break, and if one part of the chain breaks down you have lots of electrons backing up and becoming Problematic. Letting the protons bypass the normal process more easily mitigates that danger even though it causes more of the normal operation of the mitochondria.
But the same number of successful proton pumping operations are still happening, right? There's just a bunch of extra unsuccessful ones as well. It's possible that my inorganic chemistry background is letting me down here.
Right. The proton pumping setting up the potential happens just like before. It's the electron dancing down the potential ladder making ATP that fall back on to the soft proton when they trip, to strain a metaphor.
I think I get it - the theory here is that the extra protons create metastable states that trap rogue electrons without producing free radicals, right? That makes a certain amount of sense.
Thank you very much for taking the time to explain it to me.
Don't think electrons of the type you appear to be thinking are involved in making ATP. The electrons that come out of the citric acid cycle are passed along a chain of membrane-bound proteins until they reduce O2 to H2O. The reaction to create ATP from ADP is not a redox reaction and happens somewhere else.
As I understand it is the existence and magnitude of the proton gradient that increases free radical production. Thus by reducing the magnitude of the proton gradient you would get less free radical production. Cells can increase their uncoupling in response to oxidative stress. All else equal this decreases ATP production but still above minimum, well except for the lens cells for some unfortunate individuals. I also imagine that uncouplers should reduce your capacity for physical labor.
Isn't it the creating of the proton gradient by the electron transport chains that risks, well, leaking electrons? Does ATP synthesis itself even involve redox?
The electron transport chain where high energy electron goes from donor to acceptor ending up with the one of the best oxidisers (electron acceptor), oxygen creates the proton gradient. This the oxidative step. Then protons flowing back via ATP-synthase then puts a phosporyl group on ADP, making ATP. That is the phosphorylation step. Together they are oxidative phosphorylation.
I'm not a mitochondria expert but yes the electron leakage should be in the electron transport chain. But the bigger the proton gradient the more the electron chain leaks. You can read more in the introduction part of this paper: https://www.sciencedirect.com/science/article/pii/S000527281830135X#bb0060
No, the phosphorylation of ADP to create ATP is not a redox reaction. It's a thioesterification or condensation reaction. No atoms change oxidation state. I think the confusion arises because the phosphorylation is *coupled* to a redox reaction, which is the reduction of O2 to H2O. That's why it's called "oxidative phosphorylation." The reduction of O2 provides the energy for the otherwise energetically uphill phosphorylation reaction. But in mitochondria these reactions occur in different places. The reduction of O2 happens along the electron transport chain, while the phosphorylation of ADP happens in a nearby membrane-bound enzyme.
Tried getting it off Ali baba once but it was just orange died sawdust. Also my family decided I was on meth because I was involved with a seemingly mysterious substance tied to weight loss that might explode and they didn't understand my explanations...
Props to all the good people on AliBaba who look out for their customers by sending them sawdust instead of dangerous drugs that could kill them.
In my life I have still managed to buy motorcycles and guns, so alas it is to limited avail; high risk tolerance, uhhh, finds a way
So it actually worked for you?
How did you determine it was sawdust?
Correction to "They pump protons across a membrane, creating pressure for electrons to travel the opposite direction." Actually they create pressure (potential) for electrons to travel in the *same* direction. When positive charge goes one way, negative charge also "wants" to go that way, following its potential energy gradient. Making electrons travel in the opposite direction would cost even more energy, defeating the purpose.
Argh, you're right, thanks, fixed.
>They pump protons across a membrane, creating pressure for electrons to follow. This forms an electrical gradient...
I argue for removing "creating pressure for electrons to follow" entirely, because that misleadingly suggests that this pressure is somehow necessary or relevant for the potential difference. In reality, the proton concentration differential is enough.
Yes, that is a strange statement. In the first place, it's not true. The *electrostatic* field of H+ is very well shielded in water, that's why solvated H+ (i.e. pH < 7) is stable. So while there is a voltage across the membrane, it's not nearly enough to rip electrons loose from wherever they're bound and hustle them across the membrane. The gradient of H+ is purely in the chemical potential, as far as I know, and the same (entropic) driving force would exist even if the species in question were neutral. The only reason cells do it with charged species (H+ in the mitochondrion, Na+/K+ in neurons et cetera) is that the charge makes it difficult for these small atoms to cross back over the membrane anywhere and destroy the gradient, which they would otherwise do, because they are very polar and the membrane is nonpolar -- their solubility in the lipid bilayer is very low. Perhaps something else was meant, and I'm not understanding it.
This isn't how it works at all. The electron transport chain doesn't involve free electron movement or net electron movement across the membrane.
Electrons get transported from food (fat/carbohydrate) to oxygen via a series of reducible cofactors (the electron transport chain).
The proteins that catalyse these reactions use that energy to pump protons out of the lumen. The protons can (mostly) only come back through the FOF1 ATPase, which makes ATP when it happens.
Also, dinitrophenol doesn't "punch holes" in the membrane; it's not a pore (things that actually punch holes in membranes cause massive necrosis - I'm familiar with two examples, one of which is part of the immune system and one of which is snake venom). The trick with dinitrophenol is that it's acidic (at just the right level to be partially ionised at biological pH) and that it's lipophilic enough to pass through membranes *even while ionised* (the aromatic ring and the delocalisation of the charge over 6 atoms help with that). So, since the pH on the two sides of the membrane is different, it tends to lose its proton inside the lumen, pass out, pick it up outside and come back in.
It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!
But obviously it's not so easy in practice as human bodies are vastly complicated biochemical laboratories operating under sometimes faulty instructions.
We ought to put the calories to work digging ditches and filling them back in so that they'll have something to do and will have earned their wages.
"Pumping protons across a membrane that diffuse back" actually seems like the microbiology analogue of what you suggest.
Very Keynesian. I approve.
It’s also a reference to an older SSC post: https://slatestarcodex.com/2018/05/16/basic-income-not-basic-jobs-against-hijacking-utopia/
Another dvorak user? I'm curious when and why you learned it.
If your username is an ironic reference, that's cool too.
Guilty!
I didn't feel like using a preexisting handle here, but couldn't come up with anything good on the spot, so I just typed the home row in order.
I've been using dvorak for 3-4 years now. I didn't have a very good reason for switching, mostly it just sounded amusing to see if I could reprogram my typing muscle memory. I've previously written a bit about it here: https://www.schlaugh.com/~/cdvhauo
Colemak in the house :)
Nice! I've never looked at Colemak before now. Definitely makes the right call regarding the positions of AZXCV for the keyboard shortcuts.
I'm a dvorak vim user who doesn't remap the movement keys HJKL, and it's not too bad. Colemak doesn't seem to do so well on this metric: JK (up/down) switched around and all 4 of them in the left pointer finger's domain.
Still, I would probably choose Colemak over Dvorak if I were to go do it over again.
Almost all drugs except for some newer ones are making some part of your body less efficient, though not this directly. It’s a lot easier to turn harmful machinery off than to insert useful new machinery.
That may well be, but it's hard to argue that mitochondria are harmful machinery. This is like punching a hole in your gas tank because you have a crush on the gas station attendant.
It's not about turning the whole energy-making process off, just safe ways to make it slightly less efficient since it's tuned to solve the obsolete problem of scarce calories
> It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!
Blame evolution for making eating a terminal goal. Making bodies less efficient might be easier than fixing this.
I've read that among a certain segment of the naturally thin population they naturally release excess calories as heat rather than storing them as fat.
I have always been on the thinner side, although I can gain weight, and I also "run hot". My appendages are frequently warmer than other people's. That could be because I have a higher core temperature or a higher peripheral temperature alone. I also have higher blood pressure so maybe there's just more convection of heat away from my core. Either way I'm shedding more heat than normal, and am more tolerant of cold temperatures and less tolerant of warm temperatures.
hm, this is interesting. i'm also on the thinner side and have been struggling to gain weight, but I definitely feel colder to the touch than average (which i always attributed to the lack of body fat to keep me warm, also im AFAB). that said, i am also more tolerant of cold temperatures than warm ones, so maybe (anecdotally ofc) there's some correlation there.
I'm thin and cold too, but I do fidget a lot - I have a tendency to twitch my leg rhythmically and such. This might contribute to excess calorie expenditure. It does seem to stop when I'm hungry, though I'm not going to claim that there's an actual energy management relationship there.
Every thin person is probably such due to a confluence of factors. I mostly attribute my thinness to the small portion sizes my mother fed me as a child.
I'm thin, tall, and cold (which could be from lower circulation due to longer limbs). I'm less tolerant of cold than of heat.
Between you and Jack C’s reply to the comment it feels like knowing somebody is tall and thin doesn’t really predict very much
Hey Jack, I would also fit this description - tall, hot, restless, need to jump in the river even in winter - and my wife (African, hates the cold, sleeps under 2 duvets) is worried about my blood pressure so we've been monitoring it over the past couple of weeks - it's definitely high and fluctuates wildly throughout the day, so I'm getting it checked out properly at the GP tomorrow. I like the idea of investing in big mitochondria though 🤣
Here's an older SSC post with something related:
https://slatestarcodex.com/2017/04/26/anorexia-and-metabolic-set-point/
The relevant quote:
> Some more evidence: people with anorexia fidget like crazy. This is the conventional wisdom among generations of psychiatrists, and has been confirmed in studies – see for example *Measurement Of Fidgeting In Patients With Anorexia Nervosa Using A Novel Shoe-Based Monitor*, which found anorexics fidget almost twice as much as healthy controls. This seems really damning to me. Consciously deciding to fidget is hard. If you don’t believe me, try to fidget as much as possible for the next two hours (the length of the study linked above) and see how well it goes. Most people just can’t do it. On the other hand, fidgeting (renamed to the more dignified “non-exercise activity thermogenesis”) is the classic strategy that the lipostat uses to maintain unconscious control over weight...
> A purely social paradigm of anorexia can’t explain the fidgeting; a biological paradigm outright predicts it.
Wow! Do you mean psychological paradigm? It's not that your conscious mind holds the mistaken belief that your fat when you're not. Or that you're attempting to control one part of your life when you can't control others. On a fundamental biological level your body thinks it's fat when it's not.
I can go on and on about the superiority of a "biological paradigm" for AN. Here are a couple tantalizing links:
* https://relative-energy.tumblr.com/post/183390573416/activity-based-anorexia-and-animal-models
* https://relative-energy.tumblr.com/post/182904564621/shan-guisingers-2003-paper-adapted-to-flee
See also this from SSC: https://slatestarcodex.com/2018/12/05/giudice-on-the-self-starvation-cycle/
> Do you mean psychological paradigm?
Rather than "social paradigm" or rather than "biological paradigm"?
I would expect the social paradigm to explain the fidgeting as nervous movement, the logic being that it's a stressful condition or stressed people tend to develop anorexia. I don't find the idea convincing without further explanation.
Anecdotally: my friend who has low body-fat and was a sports players in his youth and early twenties used to run very hot all the time. Hot to the touch. When I was fit, more fit than usual, I also felt very warm.
On the other hand, people who are thin naturally have less insulation. This might just be one of those reverse causality situations - thin people are less insulated and so lose more heat.
Worth noting: tall people apparently have higher BMI than short people, which may well be because of the square-cube law.
I've been called a space heater by my girlfriend...
First, I am disappointed that there is no "conscious uncoupling" joke in here. A missed opportunity! Second, pretty sure that instead of "all is not lost" (implying that nothing whatsoever is lost) you mean "not all is lost" (implying not everything is lost). Sincerely yours in logical pedantry,
That might be logical, but "All is not lost" is a fixed phrase, logic be damned!
https://www.macmillandictionary.com/us/dictionary/american/all-is-not-lost
Doesn’t the dictionary also allow “literally” to mean “figuratively”? So YMMV.
Modern dictionaries aim to describe language as it is commonly used, not to prescribe how it should be. I think it's wrong to say they "allow" it - they observe that it gets used that way.
You'd think that, but that's because the English have an inferior practical philosophy of language. In contrast, the motto and job of the Royal Academy of Spanish (which writes the Spanish dictionary) is "to clean, make certain, and give splendor". This is why we Spaniards can have nice things, like not having spelling bees because the correspondence between the written and the spoken word is pretty much* unambiguous.
On the danger of conflating English and logic:
https://journeys.dartmouth.edu/folklorearchive/2017/11/13/a-carton-of-milk-and-some-eggs-joke/
"All is not lost" is perfectly technically-correct if you just interpret it slightly differently - as "it is not the case that all is lost" ("is all lost?" "it is not"), rather than as "it is the case that all things are not-lost" ("what is not lost?" "all is")!
“All is not lost” I would formalize (well, quasi formalize; this is a comment section!) as (x) ~(Lx). “Not all is lost” as ~(x)(Lx). Those aren’t equivalent. Would you do it differently?
So to get into my position here in more detail:
You can interpret "all is not lost" in one of two ways, or at least two that are clear to me at a glance. One is the way you're interpreting it; the other is the way that's equivalent to your formulation of "not all is lost". Personally, I find the latter interpretation more intuitive.
To interpret "all is not lost" as "it is not the case that all is lost", logically equivalent to "not everything is lost" or "out of all things, some are not lost", I would take it as an answer to the implicit question "is all lost?", which I think is what most people tend to mean when they use the phrase. "All is not lost" under this interpretation describes a world where we were worried that all might be lost, but then found out that this isn't true, and some things still remain. I think that's the connotation the phrase is reaching for in its standard usage.
(Equivalently to that implicit question, you could also read it as a contradiction of an implied previous statement: "All is lost!" "No it's not!")
To interpret it as "nothing is lost", I would take it as an answer to the implicit question "what is not lost?", answering with "all" i.e. "out of all things, none are lost". This interpretation feels more awkward to me, linguistically speaking. It's grammatically viable but it doesn't feel like the natural way to phrase the sentiment; an ordinary English speaker, trying to express "nothing is lost", would probably use those three words.
As for "not all is lost", I think we lose something by moving to this phrasing from "all is not lost"; specifically, it muddies the connection to the implied question or statement. Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage. "Not all is lost" is also a valid negation here, but in my opinion it's deemphasizing that implicit relief and instead putting more emphasis on the implication that although not all things are lost, some of them probably are. Less relieved, more foreboding.
“Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage.” Not when quantifiers are involved they don’t. That was my point. If I said “all tennis players own a racquet” you would not deny that by saying “all tennis players do not own a racquet.” That would be kinda dumb. You would correctly negate it as “not all tennis players own a racquet.” Same for “all is lost”.
In my experience, in ordinary colloquial English, it absolutely is the case that people will negate "X is Y" to "X is not Y" even when you could interpret the sentence as involving a logical quantifier, because most colloquial English-speakers aren't interpreting their sentences as involving logical quantifiers; and in this case, under my preferred interpretation, the word "all" is not in fact being used as a logical quantifier.
Consider the exchange: "Brown bear, brown bear, what do you see?" "ALL", as seen in a 2014 Tumblr meme, surely a valid example of colloquial English. "All" is not functioning as a logical quantifier here; it is a noun, meaning "the totality of things". That's a perfectly normal thing for the word "all" to mean.
"[The totality of things] is lost" is a sentence containing no logical quantifiers, only a noun, being linked to an adjective. Its straightforward negation is "[the totality of things] is not lost".
Or for a slightly more reputable source, Wiktionary gives an impressively detailed list of possible senses in which the word "all" can be used, and although the first one seems to be the logical-quantifier-style usage, the only examples given of that usage involve it quantifying over a specified subject; "all tennis players", in your example, or "all my friends", "all contestants", etc. in Wiktionary's. The next usage listed is as a (pro)noun, meaning "everything", with examples such as "she knows all and sees all" or "those who think they know it all". This is the usage category into which I believe "all is not lost" falls.
All instances of translating idiomatic language word-by-word into logical notation are not useful.
In the same vein, I've always been annoyed when people write "everyone is not X" when they clearly meant "not everyone is X"...
Exactly. Or when they say “all that glitters is not gold”, implying that even gold itself does not glitter, instead of “not all that glitters is gold.”
There's some wonderful potential for Moloch tie-in with the only surefire weight loss pill involving burning from the inside
Moloch, whose cells are blazing furnaces!
Mitochondria in endotherms have proteins other mitochondria don't? And they're only expressed in certain tissue types? That strike anyone else as deeply weird?
Interesting, I never knew that about pigs/boars. So they are the only animal family inside their order with a defective UCP1, and also the only ones to build nests before giving birth - nests that provide some thermal insulation to piglets. I.e. pigs are so easy to fatten because they cannot as easily convert energy to body heat.
Is that evolutionarily related? I mean that boars have somehow acquired the nesting instinct (for sows to build nests, for piglets to always return to the nest) - they are otherwise quite intelligent, whereas "nesting" can yield other advantages - and then *as consequence* lost the selection pressure on keeping a functional UCP1?
Why don't we raise more reptiles for meat then?
I’m guessing because they are mostly carnivore, and we’d have to provide herbivores to feed the - so it’s easier to just raise herbivores as food for us?
Why don't we just choose the lizards that are herbivorous then? Surely there are some edible, herbivorous lizards out there?
Production and consumption cycles have to work in tandem for something to really take off, I guess.
There are alligator farms and outlets selling alligator meat, and as far as I'm aware, it's expensive. I don't know the purely material calculus of "how much food provided for how much meat obtained" - is it more or less viable than with more conventional cattle - but the economy of scale, the efficiency of the supply chains and their ubiquitousness, is nowhere near comparable.
Today's meat industry that deals in "regular cattle" has grown upon a millenias-old production/consumption cycle where production relied on small farmers. The production-side got incredibly industrialized (to the near-extinction of small farmers, in some parts) but it was able to do so only by building upon the pre-existing consumption side of that extremely well-established cycle.
No such production/consumption cycle for alligators had taken off in past millenias, since not nearly as many "small farmers" were interested in cultivating alligators. As for smaller reptiles, they have the same disadvantage as smaller mammals. Hare farms exist, but their share of worldwide meat production is negligible; too much "processing work per kilo of meat" for it to ever spin into something significant. I suspect it'd be likewise with smaller reptiles, except that small reptiles additionally lack the appeal to consumers.
Is being fat the same thing as metabolic syndrome? Does DNP causing people to lose weight necessarily mean they're getting healthier?
Good question, I don't know.
The experiments by Jules Hirsch (which found that fat people who lost weight metabolically resembled starving people, not healthy thin people) would suggest no. Metabolic syndrome is its own thing which can affect both fat and thin people, and there's at least some evidence the casuality goes the other way--some part of metabolic syndrome causes weight gain, instead of the other way around.
weight loss normalizes a ton of metabolic syndrome related issues, though.
Insulin resistance and hypertension (when it is caused by obesity) rapidly normalize with radical weight loss, as the CALERIE trials and the Biosphere experiment demonstrate.
I'm not aware of any evidence metabolic syndrome-->obesity causality. Can you post relevant papers?
Can we not do links on substack? That sucks
"The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome" by Kitt Falk Petersen, et al
"Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance" by Kurt Højlund
"Acute postchallenge hyperinsulinemia predicts weight gain: a prospective study " by R J Sigal, et al
Research into the Dutch Hunger Winter also shows a bunch of interesting effects--individuals exposed to famine at a specific point in gestation had much higher rates of obesity, type 2 diabetes, etc, than their family history or cohort would suggest.
The CALERIE trial was specifically looking at non-obese inidividuals, so it's hard to draw conclusions from it. For one, the string of 'obesity paradoxes' show that obese individuals with hypertension, type 2 diabetes, etc, do better than normal weight individuals with those conditions, and weight cycling--repeatedly losing and gaining weight, which is the usual outcome of any dieting attempt ("Medicare's Search for Effective Obesity Treatment" by Mann et all, although every meta review will show this)--worsens outcomes. Obese type 2 diabetics who lose weight seem to die sooner than those who don't ("Mortality Risk by Body Weight and Weight Change in People with NIDDM" by Chaturvedi and Fuller). Obese people with hypertension seem to live longer than thin people with hypertension ("Is Hypertension More Benign When Associated with Obesity?" by Barrett-Connor and Khaw), and interestingly the association between obesity and hypertension, which is already relatively weak, weakens even further when you study cultures where dieting isn't common, suggesting that weight cycling as an effect of dieting might be the culprit, not weight itself ("A Cross-Cultural Perspective on Obesity and Health in Three Groups of Women" by Bindon et al, "The Prevalence of Hypertension, Obesity, and Dyslipidemia in Individuals over 30 Belonging to Minorities from the Pasture Area of Xinjiang" by Yao et al)
Thanks for the links. I agree the CALERIE trials were looking at non-obese individuals, but I don't think that makes the results harder to draw conclusions from. BMI is a continuum. Isn't it quite striking that even within the "normal" range, though at the higher end of it, weight loss through caloric restriction has beneficial effects in exactly the predicted direction?
And the VIRTA trial shows normalization of insulin resistance in diabetic patients with weight loss. I think there's a also a non-ketogenic, very low calorie diet showing similar effects but I can't find it right now.
And the GLP-1 agonists seem to work through weight loss, mediated by direction action on appetite and other assorted things (slowed gastric emptying, nausea, etc.). Though there's likely direct effects of GLP-1 agonists on insulin resistance, so that's murkier.
Re: the obesity paradoxes, some can be dismissed with the well-known phenomena of cachexia with cancer and other serious illnesses .Unexplained weight loss is a classic red-flag for a bunch of conditions. So some of that is comparing people who will die from another condition, that are experiencing weight loss because of that, and incidentally experiencing weight loss.
Regardless, while the epidemiology you cite paints a mixed picture, I think the interventional literature paints a more clear picture of excess energy intake as the primary/initial defect in most people who are obese who later get metabolic syndrome.
The obesity/hypertension stuff suggests to me that hypertension that is caused by obesity is less harmful than other types of hypertension, not that obesity per se is protective.
In terms of literal definition, no. The International Diabetes Foundation defines it as:
central obesity (i.e. large waist circumference) AND two of raised triglycerides, reduced HDL cholesterol, raised blood pressure, or raised resting fasting glucose. See Wikipedia (https://en.wikipedia.org/wiki/Metabolic_syndrome#IDF). Definitions from WHO and others are similar.
So if "metabolic syndrome is when your doctor says you have metabolic syndrome", you can be obese and not have metabolic syndrome. From the "metabolic thing is the idea that we try to approximate with the IDF definition" then that's less clear. But I think researchers focusing on metabolic syndrome (I work with some of them) do not just think of it as simply obesity and would tend towards saying they're distinct phenomena.
>Is being fat the same thing as metabolic syndrome?
No. The lipodystrophic spectrum is lean, but has metsyn, while the metabolically healthy obese are, well, obese, but don't have MetSyn. This appears to be the result of individual variation in thresholds beyond which you can't handle more energy storage.
https://pubmed.ncbi.nlm.nih.gov/25515001/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399621/
>Does DNP causing people to lose weight necessarily mean they're getting healthier?
In areas related to energy excess pathologies? Yes, any method of weight loss - aside from chopping off your limbs or the like - will improve any issues arising from energy toxicity, if you have them. Overall? Hard to say. You could ask the same thing about using heroin to lose weight.
Not sure if I misunderstood something: how do you get from 10 000 users per death times 23 deaths to 2 300 000? Shouldn't it be 230 000, which is still more than I'd expect for the number of PED-munching bodybuilders in the UK, but at least a bit more plausible?
You're right, sorry.
While shilling is in fashion, let me shill for Nick Lane's book *Power, Sex, Suicide: Mitochondria and the meaning of life* which is really interesting and gives you a better sense for why this whole *decoupling* business is really important and interesting. Seriously it's on of the 10 best non-fiction books I've read and I go through 25 or so a year.
I endorse using this thread for general shilling of mitochondria.
I also found that book worthwhile.
All of Nick Lane’s books are great!
I read the vital question and it was up there with the selfish gene for most mindblowing biology books. Awesome author, will check it out.
Thanks Andrew - love that stuff and just ordered second hand from the Book barn for £6.33. Sorely tempted as I am to to invest our meagre family savings in big, hot mitochondria, I suffer from chronic financial risk-aversion (I blame my metabolism, and my parents of course)... BUT if Scott were to actually provide a link to buy shares direct from him or his friend, I'd deffo reconsider 😉
First with "Gabriel Over the White House," and now with this article, I read this piece with increasing certainty that this would turn out to be some kind of satire, which rapidly declined as no puns appeared in the last few paragraphs.
Instead it turned into an unexpected infomercial.
I'm excited to see this post! Low dose DNP (2-3mg/day) has been a life saver for a number of individuals that I have spoken to in the past few months, myself included. There's a few private nootropics groups that are finding great results with it. And, a bodybuilding post on low dose DNP has some great excerpts from the recent research studies.
Low dose mitochondrial uncoupling has huge potential. DNP should not be slept on.
2-3 mg/day? Isn't the normal dose more like 150? Does 2-3 make you lose weight? How quickly? Or what else are people using it for?
Those "normal" doses are for fat loss. However, two recent studies have shown that low doses can have profound health benefits. I've talked to people who have experienced a wide range of effects from low dose DNP, the main ones being increased energy, lessened fatigue, higher quality sleep, less need for sleep, decreased "brain fog", etc. So, nootropic, energy, and anti-aging reasons.
Good excerpts from the low dose studies here: https://www.professionalmuscle.com/forums/index.php?threads/dnp-as-nootropic-life-extension.165052/post-2896090
If you want more info on who's using low dose DNP, and where to talk to them, etc. I could make that happen. It popped up on the radar of a few nootropics groups back in October.
Can confirm at higher low-dose—thanks for the links as was not aware of super low dose. Have been trying 50-70mg per day off and on for past couple of weeks after trying full dose for weight loss a long time ago (not tolerable). Found going much over 100mg hits energy level and mood hard.
Do you notice any weight loss effects in the 50-70mg per day range?
Can you point to the other groups you mentioned? As I’m also on low(ish) dose it would be helpful.
How can I contact you? I'd rather not give out the groups publically, considering the experimental nature of them, and the potential for public scrutiny and prying eyes to negatively impact them.
Regardless of the genuine merit of mitochondria decoupling, the discussion in your link makes me a little nervous. The 'study' by Geisler (actually a single-author review. Published in Cells, not to be confused with Cell) is a sprawling, but ankle-deep overview presenting DNP as a strong, even revolutionary candidate for a dozen of the most 'interesting' diseases of our age, from Alzheimer's and ischemic stroke, to diabetes and, uh, concussions?
The intro gets us off to a strong start: "In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically". Oh.
Let's skip ahead to the COI stuff. "John G. Geisler is a founder and shareholder of Mitochon Pharmaceuticals, Inc. MP201 (DNP prodrug) [...]. ". Ah.
I'm now strapped in, and ready for the kind of stuff you see from conflicted authors in obscure journals. Neither are, of course, incompatible with good science, but let's probably not ignore the red warning lights illuminating our entire dashboard.
What follows is a sequence of strong claims on the back of a sparse constellation of mouse models, and even weaker appeals to genetic regulation patterns. The theme of 'ROS bad' does a lot of work throughout, which is Not Wrong, but as vague as mechanistic claims really get in biomedical research (is there a more widespread meme than 'take my supplement to fend off ROS/inflammation and live forever?).
Some of the highlights include a "Neuroprotection" section clocking in at 52 words (I would have thrown in a shrug emoji). Hot Takes are casually dropped throughout, like author's view that the field of dementia research have wasted their efforts on downstream symptoms rather than the Real cause of disease onset (you guessed it): the mitochondria.
My courage ran out when I went look into the 'ischemia' chapter. The author start off strong with 'A fascinating example of DNP’s capacity to become protective for the threaten tissue or penumbra was elegantly demonstrated in a rat model of cerebral stroke', then go on to boldly claim that 'In ischemic stroke, the data suggests that the first line of care would be to provide tPA back-to-back with DNP'. This is all on the back of a single study of EIGHT MICE! Maybe let's hold our horses just a little longer before we make grand allusions to patient care?
So, yeah. Bit worrying to come upon a forum passing this around uncritically as evidence for taking DNP supplements. I don't really want to get into the second 'study' (also a review, same author), except to point out I'm not wild about the claim that few people died as a result of DNP in the 1930's, and therefore the stuff can't be that bad (this is brought up in both reviews). Most deaths would not have been the obvious result of DNP intake, and this would be basically impossible to tease out using the public health surveillance infrastructure of the 1930s (it's still not easy).
(I just realized that Scott actually links to this review in his post, though only in passing to bring up Mitochon's trial evaluating DNP for Huntington Disease)
An 8-mouse test sample? That's absurd. Everybody knows that high-quality research only comes from 10-mouse sample sizes!
Thanks for the examination, I really appreciate that. Mediocre quality of studies / reviews aside, I can personally atest to dramatic positive effects of 2-3mg DNP a day. I've played with all kind of compounds the past 12 years, and have rarely encountered effects as profoundly positive as I have with DNP, as have others.
This is not to say that these few anecdotal reports belay any concerns of health and safety. But, when we're talking doses tens to hundreds times lower than what has been observed to cause issue, I think anecdotal evidence does become relevant in the evaluation of low dose DNP.
"This makes your body's energy production less efficient, meaning you have to burn more calories per amount of metabolism you want to do. Hence the weight loss."
Gary Taubes hardest hit.
Actually, I don't think so. Taube's argument has never been that caloric balance has nothing to do with weight gain or loss. His point is that it fails to explain. Like trying to explain my increasing weight by saying that I am experiencing an increased impact of gravity. Trivially true, but not the least bit useful. What I would note about this mitochondrial line of thought however, is that, though potentially beneficial, it does not address the reasons for obesity or the obesity epidemic. If I were Gary Taubes, I would make that point. Which I just did. Even though I am not Gary Taubes.
BTW, the idea of uncoupling mitochondria by changes in lifestyle and/or diet (as I recall) has been around the "keto-community" for a while. There are numerous YouTube lectures about it.
All I'll say is that I've read at least one of his books (maybe two...can't recall) and listened to a few interviews with him. If that is his argument, he doesn't make it well. To wit, quotes like this one: "The science tells us that obesity is ultimately the result of a hormonal imbalance, not a caloric one—specifically, the stimulation of insulin secretion caused by eating easily digestible, carbohydrate-rich foods"
But of course you can't literally put on mass due to the secretion of hormones. The hormones have to be acting on metabolism, either getting you to want more calories, or getting you to waste fewer.
Sometimes the fact that something can be both true and of no explanatory value is difficult to grasp and can be difficult argument to make. In the quote you provide Taubes seems to me to be saying that caloric imbalance tells us nothing about the causes of obesity. He is not saying that the first law of thermodynamics doesn't apply to humans. Of course it does. But it tells us nothing about why some of us get fat and other don't. Here is Taubes making that point:
"Why is it that from the moment you enter medical school to the moment you retire, the only disorder that you will ever diagnose with a physics textbook is obesity? This is biology folks, it's endocrinology, it's physiology - physics has nothing to do with it. The laws of thermodynamics are always true, the energy balance equation is irrelevant.
If someone's getting fatter I guarantee you they're taking more energy than they expend (as long as they're getting heavier). And if they're getting leaner I guarantee they're expending more than they're taking in. [It's] given, let's never discuss it again. And if you say it to your patients you're telling them nothing.”
Also, this:
“All those who have insisted (and still do) that overeating and/or sedentary behavior must be the cause of obesity have done so on the basis of this same fundamental error: they will observe correctly that positive caloric balance must be associated with weight gain, but then they will assume without justification that positive caloric balance is the cause of weight gain. This simple misconception has led to a century of misguided obesity research.”
That's terrible philosophy of science by Taubes. It isn't that positive caloric balance is merely "associated" with weight gain, but that is a causally necessary condition for weight gain. And if you stop it, then it prevents weight gain. Not sure if he's committing a fallacy of equivocation on "cause" or what.
I can't remember if this is specifically Taubes's argument, but he's pushing back on the notion that all bodies treat calories the same. Metabolism is complicated and poorly understood, but people believe "calories in, calories out" is a sufficient explanation for weight loss/gain. Taubes says it isn't, and that the oversimplification is absurdly unhelpful.
For example: say we have two women. Both are 5 foot even. Both are exactly 120 pounds. The common calories in/calories out explanation would say that if both of them ate exactly the same number of calories for the day and did exactly the same activities, both women's weights would be affected in the same way. This does not happen.
For one, let's say one of them used to be 200 pounds but has lost weight. This has adversely affected her metabolism--all else being equal, she's burning about a quarter fewer calories than the other, because her body has throttled her metabolism. Even if she hasn't, basal metabolic rate varies from person to person, and for women, varies depending on where they are in their menstrual cycle. Stress also causes it to go up or down. All of these are invisible processes that mean that even if our two women eat exactly the same foods in the same amounts and do exactly the same activities in the same way, their bodies will not treat these calories exactly the same way.
Taubes is basically saying that the equation isn't "in - out = weight". It's more like "(in * a bunch of variable metabolic stuff) - (out * a bunch of other variable metabolic stuff) = weight".
Taubes, I think, would say that caloric balance as the causal explanation for obesity is a hypothesis. It is based on a law of physics, but that doesn't mean that it "works". So we have to test the hypothesis against observation. He notes that the hypothesis fails to predict what we observe (e.g. children consistently run positive caloric balances but they grow taller rather than fatter, the obesity epidemic began in the late 70's in the US but people didn't start eating more or exercising less, diets based on calorie restriction don't work, etc.). In summary, he subjects the calorie balance explanation of obesity to empirical tests, finds that it consistently fails to predict and so he rejects the hypothesis. This sounds like good science.
The alternative approach has been to assert that caloric balance must be correct regardless of the evidence because it is derived from the first law of thermodynamics. This logically leads to the idea that obesity is a character problem (some combination of sloth and gluttony) rather than a medical or biological problem. As Taubes puts it, it leads to thin people telling obese people that they would be not be fat if they were as virtuous as the thin. Decades of this type of approach has completely failed to stem the tide of obesity.
Along those lines, I think that your assertions are not well supported. Gravity is necessary for weight gain, but doesn't explain the obesity epidemic. And it is not necessarily true that lowering calories results in weight loss. If you substitute a 2000 calorie/day diet 95% of which is protein and fat with a 1900 calorie/day diet of 95% carbohydrates you will not lose weight - you would likely gain weight. For that matter, I could eat 4000 calories/day of grass and I wouldn't gain weight, because, unlike cows, the human digestive system doesn't use fermentation to convert significant calories into metabolic fuel. This should be enough to prove that the simple "calories in, calories out" model is at best a gross over-simplification.
Obviously, a more-complex model is going to curve-fit better than an simpler one. But that in no way implies that calorie restriction of some sort is not a necessity for weight loss.
I am not going to go down the rathole of the diet-obsessives here, but suffice it to say that there is a lot of evidence of increased caloric intake and lower caloric outgo in the U.S. since the 19th century, when people ate candy for a meal and expended huge amounts of calories in their jobs. And there are scientists who have specifically caught Taubes out on many of his claims.
"something can be both true and of no explanatory value is difficult to grasp"
Let us try this example.
An airplane has crashed. A perfectly correct, true explanation is: "that is because the force of gravity was stronger than the lift generated by the wings".
True, but useless. It is not clear WHY that happened and it surely won't help future pilots avoid the same fate.
The standard obesity explanation "he gains weight because he eats more calories than he burn" does not really explain anything either. But once you delve into Taubes' argument about hormonal imbalances, you start to understand how the natural balance between in and out gets out of whack.
When the conclusion being drawn is that engineers should ignore lift and gravity in analyzing the causes of crashes, then the critic is making a similar mistake to what Taubes said above.
"Ignore" is one thing, "make it a central point of the investigation" another. Lift and gravity are proximate causes and are to be treated as such. In order to prevent further crashes, you need to find the ultimate cause (pilot error, construction flaws) and remedy it.
No sane engineer would try to prevent plane crashes by redesigning the wings to generate more lift.
"As far as I know, DNP is the only substance to be banned by both the FDA and the Department of Homeland Security for unrelated reasons."
"Of course, if the FDA approved it for Huntington’s Disease, it would be FDA-approved, and usually that means it’s legal to prescribe for anything."
Finally I'll be able to get a prescription to get that stump out of my yard!
Apparently non-lethal doses of this stuff shortens the lifespan of birds...
https://www.utu.fi/en/news/press-release/illegal-diet-pill-DNP-might-kill-you-on-the-long-run
As would lethal doses, presumably.
why are they feeding it to birds instead of mammals?
I have no idea.
There was also recently news of a diabetes medication that causes weight-loss [1, 2]. I wonder what you think about this? The mechanism of action is allegedly loss of appetite though (and not hypercharged metabolism).
[1]: https://www.medpagetoday.com/primarycare/obesity/91146
[2]: https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
Seems very plausible and exciting.
Doesn't depression reduce appetite sometimes? It would be unfortunate if that were the mechanism of the mechanism.
Also slows down NEAT and a host of other things on the "calories out" side of the equation. And also, other times is greatly increases appetite...
All the GLP1 analogs are very effective and have been used for a number of years in a more aggressive fashion by progressive endocrinologists for non diabetic weightloss. I have been on the 1.0 dose of semaglutide, after being on liraglutide (victoza) for a number of years to successfully prevent recurrence of metabolic syndrome. My weight still goes up and down but not as much. The GLP1 analogs work primarily by slowing stomach emptying but it turns out also improve CVD through other mechanisms and have independent central effects. My endo has had great success with the currently marketed semaglutide doses and has been telling me that the 2.4 dose was going to be a game changer for a year.
Do you have further info / reading on this? How did you find a doctor even willing to think about these things? I spent 3 years pre-covid losing about 120 lbs, and due to various shelter in place issues have put about 80 of it back on. I'm pretty convinced that I have hormonal issues but have been unable to find a doctor who will look away from the screen and actually talk to me outside of a bariatric surgery clinic, and I don't want surgery if I can avoid it. I'm pretty fucking out there on a bunch of physiological measures (6'3, about 210 lbs of lean mass according to dexa, which is so far on the right tail for people who don't use steroids I might as well be from a different planet) and mental health measures (litany of diagnoses). When the apocalypses wasn't in the air I could handle real life + weight loss + other wellness goals. Since last year, I'm barely able to handle the real life part. I would love to find a "progressive endocrinologist" that can give me more than a thyroid checkup and say "you are ok!"
Look at the NEJM link in the @Thomas Kehrenberg above:
Once-Weekly Semaglutide in Adults with Overweight or Obesity
https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
GLP-1 and Obesity By Derek Lowe 15 February, 2021
https://blogs.sciencemag.org/pipeline/archives/2021/02/15/glp-1-and-obesity
That research was funded by Novo Nordisk. They are currently selling the drug as a Type II Diabetes treatment, under the trade name Ozempic.
One fly in the ointment is that retail Ozempic is $900/injector. If they are serious about the 2.4 mg dose it would be $2,700/week ~$10,ooo/month.
My daughter used the Ozempic for a yaer and lost ~40% of her initial body weight. She start6ed at 0.25 mg, and went to 1 mg in stages. She thought the 2.4 mg was a typo.
I have started to discuss it with my doctor, and he is a bit taken aback by the dose also. Is there any way for you to off line me the name of your doctor
Sounds like this indirectly adds some credence to the claim that lowering your thermostat helps lose weight
You'd think it would work that way - the body should have to use more energy to stay warm if it's colder - but my father (who I consider a very credible source for things) says that lowering ambient temperature actually slows metabolism and reduces net energy use unless it's actually cold enough to make you start shivering.
Depends on your individual body's reaction. Temperatures cold enough to make me start shivering and presumably burn energy result in my body raising my hunger by more than enough to compensate - I can gain weight on beans and rice. Which is not normally the case!
My experience of med students is they forgot all of this ATP stuff the moment the exam is done as they claim it’s never actually useful as a doctor. As someone interested in biology, it is also intensely boring. I wonder how much Scott had to make himself look all this stuff up again. Then again, he’s been able to write about intensely boring biology before (obviously making it interesting when he writes about it, maybe he should write a textbook)
I had to look it all up again, and still got some of it wrong before commenters corrected me and I edited it.
I had never heard mitochondria described as "proton pumping" across a membrane before. That makes it sound like a fuel cell. Maybe that's a good analogy for the less bio inclined.
It is an electrochemical process that uses membranes a lot like a fuel cell. That's why we breathe oxygen: you can get a lot of energy by giving it the electrons it wants.
https://en.wikipedia.org/wiki/Electron_transport_chain
The names of, say, the intermediaries of the Kreb's cycle are indeed boring, and read like genealogies." Then Fumarate begat Oxaloacetate, who begat Citrate..."
But the story in broader terms is pretty cool from a logistical standpoint, with various raw materials being shuttled into the various factory like organelles and so forth.
Can we make offers, like on Shark Tank? I'll put up 25 grand for, eh....a 50% stake in the company.
Well, it's a YC company, and the standard YC investment terms make it worth a minimum of $2 million for the whole thing. So you're gonna have to start the bidding a bit higher.
I'll do 30k, not a penny more. Come on, you can buy a Dodge Charger for that much! And I'm takin' all the risk, here!
It's pretty easy to make with simple chemistry equipment. But given that nitroaromatic compounds can have some pretty nasty toxicity, especially to liver, I would stay well away from DNP. https://link.springer.com/article/10.1007/s13181-011-0162-6
In this sentence: "Treat a hundred cases of obesity in exchange for one or two cases of cataracts (and some skin rashes, and some liver issues, and maybe a small risk of explosions) - is this obviously a bad deal?" Do you mean "*Trade* a hundred cases..." instead?
Treat makes sense -- doctors treat patients.
I've always found it curious that none of the easy exploits tried on the human body seem to have ever worked. Something like true nootropics, or just a good weight-loss pill, anything that would feel like cheating. As if there's some natural law preventing it. Or do we just call the working stuff medicine?
The body is governed by a thousand fine-tuned interlocked feedback loops. Changing one feedback loop without fucking up the others is hard.
Evolution had millions to billions years to optimize things. So it's not really surprising that it didn't miss much of low-hanging fruit.
Many performance enhancing drugs banned by sports leagues do work. They tend to require unsafe doses when everyone you're competing against is also taking unsafe doses, but for people not trying to compete, there are fairly safe doses of most things that can get you a mostly free lunch, aside from the fact they're largely illegal and thus somewhat expensive and difficult to obtain.
Plain old amphetamines do a pretty good job of boosting mental acuity and causing weight loss. HGT shots will transform your body pretty dramatically. But I think we tend to ban anything that seems too easy.
Some people would say exercise and eating less *is* the "easy" hack. But nobody likes those people.
What's HGT?
Typo: meant HGH (Human Growth Hormone)
The thing is, there's probably evolutionary reasons why humans produce the amount of HGH and phenethylamines that they do.
Humans at this stage of development won't continue to evolve in the same way they did before. Reproduction for us is gated behind social constraints moreso than survival constraints.
You ever noticed how many people drink coffee? How many fluoridate their teeth? Or use contraceptives?
Things that feel like cheating:
- vaccines
- antibiotics
- adderal
Vaccines have worked great. They're almost magical: you give the body some dead virus, and it figures out how to make a wonder drug that'll prevent you from ever getting infected? Miraculous!
Antibiotics have worked great. Who knew that penicillin could cure so many unrelated diseases in so many different organs?
If it was an easy exploit, evolution would have found it a long time ago, most likely.
Maybe long-term exposure to abundant calories might eventually find some new points of optimization, but we're likely to be engaged in mass genetic engineering long before natural selectin can have any appreciable effect.
Just laughing at the fact that the replies to Oskar are a mix of:
1. "Of course evolution made use of all the low-hanging fruit, so there's none left."
2. "Here are some examples of low hanging fruit that humans currently take advantage of."
If you are interested in obesity and weight loss, there is at least one pharmaceutical in clinical trials:
GLP-1 and Obesity By Derek Lowe 15 February, 2021
https://blogs.sciencemag.org/pipeline/archives/2021/02/15/glp-1-and-obesity
Once-Weekly Semaglutide in Adults with Overweight or Obesity
https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
That research was funded by Novo Nordisk. They are currently selling the drug as a Type II Diabetes treatment, under the trade name Ozempic. Some doctors are using it off label as a treatment for obesity.
Is that why YouTube keeps telling me I should ask my doctor about it? (That's the one with the jingle that's taken from the 1970s song "Magic", right?)
Typo: produg -> prodrug.
(I had believed that) the problem with weight loss was that the body would notice what you're doing and correct for it by making you want to eat more. Weird that this pill would get around that problem.
Why are there different endings for this post between the web version and the one that I was emailed through substack?
The email reads, "...A friend of mine works there and asked me to write a post shilling their work to potential investors. I don’t usually do this, and please don’t take this as carte blanche to ask me to shill your company. But I figured this field was interesting enough to make an exception."
While the post is "...A friend of mine works there and shilled his company hard enough to get me interested in this. He’ll probably show up in the comments section, so you can ask him if you have any questions."
See this comment that convinced Scott to change the post:
https://astralcodexten.substack.com/p/shilling-for-big-mitochondria#comment-1397199
Because I edited it after some commenters expressed concerns with the original version, especially that I was in violation of securities law by linking to an investment pitch.
Aaah okay. I answered your survey having NOT read the original post, and my thinking remains "go ahead and post such things and assume we (your readers) know how to think for ourselves". BUT now that I see your original wording, I can see where it blurred a line. I personally think it's fine for you to continue to tell your readers "here's a thing and some info and my opinions and you readers are thoughtful and can make choices for yourselves". At the same time, (and as a not-lawyer), I respect that you can't just ignore actual laws that don't care about your intent or your trust in your readers' abilities to think for themselves.
Why no animal studies? Do mice spontaneously burst into flames when they take 2,4-DNP? Enquiring minds want to know.
There are lots of animal studies. It works more or less the same way in animals as in people, although with some differences (animals don't develop cataracts unless you put a lot of work into finding the right animal model).
There are now obesity drugs that are safe and effective, so I have to quibble with the subtitle "the only diet pill that really worked". The latest trials of semaglutide report ~15% weight loss with modest side effects. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
Yeah, that was just after I wrote this article, and I agree it lessens the punch. Are there any others?
The best one right now just as far as weight loss, last i heard, was phentarmine+ topiramate, but that works substantially less well (with the highest dose giving like 7 percent more weight loss than placebo).
Wait, i misread the graph, it's 9 percent
Semaglutide used in the trial cited above was not a pill but an sc injection (although the pill is available as well), so the subtitle of Scott's article is still technically correct.
There is another GLP-1 agonist approved by FDA for obesity in 2014 -- liraglutide, but it is much weaker than semaglutide. In a head-to-head blind trial, liraglutide at the recommended dose gave 8% weight loss, while semaglutide at the highest dose -- 14% weight loss https://pubmed.ncbi.nlm.nih.gov/30122305/
The ECA stack has a big following in bodybuilding communities
Nothing as effective. Plenty of drugs that do result in significant weight loss, but have side-effects that make them somewhat inadvisable for the modest amount of weight you lose.
Technically semaglutide is an injectable, not a pill. :)
It's both.
'They pump protons across a membrane, creating pressure for electrons to travel the opposite direction.' That can't be right, the electrons would have to be under pressure to travel in the same direction that the protons did.
this seems like a $20 bill laying on the ground—why doesn’t the body do this auto-regulation on its own? Or, in other words, why isn’t this a free lunch?
I think for obesity the answer is that almost no people outside a modern society are obese. It seems to be a completely new problem and evolution didn't need to come up with answers.
I'm more surprised that the body doesn't naturally use this to generate heat! There's lots of anecdotal evidence (including from the Soviet soldiers) that DNP lets you tolerate temperatures you would otherwise freeze in - how come the body just gives up and lets you die instead? I have to assume it's because we evolved in Africa and didn't need it, and actual polar animals have other better techniques they use.
There's actually been a fair amount of evolution in how easy proton bypass is in our mitochondria between arctic and equatorial populations. But people have to worry about starving to death everywhere which I assume prevents us from getting to where this drug puts you.
It seems like a pretty inefficient way to generate heat. The body already goes through a lot of calories keeping warm in the cold, so accelerating that process sounds like a good way to starve. Having a fire, fur, or clothes would be much more efficient, particularly in an environment where calories are scarce.
I'd often wondered whether 2,4-DNP could be used to combat hypothermia. I suppose the difference is that we didn't evolve in conditions where we could escape the blizzard then go to the nearest burger king the next day.
How would that function have ever evolved? The condition of long-term persistent food abundance in which it might be advantageous to become less metabolically efficient and waste food on purpose has not been widely part of any animal's environment until 50 years ago or so.
This article (https://www.mitohealth.ca/what-is-mitochondrial-uncoupling/) states that animals with naturally uncoupled mitochondria live longer and the higher rate of oxidation from uncoupled mitochondria can eliminate polyunsaturated fatty acids (industrial seed/veg oil) from tissue. Sounds great! I wonder where a person's base level of energy production settles if they are cycling a drug like this. If the mitochondria have to work less hard while on the drug, does the body reduce the reproduction of new organelles? Probably not a big deal for someone who's struggling with obesity, but efficient mitochondrial function is a hallmark of youth and a trade-off between slimmer and less energetic/youthful might not be so straightforward.
The body does auto-regulate it, same in the obese as in the lean. The problem is that the obese regulate it to a higher setting. Given that the present environment is maximally obesogenic, one might ask why everyone isn't obese yet? (Probably because people differ in resistance to obesity.)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041792/
While I don't necessarily think T-Nation is the greatest source of information, this guy lists 9 other controlled substances bodybuilders use to lose weight loss in an article explicitly saying not to use DNP: https://www.t-nation.com/pharma/how-bodybuilders-really-get-ripped
You probably shouldn't use them either unless you're in a country where they're not illegal and know what you're doing, but is there any good reason to think any of these hormone-based approaches that don't manipulate your mitochondria don't work? I'm inclined to believe anything used by pro bodybuilders who make no claim to being "natural" probably works.
I got really excited/ confused for a moment seeing DNP, as in my profession that stands for do not populate/place, then was amused/ disappointed when it was a chemical.
I keep reading "DNP" as "Democratic Nationalist Party."
I guess that'd explain why it was banned - both Red and Blue tribes oppose some part of it.
Moderately related: https://m.youtube.com/watch?v=kXpzp4RDGJI is a nice video that shows how a mitochondrium turns the potential difference into ATP by rotating proteins.
I ran the numbers on this back in 2017 and decided that since cataract surgery exists it was *totally worth* a ~2% risk of cataracts to be able to lose weight as much as I want (albeit with very careful dosing) via a mechanism distinct from the usual weight-loss mechanisms. So I bought some DNP, used it to lose ~20 lbs in 3 months...and then absolutely *did* get the cataracts! About 6 months after I’d stopped taking DNP my vision grew cloudy (like being in heavy fog), the effect going from “annoying” to “can barely see well enough to cross the street safely” over a couple months. I found a good surgery center and had my lenses replaced ASAP with a high-tech plastic equivalent. Then (as expected) my vision got cloudy *yet again* necessitating a followup “zap the rest of the haze with lasers” procedure. Now my vision is okay again, but it was touch-and-go for a while.
Pre-cataract me thought having had cataract surgery would *eliminate the main risk* thereby giving DNP an even BETTER risk profile but post-cataract me thinks DNP is probably scarier than I gave it credit for, so I haven’t gotten any more.
Did you independently find the 1-2% number for cataracts?
Why did your vision get cloudy again after you had replaced the real lens with a plastic one?
How does the plastic lens work compared to the real one?
What dose of DNP were you using?
Did you gain the weight back?
I independently calculated the <2% number based on the reported side effect levels versus estimated use levels - some of this was from medical reports written around the time the FDA banned it.
The followup eye procedure I expected to need (and in fact did need) is called a YAG Laser
Capsulotomy. Your lens sits in a capsule; both the lens *and* the back of the capsule can become cloudy. So the lens gets cloudy, you break up the lens and replace it with a plastic one, the disturbance from the surgery (or whatever) somehow makes the capsule itself go cloudy and they...zap a big hole in it with targeted lasers (while you’re hoping they remembered to change the laser setting from “bulldozer” to “eyeball”). More on the YAG procedure here: https://www.uofmhealth.org/health-library/hw36757
Pre-cataracts I had decent up-close vision *without* glasses but needed glasses to see marginally well at a distance. After multiple expensive procedures I now have good distance vision *without* glasses but (a) I now need reading glasses to focus up-close (as is appropriate to my age), (b) there is a substantial “halo” effect (worse than before) around bright lights at night.
I got “Symfony” lenses which are supposed to allow both distance and close vision without glasses. They *kind of* do that - I can read my watch without glasses. But for *comfortable* close reading I need reading glasses. My best corrected vision is now excellent in one eye and pretty good in the other.
[Cautionary note: If somebody is thinking of using DNP I strongly suggest they find a good laser eye surgeon and get their prescription taken right *before* they start DNP. The fact that the cataract comes on *so suddenly* is a problem because to correct your vision *well* with an artificial lens they need to know your exact current prescription, which requires *guesswork* if the cataracts get too bad to see or measure through by the time you’re in their office.]
I obtained 200mg DNP capsules; my typical dose level was about 2 capsules per day for no more than 2 weeks at a time.
I did eventually gain most of the weight back.
On a re-read I notice I didn't directly answer the lens question. So: I would say the plastic lenses are on balance *probably a bit better* than my original-equipment lenses, my "night halo" griping notwithstanding. (There are tradeoffs to be made between various things a lens can be good at; I think the designers made good choices.)
Note that to get my now-satisfactory results did require a half-dozen procedures and something on the order of $10k. The procedures were: (1) replace one lens. (2) a month later, replace the other lens. (3) One of the lenses didn't end up well-centered, so go back for a "nudge" operation to reposition it better. (4) the correction level isn't great in one eye (the magnification level of the lens probably wasn't a good match to my prescription) so reshape the exterior with PRK to fix that. (5/6) then the fogging came back so do followup YAG Capsulotomy (x2) to fix that. Yay, victory!
PS: my "bulldozer" comment was an old Dave Barry line, of which I just found the original version:
'For example, in the past decade scientists have developed the laser, an electronic appliance so powerful that it can vaporize a bulldozer 2000 yards away, yet so precise that doctors can use it to perform delicate operations to the human eyeball, provided they remember to change the power setting from "Bulldozer" to "Eyeball."'
As grad student studying a lot of biochemical pathways in the body, I got curious about mitochondrial decoupling. I decided to experiment on myself with a seaweed extract which supposedly could have a mitochondrial decoupling effect in fat tissue. I didn't noticeably lose weight while taking it (maybe I just subconsciously increased my calorie intake since I wasn't actively dieting?) but I did get Really Uncomfortably Warm. Like, so warm that I was running like three or four degrees above my normal and it gave me trouble sleeping. I also noticed a sense of increased energy, but decided it wasn't worth the uncomfortable warmth after a few months and stopped taking it.
From a health perspective, how useful would this really be? I am asking a causality question. If we assume that, for example, Type 2 Diabetes is caused by being overweight then losing weight by mitochondrial decoupling would be a good thing. But my understanding is that the relationship between Type 2 Diabetes and obesity is not so simply causal. So, this drug could result in a population of people who suffer the maladies normally associated with obesity but who are not obese. Not nothing, but not great either.
*A population who suffer the maladies normally associated with obesity, and also some of them will be blind or have liver/kidney damage (never mind whatever other fun side effects we may find in the meanwhile)
Being too fat is causal in diabetes. But the absolute degree of fatness is irrelevant, you are above the threshold where it becomes a problem, or you're not. Doesn't matter if you're 50kg or 500kg.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399621/
My understanding is that Type 2 Diabetes is caused by chronic insulin resistance, which also tends to cause obesity. My simple (minded?) question was whether it is possible to lose weight by using a drug that increases basil metabolic rate while allowing you to remain insulin resistant. If you took that drug and subsisted entirely on sucrose, would you run no risk of diabetes? I don't know.
Insulin resistance is a cellular mechanism against energy excess. Cells use it to avoid being overfed until they die. This is normal and desirable. What's not desirable is when your entire system, chronically (as opposed to momentarily, after a meal), is insulin resistant, which just means that you have an energy containment problem.
Type 2 diabetes is when your energy containment capability is so wrecked that your glucose homeostasis goes, and it is one of the last things to go, being one of the most ancient parts of metabolism. IMO, diabetes should be diagnosed at the "insulin resistance" stage, not at the "hyperglycemic" stage. It's the same disease, just a different severity thereof.
If you subsisted entirely on sucrose, drug or no drug, you would probably partly or fully heal your diabetes. Check out Minger's write-up of low-fat diets, especially Kempner's rice diet.
https://deniseminger.com/2015/10/06/in-defense-of-low-fat-a-call-for-some-evolution-of-thought-part-1/
In Texas, a century from now, going to jail for tax and insurance fraud will be as honorable and as much of a way of life as dying in a cattle raid was for the Irish.
Mitochondria uncouplers sound like they could plausibly mess with the heartbeat, in potentially dangerous ways (Specifically ventricular repolarisation, ie QT interval prolongation and the like). When you prevent ventricular myocytes from accessing the energy they need, you run the risk of delaying, or otherwise altering the fairly precise electrical patterns that keep the show running.
A (very) quick google doesn’t bring up a whole lot for me; is this a concern you ran into during your research for this post?
Chubbyemu on youtube just released a video about a DNP near-death case: https://www.youtube.com/watch?v=ChPeG19qKUo. He also has an in depth interview with the survivor: https://www.youtube.com/watch?v=o15HCjtSkug
And David Sinclair was just on the Smartless podcast, a great episode: https://www.smartless.com/episodes/episode/d2bb7c57/david-sinclair
"Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them."
This is counterintuitive, but seems to check out. As part of their normal functioning, mitochondria generate ROS, increasing oxidative stress. If you make them less efficient, it stands to reason that they'd do more of that, but it turns out that this reduces ROS generation and oxidative stress.
I feel like I'm missing something important about the mechanism of action.
High proton gradients across the mitochondrial membrane leads to the protons of the electron transport chain being in a very reduced state, and in a reduced state they're more likely to donate an electron to an oxygen molecule to create ROS. I think of it as the ETC getting "backed up" basically, and decoupling helps deal with the backup in the absence of more demand for ATP.
This is a good excuse to plug my favorite crackpot biological theory: "mitonuclear match" which is basically how well the proteins that move protons across the mitochondrial membrane work together, plays a central role in the relationship between fertility and longevity across all species. https://nick-lane.net/wp-content/uploads/2016/12/Lane-Bioessays-mitonuclear-match.pdf
I previously competed in bodybuilding at a high level. One of the most interesting protocols that I have seen for DNP involved using it to counteract accumulated insulin resistance secondary to the usage of insulin and/or growth hormone. DNP seems to very quickly restore insulin sensitivity above and beyond the effects that one would expect from weight loss. These effects persist after the user stops use of DNP. I would be interested to see whether these new mitochondrial uncouplers have similar effects, which would make them useful for a still wider population.
Equator Therapeutics is a fantastic company and I am proud to be an Investor! That said, it is a private company and there are not always opportunities to invest in this or any cutting edge biotech startup. Lastly, as many commenters have correctly mentioned, startup investing is risky and you should consider the capital to be very much at risk. But, yes I think Jonah and his co-founders are brilliant and I am very encouraged by Equator's progress to date and their singleminded focus on getting this right for the sake of humanity - David Segura
GLP-1 agonists work. https://www.nejm.org/doi/10.1056/NEJMoa2032183 The results of this recent RCT are pretty striking, though it’s over a longer time span. It kind of blows my mind that with all these crazy new onc and rare disease breakthroughs, gene therapies, immonumodulators etc. that we don’t have have an effective, safe widely available way to interrupt/circumvent metabolism. And very few seem to be working on anything despite the country being 2/3rds overweight or obese and rising and colossal health externalities. We seem to be sticking to the good old Protestant willpower model as physicians, without even adequate tools (like prescribing food) to ensure patients actually eat healthy and exercise.
In a novelty shop when I was a lad they sold a box labeled something like "Weight loss miracle. Not a diet, not an exercise plan, not a pill." When you popped the lid, inside was a set of utensils--A fork with the tines cut off along the bias, half a butter knife, and a spoon with a hole in it.
Fascinating! I've known of dnp for some time including the dangers but never knew the backstory. Where can we invest? I can't be find the link. The story was well worth making the investment IMO
Apologies. Should have followed the comments, I will find it myself.
> The tragic history of the only diet pill that really worked
Scott, did you look into ephedrine hydrochloride?
Decent starting overview:
https://www.sciencedirect.com/topics/neuroscience/ephedra
If you want to research deeper, "ephedrine thermogenesis" brings up a lot of papers.
Quick summary [*] — it seems safe under MD's supervision. Certain people should never take it under any circumstances. People who can take it should do it carefully. Because people would sometimes use it recklessly and have adverse outcomes, it got banned from being prescribed or advertised as being for weight loss. Controlled status varies tremendously worldwide — it's OTC (but you have to show valid ID) in the United States; it's outright banned in some places and completely uncontrolled in others.
[*] (Relevant disclaimers: just my reading of the medical and scientific literature, but not a physician, not giving advice, might be mistaken, everyone should do their own research and talk to your physician, etc, etc, etc.)
The low theraputic index seems almost a dealbreaker in this case. You can't beat thermodynamics, and this is a particularly brute-force thermodynamic approach to weight loss. 500 kcal of the food you ate today doesn't turn into fat because it turns into heat instead, and any bit of cleverness that makes it so you don't get the heat means that this mechanism at least doesn't spare you the fat.
If the math works out that you can safely use some variant of the leaky-mitochondria trick to lose 2 lb/week, and *maybe* 5 lb/week, but 10 lb/week puts you in heatstroke territory, then the problem is that you can't have anything with the status of an FDA-approved diet pill that won't have more than a few people thinking "I *really* need to lose 10 lbs this week to fit into my wedding dress, so I'm taking the whole month's prescription this week and I promise to eat healthy after the wedding". There was apparently some of that in the 1930s, and the British bodybuilders, but I think there's a lot more pressure to be thin now than there was in the 1930s.
I say almost a dealbreaker, because the prodrug approach has an out: if you can find a prodrug where the metabolic transformation upstream of the mitochondria is a rate-limiting factor *and* saturates well below the "cause heatstroke" level, then you might be able to make this tolerably safe. That's a pretty tall order, but as you say, for an effective counter to obesity it's worth taking a look.
1. Metformin also does something to mitochondria, right? That maybe makes them work less well? This study (https://pubmed.ncbi.nlm.nih.gov/30548390/) complained that metformin reduces how well mitochondria respond to exercise. But isn't that (at least part of) the point? Would any scientists or doctors like to explain this legibly to us social science types?
2. After I read Scott's Fussell book review, I thought, "no need to use the Greek -on to -a plural suffix for 'rhododendron.' That's a bit much for flowers. It's not like they're mitochondria." And here we are, reading about mitochondria.
2a. Rhododendrons are definitely not a high-status flower these days, at least in the DC suburbs. They are often kind of a lurid pink or red. I had them ripped out when we moved to our house and replaced with hydrangeas, which are definitely the high-status flower du jour. Something to do with the ascendancy of Mark Sikes and his mania for blue and white.
Hydrangeas are high status? Wow! They're a staple of Irish country gardens and definitely regarded as old-fashioned. They'll be white and blue if you plant them in acidic soil, pink if in alkaline soil. You can often see different coloured flowers on bushes depending on the patch of soil they grow in:
"It's aluminium sulphate which makes the petals blue, and this is only available for uptake by the plants' roots in acidic soil. If you don't have the right soil, a good way to ensure ideal conditions is by growing the plant in a container where you can use an acidic compost and occasionally top it up with aluminium sulphate.
A simple soil test from your local nursery can help determine your pH level, which will determine your hydrangea colours. Generally, soil with a pH below 6.0 (acidic soil) will produce blue hydrangea blooms, and a pH above 6.0 will produce pink hydrangea flowers. Depending on your preference, you are able to change the colour of your hydrangea blooms to fit your desired colour."
Here's someone who did a tour of Ireland and got a bit excited about the hydrangeas:
https://aheronsgarden.com/2012/08/17/the-grand-hydrangeas-of-ireland/
Sometimes I even see single globes of hydrangea flower which are pink on one side and blue on the other.
I could guess that blue hydrangeas are higher class than pink hydrangeas, though at least it's a light pink.
Yes, I came here to say the same thing about metformin.
It seems like metformin is, in addition to its other activity, a weak mitochondrial decoupler.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147388/
Wait, so *Parasite Eve* was a documentary ? Live and learn.
https://parasiteeve.fandom.com/wiki/Parasite_Energy#Liberate
> It next shows up in history books on the Eastern Front of World War 2, where Soviet soldiers would - I can’t believe I’m writing this - take it to keep warm. There’s something quintessentially Russian about this, like a cross between the Platonic essences of AK-47s and Krokodil.
You can tell Scott has never had to survive (northern) winter without heat. :P
I absolutely would have taken DNP for warmth at the time, and I was aware of it, but had forgotten the name and couldn't find it again.
> Remember, mitochondria are the powerhouse of the cell. They pump protons across a membrane, creating pressure for electrons to follow.
It might be interesting to note that the enzyme producing ATP is quite literally a turbine (https://www.youtube.com/watch?v=kXpzp4RDGJI), although with effectively zero inertia.
I'm not sure this is a responsible post, given the tendencies of SSC/lesswrong readers to lifehack their way into trouble and wildly overestimate their competence.
The surprising part for me was hearing that bodybuilders are concerned with weight-loss.
I'm a skinny guy who knows I'll never have bulky muscles without serious weight gains. I guess I always assumed increased calorie intake was a natural perquisite for bodybuilding but in retrospect its obviously more complicated than that.
Bodybuilders that participate in competitions get their body fat % as low as 3-4% and dehydrate themselves for maximum visual effect - which is, to say the least, unhealthy. Also, caloric surplus is needed to build muscles so time and effort spent cutting is time not spent bulking, and in fact, actively wasting away.
The entire bodybuilding sport is Goodhart's Law in action, where you start with muscles as a reasonable proxy for health and fitness, and end in very weird places.
They tend to alternate between "bulk" (high caloric intake to build up muscles) and "cut" (low caloric intake to reduce fat) cycles.
How much safer would this be if the half life were only 8 hours? Or what if we targeted the effects better? Presumably our striated muscles have to be good at thermoregulation.
BAM-15 is an unfortunate name if it does end up exploding
Lmao
But do the metabolic processes that are accelerated by these compounds produce toxins, perhaps some of the same ones causing negative consequences of obesity?
I recall some research from the past couple of years documenting that the mitochondria of ME patients ("chronic fatigue syndrome") were producing only about 50% of the energy that normal mitochondria produce. So I've been lazily guessing that an excess reliance on stress energy might be responsible for one of the most commonly expressed complaints: the all-over burning sensation beneath the surface of the skin. But this fascinating write-up of DNP gives much food for thought.
Gabapentin is one of the most common drugs used for treating the neuropathies associated with many ME patients (and most fibromyalgia patients, who tend to have varying levels of chronic fatigue) -- and gabapentin causes weight gain pretty much no matter how much you eat.
There are so many interconnected mysteries remaining, but I'm having a hard time imagining anyone intentionally wanting to cripple the main source of normal, healthy energy production. I'm no scientist, but it strikes me as akin to, say, cutting off your hands to protect you from the dangers of smoking. And it seems super weird that anyone who is interested in athletic performance would venture down the path of punching holes in their energy factories! Surely that could never be sustainable.
When I got sick about ten years ago, I was diagnosed with central neuropathy, peripheral neuropathy, small-fiber neuropathy (which IS fibromyalgia, if you believe my neurologist) -- and also an EDS-type connective tissue disorder. But I most identify with chronic fatigue syndrome (ME -- except I doubt that mine was caused by a virus) because it better captures the utterly systemic nature of the illness.
There's a good reason ME/CFS patients use the shorthand of "flu-like symptoms": because most others can imagine what a full body/mind/energy debilitation from a bad case of the flu feels like, while they tend to associate fibromyalgia, for example, with pedestrian aches and pains. I could go on and on with a list of my other symptoms (like a full year of hives/rashes upon getting sick, and of course the burning -- there's always the burning) as well as diagnoses (IBS, orthostatic hypertension), but they all seem connected at a cellular level.
So, I do hope whoever's working on this stuff for weight-loss reasons contributes to furthering the overall science (which might also apply to Long Covid). But I also hope potential consumers remain extremely wary about playing around with such a central engine of the entire body.
Can't quite shake fascination with Russia's industrial application of DNP as an antidote to freezing. One has to wonder, if DNP had been readily available in Texas last month, how many would have voluntarily tried it (rather than firing up barbecues and other CO2 producer heaters in enclosed spaces)?
Wouldn't have worked unless we already had it in our cabinets. I was not going anywhere on streets with an inch of snow covered by a quarter inch of ice covered by little bits of cars that had ventured out onto it.
We are finally understanding the biology of obesity and body weight regulation. Look at semaglutide 2.4 mg with papers in NEJM, Lancet and JAMA showing ~15% weight loss on average. Why do you want to go down the sordid trail of dangerous and stupid weight loss shams, when we have medications with an evidence base to review. Semaglutide is submitted to the FDA for review this summer for a weight indication. It is already approved for diabetes and has a cardiovascular outcome trial underway. There is no need to pursue the dangerous DNP.
My understanding is that exercise isn't great for weight loss because it makes people hungrier, canceling out the extra calories burned. Why does DNP not have the same effect?
The general rule of thumb for steady state drug concentrations in pharmacy is around 5 half lives so if DNP has a 36 hour half life it takes around a week before it hits its stable in vivo concentration which makes it no surprise people are mucking up the dose.
Ah, so that's why Mr. Freeze has to stay inside a cold suit.
For the past several years I've fantasized about DNP on cold winter days but this has put me off it
Scott, what's your take on CoQ10? Lot's of new supplements of CoQ10 are hitting the shelves and they say it makes your metabolism young again -ish. Thanks
When Scott mentions the relative risks of the drug verses obesity he's falling into a fallacy I see many doctors fall into. It's kind of related to goodharts law.
That is confusing a correlated marker of ill health with a cause.
Obesity does have some direct impacts on health but also is a correlate of other things that have serious impacts on health.
Insulin resistance and metabolic syndrome is probably the main one. Lack of exercise and an unhealthy diet is another. Stress and social social isolation correlate to obesity. Hypothyroidism, certain viral infections, certain psychological problems, and on.
To do a proper risk reward analysis we would need to run an experiment on at risk obese people and see what effects the pill has on overall morbidity and mortality. Short of that we would need to carefully try to tease apart the effects of obesity from correlates in obese individuals.
I also strongly suspect that obesity in many cases is actually a problematic adaptation of the body. A kind of lesser evil that has a purpose, like fever, inflammation or SAD. Targetting obesity with the drug not only presents the danger of the drug, and may not net the benefit of reducing all the correlated morbities, but also may undermine protective roles that obesity has.
I did a two-week DNP cycle last year. I tried to maintain an ingested dosage of ~500-600mg at all times, using a half-life calculator I maintained using Excel. I am 6'3", 220lb, so the dosage for my body wasn't extreme, but the experience was absolutely awful. I was barely able to sleep, I sweated through my sheets and my sweat was yellow and turned everything yellow. I also had insatiable cravings for food. I only ended up losing 3–4lb. It's not a miracle drug and the sides are, in my opinion, simply not worth it. A 500-700 calorie deficit over the course of several weeks would have resulted in a similar loss of weight.
The issue with mitochondrial uncoupling is that it acts generically across all cells, and while bodybuilding forums and old research establishes the obvious stupidity that comes with acute high usage (peripheral neuropathy, ocular damage, heat stroke), there’s indication that this has potential adverse cognitive effects.
The PNS effects come from damage to myelination of long nerves. But myelin also exists in the brain, and it’s a fair extension to assume that if DNP even has slight permeability across the BBB, this could have neurodegenerative effects long term.
Fuck glaucoma, make pep pills debonaire again.
Is obesity a source or a symptom? I know exercise reduces inflammation a lot, and that can look like significant weight loss.
I also know that which body types are in fashion changes mostly with which abusive partner stereotype the beauty industry is being today.
Possibly a big part of the issue is that pharmaceutical companies have a big incentive to focus on drugs rather than, say, barefoot running, and doctors usually keep up with pharmaceutical advancements more than they do with evolutionary biology and juggling and suchlike.
Mitochondria take some time to adapt to their workload, and the dose makes the poison. There's a chance it could be safe enough if one very gradually ramped up from a nanodose to a microdose, and then gradually tapered down from a microdose to a nanodose to nothing. Someone should try this on mice and see what happens before risking any humans.
I DID IT. It fucked me up and it was a year before my nerves and sense of taste began to recover. PURE FUCKING POISON. THIS IS the kind of evil p[rofitering gdamned BS that should be properly reported or completely banned from all media sources due to its' absolute manifestation of injurious affects.
I took dnp 200-400mg / each day for 9 years or so, only a few small breaks. I only stopped since I now have babies (and don't want it around the house)... It's been about a year and a half since I touched it.
I used it to maintain my weight. I'll be honest, when I was on it I never ever got I'll or sick, it was weird. Had a lot of energy too. Since being "off" I've caught a couple colds.
During and since then I had my blood work taken and everything is perfectly fine... Blood tests, Liver, kidneys, etc...all normal.
The only downside is I think I'll have cataracts soon (at age 37) since it's been difficult to drive at night (seeing starbursts since about 3 months ago but had my eyes dilated in January and eye Dr said nothing..) and about 4 years ago the eye Dr told me I had deposits on my lenses.
Another reason I stopped is that bird study saying it cut life span by 20%...
Anyway just thought I would weigh in.. never had any close calls or anything since I never went above 400mg or so.. when I saw on bodybuilding forums people doing 1g+... Just madness.