#1

Review of Anti-Aging Drugs - Josh Mitteldorf

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#2

“One of the first conclusions they draw is that the correlation between what works in mammals and what works in simple animals is very low (r=0.28, not statistically significant). Of course, it is much cheaper and more convenient to work with worms or flies instead of mice, but the chances are that our experience there will not carry over to mammals like us.”

Until I live to be 100, I am skeptical of everything I am taking. I am wondering how much money I will have spent for each additional day of life extension. :face_with_raised_eyebrow:

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#3

Unfortunately, there is no control group for oneself. So we don’t really know if there is in fact any life extension from taking supplements. We take it largely on faith.

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#4

For people unfamiliar with Josh Mittledorf:

Theoretical-biologist Josh Mitteldorf has a PhD from UPenn. He runs the website AgingAdvice.org, and writes a weekly column for ScienceBlog.com. Mitteldorf has had visiting research and teaching positions at various universities including MIT, Harvard, and Berkeley.

I generally agree with his section on rapamycin:

Rapamycin

After a Jackson Lab study found impressive LS improvement for rapa fed to mice late in life, (Harrison, 2009), there was a great deal of enthusiasm for a new longevity pathway. Sixteen years later, there are 12 rodent studies in DrugAge — more than any other substance — but results are less spectacular. Parish computes an average of 8% lifespan increase, which puts rapa far down his sorted list. This is an artifact of averaging high and low dosages, pulsed and steady, late and early administration. I personally believe rapa is more promising than the 8% would indicate.

The highest dosage corresponded to 26% LS increase in the most optimistic study, also out of Jackson Labs. People who look at the detailed biochemistry distinguish between Rapa-1 and Rapa-2, and suggest pulsing the dosage in humans. Personally, I take large doses of rapamycin 2 days a week, 8 weeks per year. For personalized recommendations, you can consult your favorite life extension doc.

and his summary:

Summary

My favorites from this list are Melatonin, Berberine, NAC, Rapamycin, and Selegiline. I can recommend the first three unequivocally. Rapamycin has down sides that you should consider, and Selegiline has effects on mood and energy that you may like or dislike. Personally, I take a variety of anti-inflammatory supplements, and I’m glad to have an excuse to eat dark chocolate. I don’t know why there have been no mouse studies of vitamin D. There are broad benefits from vitamin D, and I would be surprised if they did not include life extension.

All these drugs and supplements act within the built-in plasticity of the aging program, which is about 20% in rodents, but only 5 – 10% in humans. It is unlikely that we can stack the supplements and expect more than a few extra years of lifespan for our effort. The best reason to take multiple life extension supplements is to hedge our bets, because we really don’t know which of them are effective in humans.

Your primary life extension program is diet and exercise. Choose a diet that works for you. Stay slim. Fast for short intervals regularly, and longer fasts as they feel good to you. Choose a variety of physical activities that are self-motivating and include interval training, strength training, flexibility, balance, and endurance. Supplements and drugs are secondary.

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#5

Great post. Thank you @Bruce4654. To make it easier to send to a friend, I imported Mittendorf’s table into a spreadsheet and sorted for human lifespan where the overall impact is a bit more stark. I was pleasantly surprised to see ascorbic acid leading. I have consumed a minimum of 500 mg and an occasional maximum of five grams every day for the last 55 years, missing no more than a handful of days in that span.

#6

As far as vitamin C, I read that the body can only absorb 250 mg at one time. So I take a gram spilt into four doses. Does anyone recommend higher doses?

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#7

For cancer treatment.
I think Linus Pauling was a big proponent.

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#8

How come canagliflozin is not mentioned?

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#9

I agree that we should throw LS data on yeast, worms, and flies out the window. The contrast with mammalian biology is too great whether it’s at the cellular level (e.g no DNA methylation) or globally (e.g no adaptive immunity). At least with rodents they share the same basic anatomy and can undergo similar age-associated processes like fibrosis and cancer.

Metformin and rapamycin are arguably the two compounds for which there is the most robust evidence for life extension in rodents

It’s puzzling that he would offer this statement considering that A. there’s no evidence that metformin in isolation extends LS in non–short-lived controls (see ITP) and B. the evidence that it’s toxic: see studies he linked showing LS shortening (relative to long-lived controls, btw) as well as age/disease-associated gene expression changes like oxphos downregulation and ECM upregulation.

Epicatechin in the form Epigallocatechin gallate

Epicatechin is a flavinoid derived from chocolate. One of the happiest results in epidemiology is that people who eat chocolate live longer. In a single Chinese study of EGCG, lifespan of rats increased 14%. (The table in Parish says 11%.)

This is just sloppy. Epicatechin is not epigallocatechin (they differ by an -OH) and epigallocatechin gallate (though the glycoside could be cleaved to give epigallocatechin) would not likely produce epicatechin in vivo. I’ve been taking (+)-epicatechin for about 7 months and it’s one of the few supplements I have faith in, so I’m excited to see how it looks in the coming ITP results. I see now that they don’t mention whether they used racemic or enantiopure material, but that would be good to know.

Magnesium is listed in the Parish table with a 9% LS benefit in mammals, but I was unable to find rodent studies in DrugAge involving magnesium. Searches in PubMed and Google Scholar also turned up no mouse LS studies of magnesium. (I take magnesium supplements myself for control of blood sugar and prevention of muscle cramps.)

The Longevica patent showed LS extension w/ 3 diff Mg salts in females (long-lived controls, too), although the dosing was proprietary.

I think there is plenty of evidence now to justify life extension enthusiasts taking NAC, possibly in conjunction with glycine. But more studies would be most welcome.

My hang-up with NAC compared to some of the others I take is that redox biology is extremely context-dependent and overshooting it (reductive stress) can be just as bad as undershooting it, and in some cases antioxidants can actually increase oxidative stress. Also it’s worth mentioning that the NAC study out of the Jackson laboratory suggested that the LS extension was possibly due to NAC-induced CR, rather than an intrinsic effect.

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#10

Did you actually read the article?

It critiques the results of the Parish et.al study, where the paper is from. It seems the references are completely wrong throughout

Vitamin C actually decreased lifespan in the referenced study, not increased.

#11

Has anyone else been thoroughly unimpressed with the quality of the DrugAge database?

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#12

Yes. It’s thoroughly disappointing and Josh Mittendorf’s commentary is disappointing too. I also clicked on the link he provided to his comments on statins (he’s very happy to provide his views on these meds), and found his comments profoundly disappointing. Based on these examples I’m not going to eagerly look for more of his insights and likely avoid wasting my time on reading his thoughts. Of course, YMMV.

#13

No, I did not. Thanks for pointing this out @Yoo . Since I now see that the single study he cites was conducted on house flies, I don’t know what to make of his comment on “several different animal species” or the entries in the mammalian column.

In Parish’s table, this ranks first with just one study and an average over 24 animals of 19.6% life extension. The study was by Sohal (1985), and it reports on several different dosages in multiple animal species. I don’t know where the figure 19.6% comes from, but the conclusion of this study was that supplementation with vitamin C depressed lifespan, probably by inhibiting production of the body’s native antioxidants, including glutathione and SOD=superoxide dismutase.

Most of us know that with the exception of primates (including humans), guinea pigs, and most bat species, mammals produce vitamin vitamin C dynamically in response to a wide array of stressors. As I recall, the same is likely true of the common housefly – the sole topic of investigation in the 1985 study linked – so it is reasonable to think that exogenous vitamin c could be disruptive. In any event: houseflies and not “several different dosages in multiple animal species.”

#14

What confuses me is, despite the erudite commentary, is just how little consensus there is. I wonder whether an almost-definitive list of life extension supplements and drugs is even possible.

I read that some statisticians, after decades of work, have created a model that enables them to compare the quality of baseball players throughout the history of the game, despite all the shifting variables (like the available pool of talent – e.g., there was a time when all ball players were white). Why can’t we do the same with LE supplements?

#15

Oh, and those statisticians chose Barry Bonds as the greatest of all baseball players. Babe Ruth came in fourth.

#16

Also interesting, the more I think about the weirdness in the Mittendorf article, there is bounded evidence that vitamin C is geroprotective in humans. The most robust evidence lies in the area of immunosenescence. Human clinical trials have demonstrated that supplementation with vitamin C can restore certain cellular immune responses in the elderly to levels comparable to those seen in younger adults. Less compelling but interesting, a large cross-sectional analysis of data from NHANES revealed a significant positive correlation between higher dietary vitamin C intake and longer leukocyte telomeres. Vitamin C’s effects on skin aging is also interesting. A cofactor for collagen synthesis, C is essential for skin elasticity and structure and recent studies suggest a deeper mechanism in which vitamin C promotes the proliferation of epidermal cells by facilitating DNA demethylation of genes related to cell growth. Several other avenues of geroprotection are possible but the evidence at this point is contradictory.

#17

The thing to keep in mind is something very basic, the ancient “the dose makes the poison”.

Some molecule might be geroprotective or accelerate aging just with the given dose. That frequently confounds the various studies and reports on these substances. Vitamin C is certainly an example. In addition to dosages you have to ask about the subject - are they deficient, oversaturated, have specific conditions. It might work very differently depending on the cohort and other contexts.

Rapamycin is a good example. If we only knew rapamycin as an immune suppressant in organ rejection it would never come across our radar as a geroprotector.

All these other considerations cause me to be very cautious about claims to geroprotection by this or that substance. Maybe it is or is not because of other factors.

#18

Statins are mitochondria toxin, so i suspect him to be against them. Cholestrol is 80% of the myelin on the brain. When the elderly are put on statins they develop chronic pain n neurodegeneration a few years after

#19

Im surpriced he only takes rapa 8 weeks per year, and twize per week. Josh is very smart so i wonder his reasoning

He had great post regarding the covid vaccine during the pandemic, when most people were still sold on them, he saw right thrue the bs and now 4 years later they are all banned for xx age group due to stroke n myocarditis

#20

Yes vitamin C are one of the most important supps. It also cures cancer at high doses IV as It turns into hydrogen peroxide