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Aging and Lifespan

The First Real Anti-Aging Trial in Humans

I’ve mentioned the proposed clinical trial with metformin as a general anti-aging therapy. Here’s a profile of Nir Barzilai, the principle investigator for it. Choosing metformin was as much about going in with a drug that has a very clean safety profile as anything else:

“There’s nothing we don’t know about metformin,” Barzilai says—especially its record for safety, which he calls “critical” to the proposed trial.

His colleagues agreed, sometimes reluctantly. “Rapamycin would have been my first choice, because the animal results have been so spectacular,” Austad says. “But Nir said, ‘We can’t afford in this first trial to kill anybody.’ And I thought, ‘Strategically, he’s right.’”

Barzilai concedes that he and the AFAR-sponsored group are as interested in setting a precedent as in scoring an impressive initial success. Satisfying FDA concerns about a trial that breaks tradition and measures multiple disease endpoints in an aging population, they say, will open the door for pharma to enter the field.

The meeting with the FDA was successful, in that the agency seems open to the idea of such a trial (which has not always been the case). Now comes the money. The team estimates that they’ll need about $50 million for the trial, and are open to public funding, private funding, whatever they can get. I hope that they can round it up, because this trial (and this whole area of research) are more important than you might think. If we can increase healthy lifespan, and compress the breakdowns of old age to a shorter period at the end, we could save trillions of dollars of health care costs without anyone having any grounds to feel cheated in any way (which is always the problem with trying to squeeze money out of the system as it is). On the other hand, giving people an extra five years of decrepitude would be a financial (and human) disaster.

Which of those will it be with metformin, or the other possible therapies? There’s only one way to find out. That’s what the drug business comes down to, in the end, the fact that the only way to really be sure what will happen in people is to give the drug to people and see.

30 comments on “The First Real Anti-Aging Trial in Humans”

  1. Anon says:

    “There’s nothing we don’t know about metformin,” … except maybe how it actually works???

  2. Anonymus says:

    Metformin is as good a choice as any. However, since fixing one single cause of death is more likely than simultaneously fixing all the ailments that simultaneously plague the end of life, I can only conclude that any such anti-aging drug will only prolong life while increasing the unsustainable costs of end-of-life care. And that’s assuming it works.

  3. Barry says:

    The FDA is in the business of regulating Foods and Drugs (and Nutritional Supplements), not elixers. Until senescence is defined as a disease, the FDA has no way to approve an anti-aging drug. There is precedence. Erectile Dysfunction and Alopecia were suddenly defined as diseases when drug companies brought drug candidates forward. But until it’s a disease, there can be no FDA indication. And without an approved indication, any use is unreimbursable.

  4. Anon says:

    @Barry: That seems a bit bureaucratic and narrow-minded. Surely, if a substance can prolong and/or improve quality of life then the FDA should be able to look at it. Not say, “sorry, computer says ‘no’, it’s not listed in our database”.

    1. Barry says:

      the FDA has an “Oncology” division that will rule on drugs for cancer, and “metabolic” division for drugs for e.g. diabetes…but there’s no way to deal with a drug for life extension. Until “Old” is defined as a pathology, the FDA won’t approve such a drug.

  5. John Wayne says:

    While your health insurance company might not buy it for you, your life insurance company almost certainly will. Hyper-capitalism, here we come!

  6. Derekyouoldfart says:

    *tsk* Vested interest speaking from the top here!

  7. Lane Simonian says:

    I wonder if Barzilai knows this:

    Metformin in the diabetic brain: friend or foe?

    Metformin probably should not be given to individuals already experiencing cognitive decline at least not at the levels at which it activates AMPK.

    J Neurochem. 2011 Aug;118(4):460-74. doi: 10.1111/j.1471-4159.2011.07331.x. Epub 2011 Jun 24.
    AMP-activated protein kinase: a potential player in Alzheimer’s disease.
    Salminen A1, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M.

    “Evidently, AMPK signaling can repress and delay the appearance of AD pathology but later on, with increasing neuronal stress, it can trigger detrimental effects that augment AD pathogenesis.”

  8. Benjamin Button says:

    I already tried this on myself.

  9. johnnyboy says:

    I have no qualms with such trials, but from what I see of its proposed design (1500 treated normal subjects, followed for 5-7 years), I very much doubt it has the power and duration to detect real differences – unless the metformin effect is massive.

  10. Tom Willingham says:

    The University of Florida is in clinical trials to test the efficiency of treating lupus with metformin and 2-deoxy glucose. Results to date are promising.

  11. oldnuke says:

    Well, I’ve been taking metformin for many years. So I guess that I’ve live to be 100.


  12. Anon says:

    Sorry, Derek, it should be principal investigator, not principle. We don’t need to investigate whether the trial is principled.

  13. interested reader says:

    Obesity and consequent insulin insensitivity and type II diabetes have effects on lifespan and affect about a third of the people in the USA. Metformin is the most effective treatment for type II diabetes. Thus, it would not be entirely surprising if metformin had an effect on lifespan, but does that have anything to do with aging as a distinct biological phenomenon? Many of the studies in the aging field using flies or worms are done with animals that are fed ad libitum, similar to having a person live at McDonalds with an unlimited credit card to buy food. It is not clear to me that the underlying mechanisms of aging are being probed correctly using models such as that. I guess that it will depend on who is selected to participate in the proposed trial.

  14. Mark Thorson says:

    If a good safety profile is the first criterion, I nominate sepiapterin. The age-related diseases atherosclerosis and type 2 diabetes are associated with endothelial dysfunction, which in turn is driven by the decline of tetrahydrobiopterin throughout adulthood. Sepiapterin is a BH4 precursor that has good penetration of cellular membranes — it’s commonly used in studies which require raising intracellular BH4, because BH4 itself doesn’t readily cross cell membranes. At any reasonable concentration, it’s not toxic at all.

    (There is a study which demonstrated uncoupling of eNOS, but that was at a ridiculously high concentration of sepiapterin that displaced BH4 from its binding site on eNOS. It was thousands of times higher than anything you could achieve in a human body.)

  15. PorkPieHat says:

    How can we keep that douchebag Martin Shkreli’s hands off this one? It actually costs very little to get a prescription of metformin in either tablet or extended release forms. I can see him salivating over buying the rights to own/make this drug, esp after such a funded trial is over with positive results. If I have the power to make a curse on Tiger Woods stand (I put a pox on him that he’ll never win another major…you’re safe Jack), you should be afraid, Martin, you should be very afraid.

  16. matt says:

    I was just thinking about this yesterday, when you mentioned previous diabetic treatments had previously not demonstrated any improvement in survival. How likely is it metformin would improve survival in the general population, if it does not produce a survival benefit in that subset of population whose lifespan is decreased by the disease it’s approved to treat?

    And if it’s unlikely to have any benefit, why spend $50 million showing it’s safe but ineffective? Couldn’t they use Vitamin C instead? Come to think of it, Dr. Oz could probably point them to a whole variety of substances that are relatively safe but haven’t demonstrated efficacy for anything yet.

    Speaking to the “breakdowns of old age,” I’ve been unpleasantly reminded recently of osteoarthritis. Conservatively estimated to affect 1/3 of Americans 65 and older. It seems to me medical practice regarding OA is about where Alzheimer’s treatment was about fifteen years ago: no firm diagnosis available until after the disease has irreversibly damaged the body. No clue about the biochemical pathways involved. The only “treatments” feebly dab at reducing pain while the damage is ongoing. Biomarkers unknown. Clinical practice often reduces explanations down to insulting absurdities.

    Without a treatment for OA, at least one third the 65+ population will hardly able to move around, and thus relegated to high risk sedentary status; and/or candidates for ongoing joint surgeries and implants, and thus obscenely expensive. (Likely both.)

  17. Slicer says:

    First off, aging is not one condition that requires one therapy to treat. Metform is not an “anti-aging” drug. It will not make people be “younger”.

    If you want to reverse the damage caused by failing systems, you have to repair each one individually. Glucosepane is probably the (physically) smallest target here, although it might be more feasible to encourage the replacement of every bit of collagen in the human body- that’s how hard that stuff is to scrape off. Then there’s amyloids. And failing stem cells with an accompanying bad signaling environment. And lots of other things- de Grey’s seven categories are just that, broad categories.

    There are no magic pills. There are no miracle cures. There is no “oh if you just take this you can live forever” anything. Actual repair of human beings is not easy, and anyone who thinks it is, is guilty of the most wishful thinking.

    But difficult does not mean impossible, and either these systems get repaired or you (and I mean YOU, the person reading this) die a slow and probably agonizing death.

  18. Tuck says:

    Metformin lowers blood glucose, by impairing the liver’s ability to produce it, and it also alters and impairs mitochondrial glucose metabolism, and makes mitochondria more resistant to glucose toxicity.

    Back to the toxic effects of excess glucose…

    So yeah, it’s a good candidate for life extension, assuming excess glucose. It would be interesting to see how it works under conditions of naturally down-regulated glucose metabolism.

  19. Chris says:

    Interesting find, Lane. I don’t see any mention of cognitive function (or biomarkers) in the inclusion criteria for the trial:

    You may want to reach out to the contact listed at Einstein and share that information.

  20. PharmaHeretic says:


    Lawsuit: Scumbag Pill Price Gouger Stalked and Harassed Ex-Coworker’s Entire Family (

    “Timothy Pierotti was a colleague of Shkreli at his pervious biotech venture, Retrophin, before an alleged business deal gone awry created bad blood. From there, legal documents allege, Shkreli proceeded to harass and threaten Pierotti’s family via email, Facebook, LinkedIn, and text message. Pierotti says Shkreli—a one time Forbes “30 Under 30” honoree—even broke into various online accounts owned by his family.”

    “That same police report includes accusations that Shkreli had broken into Pierotti’s Gmail account, using that access to reset his Facebook, LinkedIn, and Twitter accounts. Shkreli allegedly went so far as to publish unflattering posts about Pierotti from Pierotti’s own Facebook account, prompting him to discover that many of his passwords had been changed without his permission.”

  21. Proteus says:

    ” no firm diagnosis available until after the disease has irreversibly damaged the body. No clue about the biochemical pathways involved. The only “treatments” feebly dab at reducing pain while the damage is ongoing. Biomarkers unknown.”

    Isn’t that where Alzheimer’s is today?

  22. DN says:

    FDA approval for life extension would be trivial. All-cause morbidity and mortality are recognized health problems. In fact, everything else is a proxy for them.

  23. cancer_man says:

    So where is the love for NR?

  24. Anon says:

    At least half of all healthcare costs are associated with end-of-life care and prolonging life (delaying death), and yet this is what we want more of? At the current rate, healthcare costs will rise to 50% of GDP by 2060, and that doesn’t factor in the extra pension costs and lost productivity of an aging population. Time for a reality check, or economic collapse. It’s one or the other.

  25. Lane Simonian says:

    Thanks, Chris for the suggestion and the link (the clinical trial phone number has since changed). I left a message.

  26. not my first rodeo says:

    The Dog Aging Project has an interesting comparative medicine approach, with an open trial to enroll pet dogs and treat with rapamycin, tracking age related parameters (heart function, immune system) and lifespan.

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