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Aging and Lifespan

Metformin for Aging in General?

Here’s an interesting report in the Wall Street Journal on plans to run a large clinical trial with metformin. That compound has a lot of effects, and many of them seem as if they could be beneficial in an aging population.

Dr. Barzilai expects to enroll more than 1,000 elderly participants in the randomized, controlled clinical trial to be conducted at multiple research centers and take five to seven years. The project is in the preliminary stages and permanent funding hasn’t yet been secured. Funding for the planning phase is coming from the American Federation for Aging Research, a nonprofit organization of which Dr. Barzilai is deputy scientific director.
The trial aims to test the drug metformin, a common medication often used to treat Type 2 diabetes, and see if it can delay or prevent other chronic diseases. (The project is being called Targeting/Taming Aging With Metformin, or TAME.) Metformin isn’t necessarily more promising than other drugs that have shown signs of extending life and reducing age-related chronic diseases. But metformin has been widely and safely used for more than 60 years, has very few side effects and is inexpensive.

I hope this gets off the ground, for just those reasons. The study itself will not be cheap, but (as the article notes) it could pioneer some ways of looking at aging in the clinic, and we need for people to be taking steps in that direction. The planet’s population, on the average, is not getting any younger, as birth rates level off (or plunge outright), and healthy lifespan is a bigger and bigger issue.

andy Walsh, an FDA spokeswoman, said the agency’s perspective has long been that “aging” isn’t a disease. “We clearly have approved drugs that treat consequences of aging,” she said. Although the FDA currently is inclined to treat diseases prevalent in older people as separate medical conditions, “if someone in the drug-development industry found something that treated all of these, we might revisit our thinking.”

As well they might. This is worth keeping an eye on, for sure.

19 comments on “Metformin for Aging in General?”

  1. dave w says:

    Hmmm… so metformin’s usual use is to relieve high blood sugar: what happens if it’s taken by someone whose blood sugar level tends to run on the low side of normal in the first place?

  2. MolecularGeek says:

    Metformin’s mechanism of action is still somewhat open to debate, but it’s generally considered an insulin sensitizer rather than an insulin secretogogue. That is, it makes cells respond to the insulin that one’s beta cells is still making rather than persuading the beta cells to make more insulin. So it doesn’t induce hypoglycemia the way that most of the other classes of anti-diabetics do, and it sometimes gets used in patients with metabolic syndrome to try and avoid the development of full-blown DM type II. This does no good, of course, if the islets shut down completely, but then you’re looking at much the same situation of type I anyway.

  3. Anonymous says:

    Obesity, Diabetes and Alzheimer’s disease have a been linked, but there is some controversy about the exact nature of the relationship. Mid-life obesity and diabetes are linked to AD, but being underweight in late-life is also linked to AD. I wonder if metformin is a missing link here.

  4. mm87 says:

    Just wanted to say that #2 is dead on. There have been some great papers to come out of the Shulman lab on AMPK action in the liver.

  5. Anonymous says:

    Many of the recent papers suggest an AMPK-independent mechanisms for metformin (at least in lean individuals). Seems a primary mechanism of action is to reduce liver glucose output (papers from Shulman and Birnbaum support this hypothesis

  6. HelicalInvestor says:

    “an FDA spokeswoman, said the agency’s perspective has long been that “aging” isn’t a disease. “We clearly have approved drugs that treat consequences of aging,”
    I read this as difficulty in selecting appropriate clinical endpoints i.e. longevity itself isn’t going to be a primary one. Reduced deterioration of …..??? I think Derek phrased it exactly right “it could pioneer some ways of looking at aging in the clinic”, with the emphasis on exactly how to best ‘look’.

  7. mm87 says:

    #5 oops foggy sick brain meant to say AMPK independant

  8. mm87 says:

    #5 oops foggy sick brain meant to say AMPK independant

  9. Anonymous says:

    Look up some reviews of the concept of the O-GlcNAc modification. It’s extraordinarily interesting. O-GlcNAc is essentially the Yin to the Yang of protein phosphorylation. But what’s more interesting is the fact that O-GlcNAc is regulated by only 2 enzymes (OGT and OGA); this is in stark contrast to protein phosphorylation which needs hundreds if not thousands of different kinases and phosphatases. Metformin clearly changes sugar/carbohydrate metabolism. Major such as diabetes, AZ, and cancer are characterized by quite profound changes in sugar metabolism. Many scientists don’t know it, but the O-GlcNAc modification is a direct branch from glycolysis. The O-GlcNAc modification is now believed to regulate the function of >90% of the entire proteome. This includes extremely interesting proteins such as Tau (which is hyperphosphorylated (the opposite of O-GlcNAc) in AZ), the enzymes that regulate DNA methylation, virtually every transcription factor, and RNA poly II, and related to this article AMPK. O-GlcNAc is even directly part of the histone code. This is only just a few proteins or classes of proteins I’ve highlighted. The main idea though to understand is that there’s simply a lot of stuff you mess up when you perturb carbohydrate/glucose metabolism, and this goes along with #3’s post–cancer, diabetes, and AZ do have some interesting links, and more evidence seems to be piling up all of the time that the link between all of those disease may be in fact O-GlcNAc. It has been hypothesized before that Metformin’s interesting properties are linked to its ability to alter the profile of O-GlcNAc because it is able to change glucose metabolism.

  10. Morten G says:

    So FDA says it is not likely to approve an anti-aging treatment,right? But they’ve approved all manner of aged-related whatever-disease. So this clinical trial just needs a list of age-related whatevers as end-points.
    Age-related cognitive decline
    Age-related muscular atrophy
    Age-related bone-thinning
    Age-related prostate enlargement
    Age-related constipation? idk, I’m not old.

  11. John Rasor says:

    Metformin also seems to have significant anticancer effects when used in diabetics. Multiple trials are currently testing it in nondiabetics for prevention of various different malignancies. With cancer overall being the second leading cause of death, the drug is effectively already being tested for life extension.

  12. matt says:

    I’m with the FDA on this one. Acting like old age is a disease is conceding a point for which there is no factual basis yet. But as Morten G points out, this is not a problem: if you can demonstrate improved survival rates for any one of the conditions, that should be enough for approval, and then you can demonstrate the rest to scoop up a few billion customers.
    I think the one miracle cure for aging is about as likely as one miracle cure for all cancers, but there’s no stopping people from swinging for the fences, and I’d be happy to get in line for treatment if they succeed.
    Wasn’t resveratrol already taking care of life extension? The line of dubious candidates goes back many thousands of years.

  13. dave w says:

    I’d go at what #12 said from a different direction – should it be necessary to “act like old age is a disease” in order to approve something to alleviate its effects? We seem to have this puritanical fixation on “normal” function, which may (possibly) be restored, but ought not to be “enhanced”. (Consider Viagra – can’t just market it to “improve erectile function”, but saying it’s to “relieve the Medical Problem of Erectile Dysfunction” apparently makes it OK… do we really need this conceptual boundary in the regulatory paradigm?)

  14. okemist says:

    Are they prescribing this off label like the Novartis compound Rapamycin?

  15. Kismet says:

    This is a distracting semantics game. Aging is a disease; or aging is the most important risk factor for age-related diseases, who cares in the end?
    A treatment that slows aging will likely slow CVD, cancer, neurodegeneration etc. To measure a slowing of aging one will have to rely on disease endpoints obviously…
    Nature. 2014 Jul 24;511(7510):405-7. doi: 10.1038/511405a.
    Medical research: treat ageing.
    Fontana L, Kennedy BK, Longo VD, Seals D, Melov S.
    Pursuing the longevity dividend: scientific goals for an aging world.
    Olshansky SJ, Perry D, Miller RA, Butler RN.
    Ann N Y Acad Sci. 2007 Oct;1114:11-3. Review.
    Rae, M. J., Butler, R. N., Campisi, J., de Grey, A. D., Finch, C. E., Gough, M., … & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science Translational Medicine, 2(40), 40cm21-40cm21.

  16. As a pharmacist, widespread metformin use in the elderly is something that makes me squeamish. Lactic acidosis is a very real danger with metformin, and the decreased renal function that comes with advanced age puts the elderly at a larger risk. It will be interesting to keep an eye on this one.

  17. Anonymus says:

    I would interested in understanding their power analysis for n=1000. How and what exclusion versus inclusion criteria are used etc.

  18. Adrian Harper says:

    Where can one sign up to participate in this study? Are there study sites across North America? I live near Vancouver in British Columbia, Canada.

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