Healthspan Campaign partner the Albert Einstein College of Medicine was recently featured in The Wall Street Journal about a groundbreaking new study called Targeting/Taming Aging With Metformin, or TAME. We had the chance to speak with Nir Barzilai, M.D., director, Institute for Aging Research, Einstein College of Medicine, and, scientific co-director, the American Federation for Aging Research, to learn more about it.
Q: Can you summarize what you’ve found so far in your research into metformin?
NB: The hypothesis of the TAME study is based upon promising research on metformin conducted by the scientific community. Below is some background on the drug and some of the more relevant findings.
Metformin is an FDA-approved drug in common use in the U.S. since the 1990s. It is the first-line drug of choice for prevention and treatment of type 2 diabetes (T2DM). The effect of metformin on aging has been extensively studied and has been associated with longevity in many rodent models (1-4). Metformin also extends the lifespan of nematodes (5), suggesting an evolutionarily conserved mechanism. A recent high-impact study demonstrated that metformin reduces oxidative stress and inflammation and extends both lifespan and healthspan in a mouse model (6).
If indeed metformin is a drug that can target the aging process, its administration should be associated with less age-related disease in general, rather than the decreased incidence of a single age-related disease. This notion led investigators to further study whether anti-aging effects can be demonstrated in the type 2 diabetes population. Notably, in the United Kingdom Prospective Diabetes Study (UKPDS), metformin, compared with other anti-diabetes drugs, demonstrated a decreased risk of cardiovascular disease (7). This has been suggested in other studies and meta-analyses and remains an active area of research (8-12).
In addition, numerous epidemiologic studies have shown an association of metformin use with a decreased risk of cancer, as well as decreased cancer mortality (13-17). There is also evidence from studies performed both in-vitro and in-vivo of metformin’s role in attenuating tumorigenesis (18-24). The mechanisms proposed relate to its effects on reducing insulin levels, improving insulin action, decreasing IGF-1 signaling (central to mammalian longevity), and reducing the senescent process (senolytics) as well as activation of AMP-kinase. In fact, metformin’s potential protective effect against cancer has been gaining much attention, with over 100 ongoing studies registered on the Clinical Trials.gov website.
Finally, a large population-based study evaluated the effect of metformin on five-year survival. The design, population selected and data obtained, will not be detailed here, but is a base for our analysis. Records of 78,000 diabetic patients treated with metformin were compared with records of 78,000 non-diabetic subjects and matched for relevant characteristics, such as age, smoking, cancer history, etc. Similar comparison was performed between 12,000 diabetic patients taking sulphonylurea (SU) drugs and 12,000 matched non-diabetic individuals. Not unexpectedly, SU-treated diabetic patients had ~40 percent greater mortality than their non-diabetic control group. However, mortality in metformin-treated diabetic patients was similar to the matched non-diabetic controls. In fact, among patients in their 70s, mortality was reduced by ~15 percent in metformin-treated diabetic patients compared with non-diabetic controls. These observations suggest that the protective action of metformin may extend beyond effects on specific age-related diseases and provide compelling evidence to support the design and conduct of studies to directly test whether human aging, and its diseases, can be effectively delayed.
Q: What is the TAME project?
NB: We hypothesize that delaying aging is the only effective way to delay age-related diseases and compress morbidity. TAME is a novel study that will recruit elderly subjects and, in a double-blind, placebo-control study, will test if metformin can delay the onset of multi-morbidities including cancer, CVD, T2DM, cognitive decline, and mortality. It is sponsored by the American Federation for Aging Research (AFAR), and I will serve as the PI. There is a wide range of involvement of gerontologists and intervention geriatricians in an executive committee and consensus committee as well as other investigators.
Q: What do you hope to achieve?
NB: The main reason to embark on this study is to convince the Food and Drug Administration (FDA) to approve aging as an indication, and thus a target for future and even better medications.
Without such a determination, the progress the field has made will not be realized because pharmaceutical companies will not develop drugs that have no indication, which is required for reimbursement by insurance companies. Indeed, metformin is a cheap generic drug that has already shown to have protective effects in diabetic patients, so it seems to be a good tool. We are confident that once FDA becomes open to aging as an indication, more and better drugs will be rapidly developed. We believe that there is a great benefit for healthy lifespan, not only to the individual, but also for the society in the form of cost savings, which is often referred to as the longevity dividend.
Q: And to end on a more personal note. You have a number of experts involved in this project, like Dr. S. Jay Olshansky and Dr. Jim Kirkland among others. What do you enjoy most about working with other experts to find answers about why our bodies age?
NB: I was raised on the belief that it is possible to change the world (or part of it). Many have said it before and failed. But it doesn’t matter, you start again with a better plan. The difference today is that by creating collaborations, opportunities, and friendships with many others we have more than a village to succeed. My confidence in our success is because the partnership with great scientists is like the egg and bacon analogy. The chicken was involved, the pig was committed, and the commitment of people like Dr. Olshansky and Dr. Kirkland, who also have the leadership abilities, will contribute to bringing this research to fruition. Similar commitment is evolving within the TAME executive committee, Drs. Jill Crandall, Stephen Krichevsky, Mark Espeland, Tamara Harris, Eileen Crimmins, Joe Verghese, Luigi Ferucci, who are all long-term friends and brilliant investigators.
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