“I would pay you if you took it away from me. I’d try to buy it back,” said Irving Kahn, the late Wall Street investment advisor when asked if he would ever retire from work . Mr. Kahn, who founded Kahn Brothers Group, Inc. with his sons more than 40 years ago, took an active role as chair of his company until his passing last winter at the ripe age of 109 years. Kahn and his siblings all lived to be centenarians and were enrolled in the Longevity Genes Project at the Albert Einstein College of Medicine’s Institute for Aging Research, with more than 500 healthy seniors between the ages of 95 and 112 and their children . The project aims to identify the longevity genes that allow “super agers” to live far beyond their age-matched peers despite unhealthy behaviors such as cigarette smoking. In hopes of discovering therapies that target the aging process, Dr. Nir Barzilai and his colleagues at the Institute for Aging Research are looking to make a cheap, generic, widely used drug—metformin—the first to be Food and Drug Association (FDA)-approved for the indication of aging.
Metformin is an oral biguanide antidiabetic medication that has been used for over 50 years. It is commonly prescribed as a first-line treatment for type 2 diabetes mellitus and often in combination with other antidiabetic medications including insulin. Metformin reduces blood glucose levels by preventing glucose production in the liver and increasing peripheral glucose utilization. Lower glucose levels lead to lower levels of insulin and insulin-like growth factor 1 (IGF-1), thereby increasing the body’s sensitivity to insulin [3-5]. High blood glucose and insulin levels are important factors in aging and cancer [6-8]. Inactivation of insulin and insulin-like signaling has been shown to increase lifespan in nematodes, fruit flies, and mice [9-14]. Furthermore, studies have shown an association between metformin and a decreased risk of cancer and cancer mortality by suppressing tumor growth through decreased IGF-1 and by reducing senescent processes [15,16]. Prospective trials are required to further evaluate these findings. Additionally, clinical trials demonstrate that metformin, compared with other glucose-lowering drugs, may decrease the risk of cardiovascular disease .
Perhaps the most striking study to date on metformin and aging is a case-control study of 90,000 patients with type 2 diabetes treated with metformin or a sulfonylurea and 90,000 matched non-diabetic controls . Consistent with previous studies [17,19], the study showed that sulfonylurea-treated diabetics had an approximately 40% greater mortality rate than non-diabetic controls, whereas metformin-treated diabetics had similar mortality to non-diabetic controls. Of note, patients in the metformin group in their 70s had a 15% reduction in mortality compared to non-diabetic controls. This observation suggests that the protective effect of metformin may extend beyond its role as a glucose-lowering treatment .
Subsequent to the aforementioned findings that metformin may have a mortality benefit beyond treating diabetes, Dr. Barzilai designed the Targeting Aging with Metformin (TAME) trial. Sponsored by the American Federation for Aging Research, the TAME trial will recruit 3,000 adults aged 70 to 80 years in approximately 15 centers across the United States who will be followed for 5 to 7 years. The study will include adults with one or two of three conditions—cancer, heart disease, or cognitive impairment—or who are at risk for them. Type 2 diabetics have been excluded from the trial in order to measure the anti-aging effects of metformin apart from its known benefit in diabetes. Participants will be monitored to measure whether metformin forestalls the onset of cancer, heart disease, cognitive impairment, diabetes, and death. Dr. Barzilai explicitly states that his goal for the TAME trial is to convince the FDA to approve aging not only as an indication for metformin, but also as a target for future and improved 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,” said Dr. Barzilai in an interview with the Healthspan Campaign, a partner organization in his promotion of aging research .
If Dr. Barzilai’s trial were to show that metformin delays age-related diseases and mortality and the FDA approves aging as an indication for metformin, most people would be candidates for such a therapy. What are the potential unforeseen effects of prescribing metformin to the masses for the prevention of aging? Luckily, metformin’s safety profile is well known after more than 60 years of use as a diabetes medication in the United Kingdom and United States. The most common side effects, which are gastrointestinal, usually improve with time and dose titration. Additionally, unlike other diabetes drugs, metformin is not associated with hypoglycemia. Perhaps the biggest limiting factor to its use in elderly adults is the historical concern over the rare adverse effect of lactic acidosis in the setting of renal insufficiency and hepatic impairment. In point of fact, metformin’s association with lactic acidosis led to its withdrawal from the market in the 1970s, although most cases seemed to occur with a related molecule, phenformin, which increased the risk of lactic acidosis by 10 to 20% compared to metformin . Although the prescribing information for metformin explicitly lists a creatinine cutoff of 1.4 or 1.5 in women and men, respectively, the American Diabetes Association and the European Association for the Study of Diabetes report that metformin seems safe unless the estimated GFR is less than 30 mL/min .
“The perception is that we are looking for a fountain of youth,” said Dr. Barzilai as he displayed a slide of the iconic 16th century Ponce de Leon painting. “We want to avoid that; what we’re trying to do is increase health span, not look for eternal life.” Current treatments for diseases related to aging “just exchange one disease for another,” said Dr. Barzilai, whereas he and his colleagues seek a treatment that delays the onset not only of a single disease but of age-related diseases in general, and in so doing, extends one’s healthy years.
Dr. Amy Shen Tang is an Internist at NYU Langone Medical Center
Peer reviewed by Michael Bergman, MD, Endocrinologist at NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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