What if we spent 80 years to get to the biological age of 60?” Dr. Nir Barzilai pronounces with gusto. Culminating a near twenty-minute TEDMED talk centered on [Growing] older without growing sicker, his proposition is not merely hyperbole. In his role as Director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx, New York, Dr. Barzilai is wholly devoted to unraveling the process of aging. Particularly, his research focuses on genes that predispose humans to exceptional longevity, arguing that a longer life can co-exist
with a healthy one.
To study the complex interaction between morbidity, mortality and survival during old age, Dr. Barzilai turned to a unique group of superagers that, like him, call the Bronx home. This distinct cohort of elderly was entirely of Ashkenazi Jewish descent, between the ages of 95-107, and had generally good health. In 1998, Dr. Barzilai’s team with the Institute for Aging Research, launched the Longevity Genes Project: a study intending to ascribe a genetic and biological signature to the exceptional longevity unique to these centenarians.
When the project ended in 2002, the recruited superagers and their children demonstrated a peculiar phenotype: both groups had higher particle size of high-density lipoprotein (i.e. higher “good” cholesterol) along with a unique mutation of the CETP gene that lowered its expression in the blood. CETP, a transfer protein, directly contributes to lipoprotein metabolism. Finally, the children with this unique HDL-CETP phenotype were also found to be less sick than age- and ethnicity-matched controls, with notable decreases in incidence of heart disease, hypertension and metabolic syndrome. All of these data together convinced Dr. Barzilai’s group that lipoprotein particle sizes are not only heritable, but they also result in healthy aging.
The team at the Einstein Institute has since built on this initial work of the Bronx superagers, establishing that these centenarians downregulate their insulin-like growth factor-1 (IGF-1) production, thanks to a specific genetic mutation. IGF-1 is intimately tied to the hormonal processes governing growth, and its mutated forms were first demonstrated to extend lifespan in yeast, fruit flies, and C. elegans. In fact, exceptional longevity has been noted in mice with dwarfism, whose 50% increase in lifespan compared to normal-growing mice can be ascribed to the downregulated IGF-1 production that is protective in aging.
Halting the aging process has served as the research focus of many, not just for Dr. Barzilai or the Einstein Institute team. This collective pursuit was celebrated in 2013 at the inaugural Advances in Geroscience: Impact on Healthspan and Chronic Disease summit hosted by the National Institute of Health. Here, the pioneers in aging research established the “molecular pillars of aging” – a complex web of interacting factors collectively driving the process of growing older. The group settled on seven: adaption to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis – a mechanism within each cell that ensures proper protein function – and stem cells and regeneration. Each pillar stands to be pursued in hopes of understanding its contribution to aging and chronic disease. What’s more, inherent to the pillars’ creation is the consensus that aging can be targeted in tangible steps. As Felipe Serra, Director of the Division of Aging Biology at the National Institute on Aging (NIA) mentioned in a 2015 issue of Science, the pillars [allow] us to think that, okay, if we understand how [aging] happens, we can maybe manipulate it.”
Manipulating aging, or “extending health span” as Sierra aptly puts it, has been hard to come by in humans. Perhaps the biggest hurdle comes from the regulatory bodies themselves; the U.S. Food and Drug Administration (FDA), for instance, does not consider aging a disease, and therefore will not approve drugs to treat it. Relentless in his pursuit, Dr. Barzilai and a reputed team of collaborators have instead opted to study aging in disguise, repurposing a well-characterized type 2 diabetes medication, metformin, for the application of prolonging healthy life. This study, dubbed Targeting Aging with Metformin (TAME), aims to set a precedent: with no unifying consensus on the biomarkers driving aging, metformin use in the elderly must not only extend longevity, but also must delay onset of chronic diseases like cardiovascular disease, cancer and Alzheimer’s.
Metformin was Dr. Barzilai’s “anti-aging” drug of choice to pursue for myriad reasons. The drug has been approved for type 2 diabetes treatment for over 60 years, with its adverse side effects both minor and well-known. It’s also generic, meaning it would be affordable for a wide application such as extending longevity. And most importantly, there has been demonstrable evidence linking metformin supplementation to increased lifespan in humans. In 2014, research from Cardiff University in Wales convincingly showed that nearly 80,000 type 2 diabetes patients on metformin treatment outlived over 90,000 individuals without diabetes, who were comparable in many other health aspects, by a margin of 15%. The effect of metformin in this population is particularly notable, as type 2 diabetes patients – even with efficacious treatment regimens – tend to have shorter lifespans than healthy individuals. How metformin works on a mechanistic level remains to be fully parsed out – but there is evidence linking it with a few of aging’s molecular pillars: reducing inflammation, interfering with energy production and metabolism, and altering proteostasis.
The TAME study seeks to enroll 3,000 men and women between the ages of 65-79 in 14 cities across the United States. However, pursuing metformin in this anti-aging context was not without speculation. Steve Austad, a co-investigator of the TAME study and researcher at the University of Alabama, initially supported the pursuit of rapamycin due to its promise in animal studies. Rapamycin broadly impacts the immune system, given to cancer patients as anti-tumor medication and to organ transplant recipients to minimize rejection. Mice aged the equivalent of 60-human years and fed rapamycin have shown increased lifespan by nearly 25%, but this treatment has notable side effects. Rapamycin is a potent immunosuppressive medication, meaning the effect of extended healthy lifespan could be convoluted by an increased risk of opportunistic infection. Equally of concern is its price tag: a rapamycin-derivative, Everolimus, has been shown to ameliorate efficacy of the influenza vaccine in a group over 65. Yet, it costs nearly $7000 per cancer-appropriate dose. Other compounds such as Resveratrol, the over-celebrated compound found in red wine grapes, was once linked to treating aging as its administration extended lifespan by 30% in mice. In the human context, however, it failed rigorous testing in phase II clinical trials for multiple myeloma, and was later abandoned by GlaxoSmithKline in 2008.
An aging population is not solely an American problem; by 2036, 25% of the Canadian population is expected to be 65 years old or older, up 9% from 2010. By this time, nearly three-quarters of these Canadians will have at least one chronic health condition, and health care expenditure on the elderly is expected to soar to $236 billion. The anti-aging research pursuits across the border are therefore ever-relevant for our aging population. But, if its several molecular pillars are any indication, aging in humans is a complex process involving synchronicity of various factors. Understanding metformin’s contribution to reversing this process will take many years, likely outliving the centenarians that propelled this work in the first place. A clinical trial of this nature, with loosely defined endpoints, also questions the magnitude of benefit that metformin must have in the elderly to be deemed a “successful” anti-aging treatment. As Thomas Rando, Director of the Paul F. Glenn Center for the Biology of Aging aptly puts it, “[d]o you take a drug your whole life hoping to live 4 percent longer or 7% longer?” Dr. Barzilai understands the caveats inherent to the TAME trial, but his enthusiasm for the drug has not faltered: “We’re not going to prevent every disease in the world,” he says. But we can target “this risk factor of aging that is so important, and take it [off] the table.”
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