In Dr. Nir Barzilai’s lectures, a woman makes sporadic appearances. Even though she is no longer living, she continues to appear because her story is truly hard to describe. She was one of his first centenarians, living in her own apartment at the age of 100 and continuing to smoke after 95 years of nonstop smoking. She gave a clear response when asked if anyone had ever advised her to quit smoking: all four of the doctors who had advised her to do so had since passed away. She started smoking again. She lived to be 110 years old. For his part, Barzilai has consistently insisted that she most likely would have gone even farther without the cigarettes. He doesn’t know. But the point he keeps bringing up is that it didn’t matter to her. She was involved in something else.
As the director of Albert Einstein College of Medicine’s Institute for Aging Research, Barzilai has spent decades searching for that something else. In order to determine what distinguishes those who live to be 100 years old in good health from those who do not, he and his team have studied centenarians—not all of them, but a well-documented cohort of exceptional long-livers. The findings have challenged the presumptions that underpin the whole wellness sector in a number of ways.
| Topic | Centenarian Research and the Biology of Exceptional Longevity |
|---|---|
| Key Researcher 1 | Dr. Nir Barzilai — Director, Institute for Aging Research, Albert Einstein College of Medicine; author of Age Later |
| Key Researcher 2 | Dr. Sofiya Milman — Director of Human Longevity Studies, Albert Einstein College of Medicine |
| Milman’s Study Goal | Recruiting 10,000 people age 95+ and their relatives to identify genetic factors driving longevity |
| Barzilai’s Core Finding | 60% of male centenarians smoked; nearly 50% were overweight; fewer than 50% exercised moderately; only 2% were vegetarian |
| Key Genetic Finding | 60% of centenarians had genomic variants inhibiting the growth hormone/IGF-1 signaling pathway |
| HDL Cholesterol Discovery | Centenarians’ offspring had twice average HDL levels — led to discovery of two genetic variants now being developed as drugs |
| Compression of Morbidity | 30% of centenarians had zero diagnosed disease; most were sick for only months, not years, before death |
| IGF-1 Paradox | High IGF-1 is protective when young; after age 50, the same levels correlate with disease and mortality |
| Supplement Warning | JAMA study of 7 million people over 12 years found 4% increased mortality in multi-supplement users |
| Four Drugs Targeting All Hallmarks of Aging | Metformin, SGLT2 inhibitors, GLP-1 agonists, bisphosphonates |
| TAME Trial | Targeting Aging with Metformin — proving a single drug can prevent multiple age-related diseases simultaneously |
| Reference Links | Business Insider – Doctor Who Studies Super-Agers Shares Longevity Secrets / USC Leonard Davis School – Valter Longo Longevity Diet Study |
Just the lifestyle data is shocking. Sixty percent of his male centenarians smoked. Almost 50% were obese or overweight. Less than half engaged in even moderate exercise. The percentage of vegetarians was only 2%. These figures are remarkably similar to the overall population of their time. Barzilai has repeatedly and unequivocally concluded that there is no lifestyle characteristic that can be identified as the action taken by centenarians to reach that point. They consumed cake. They consumed alcohol. A few of them hardly moved at all. They also lived to be 100 years of age or older, frequently in better health at 95 than people half their age.
It is not implied that lifestyle is unimportant. For the 99.9% of us who did not inherit the genetic architecture that those centenarians seem to possess, it is extremely important. Lifestyle is undeniable for nearly everyone, according to Dr. Sofiya Milman, who oversees a companion study at the same institution that aims to recruit 10,000 individuals 95 years of age and older along with their relatives. However, regardless of what they eat or whether they have ever worn running shoes, something biological is doing the heavy lifting for a certain group of people.
Barzilai has discovered that the growth hormone and IGF-1 signaling pathway is the most reliable genetic signal. It is the most common biological abnormality in his cohort, with about 60% of his centenarians having some genomic variant that inhibits this pathway. However, “abnormality” seems like the wrong word when the result is outliving almost everyone you know by three decades. The IGF-1 image defies logic. When you’re young, having high levels of insulin-like growth factor-1 is protective, linked to better health outcomes and a lower risk of disease. The relationship starts to change around age 50. Later on, increased disease and mortality are linked to the same elevated IGF-1 that promoted growth and resilience in previous decades. This change seemed to help the centenarians who had genetically low IGF-1 throughout their long lives because their bodies were now focusing on maintenance rather than growth. In the centenarian cohort, women with the lowest IGF-1 levels lived twice as long as those with the highest levels, and they had better cognitive function and no discernible negative effects from physical activity.
The story of HDL cholesterol is just as interesting. The HDL of the general population was about twice that of the offspring of centenarians, who inherited about half of their parents’ potential for longevity. A few had HDL values of 140. Barzilai’s discovery ultimately led to the discovery of two genetic variations that are currently being actively developed as medications by Merck and Ionis, not specifically for longevity but for cardiovascular protection. The evidence also suggests broader effects on cancer rates and cognitive function.
A JAMA study that tracked seven million people over a 12-year period revealed that multi-supplement users had a 4% higher mortality rate than non-users, which may be the finding that most unnerves the supplement industry. Additionally, the supplement users in that cohort tended to eat better and exercise more. The signal was not subtle, but it was unwanted. Barzilai takes a measured but firm stance on this, arguing that people should consider FDA-approved medications where safety profiles, dosage, and interaction data are genuinely available before considering any supplement. He identifies four medications—metformin, SGLT2 inhibitors, GLP-1 agonists, and bisphosphonates—that he feels satisfy the strict criteria of addressing all the primary biological signs of aging. According to his definition, supplements are chemicals in bottles that lack the clinical trial infrastructure necessary to determine whether or not they are truly fulfilling the claims made on the label.
With all of this research, it seems like longevity science is in the midst of a truly challenging transition. The popular interpretation of living to 100—eating the right foods, taking the right supplements, and getting as much sleep as possible—turns out to be very different from what the data on real centenarians reveals. It seems that exceptional longevity is largely a biological trait that some people possess and that the rest of us can only approximate through wise, consistent lifestyle choices and, increasingly, targeted pharmacology. A daily stack of supplements is a more satisfying story than that. But that’s what the evidence points to.
