Why Centenarians Are Defying Science: Secrets to Living 100+

Metformin's story begins with the French lilac, used historically for ailments like flu and malaria. It was later found to lower glucose in diabetics, but its true potential lies in targeting aging itself. The TAME trial is designed to prove that metformin can delay the onset of multiple age-related diseases in older adults who already show some aging signs. A key study by Charlotte Peterson showed that while metformin blunted muscle growth in exercising seniors, the muscle that remained was of higher quality—with improved autophagy and reduced inflammation—and strength was preserved. This trade-off means metformin should be paired with resistance training. The drug is not appropriate for young people because it lowers IGF-1, which is protective in youth. Dr. Barzilai emphasizes that metformin is a potent drug, not a lifestyle supplement, and should be used under medical supervision.

The UK Biobank analysis of 250,000 people clearly showed that high IGF-1 is protective in young adults but becomes a risk factor after age 50. Centenarians frequently harbor genetic variants that reduce growth hormone signaling, and women with the lowest IGF-1 live twice as long as those with the highest. In mice, an IGF-1 receptor antibody improved healthspan and extended female lifespan. The famous TRIIM trial by Greg Fahy used growth hormone to regenerate the thymus, but Dr. Barzilai points out that metformin was co-administered and likely drove the benefits; the epigenetic clock changes were confounded by new immune cells. Therefore, chronic GH therapy is not a safe longevity strategy.

Dr. Barzilai and colleagues measured 5,000 proteins in blood from participants aged 65–95. They identified proteins that originate exclusively from specific organs and used them to calculate an organ-specific biological age. The correlation between organs was about 0.8, meaning most people age uniformly, but a subset show discordant aging—e.g., a slow overall ager with a rapidly aging brain or liver. This opens the door to asking why a particular organ is aging faster (alcohol? cancer? genetics?) and targeting interventions accordingly. Together with Dan Belsky, he is leading an ARPA-funded project to find biomarkers that change with therapy, using samples from trials of metformin, GLP-1 agonists, SGLT2 inhibitors, and lifestyle interventions. The goal is to have clinically relevant tests within 18 months that can show in as little as three months whether an intervention is moving biological age in the right direction.

By studying the offspring of centenarians (who share about half the longevity genetics) and their spouses (who share environment but not longevity), Dr. Barzilai found that while centenarians had average HDL levels (45–55 mg/dL), their offspring had HDL levels as high as 140 mg/dL. Since HDL normally declines with age, this suggested that maintaining high HDL is a longevity factor. This led to the identification of functional variants in the CETP and APOC3 genes. The CETP variant increases HDL particle size and quantity, while the APOC3 variant keeps triglycerides low. Both are associated with better cognitive function and lower cancer incidence. Drug companies Merck and Ionis developed CETP and APOC3 inhibitors, respectively, originally for cardiovascular protection, but the data suggest they act as broad-spectrum aging drugs.

Dr. Barzilai's centenarian studies found that 60% have genomic alterations that inhibit the growth hormone/IGF-1 signaling pathway. Women in the lowest half of IGF-1 levels lived twice as long as those in the upper half, with better cognition and no loss of physical function. Analysis of 250,000 people in the UK Biobank revealed that high IGF-1 is protective against all diseases (except cancer) and mortality in youth, but after age 50 the association flips—high IGF-1 becomes linked to increased disease and mortality. This antagonistic pleiotropy suggests that after midlife, the body should shift energy from growth to maintenance. In mice, an IGF-1 receptor antibody extended female lifespan by 10% and dramatically improved healthspan (running, cognition). A deletion in exon 3 of the growth hormone receptor was three times more common in centenarians, and cell studies showed that during puberty the receptor was hyperactivated (making them taller), but later in life it was hypoactivated, resulting in lower IGF-1. These findings collectively argue that chronic elevation of growth hormone/IGF-1 in older adults is detrimental.

The TAME trial is designed as a secondary prevention study: it will enroll older adults (around 65) who already show some signs of aging (e.g., slow gait, prior heart attack) but are not super-healthy centenarians. Participants will be randomized to metformin or placebo, and the primary outcome is the time to occurrence of any age-related disease (cardiovascular, cancer, cognitive decline, etc.) or mortality. The trial is agnostic to which disease appears first—the hypothesis is that metformin will delay them all. This design, endorsed by the FDA, serves as a template for industry; for example, Lilly is considering a similar trial for GLP-1 agonists. Because the outcome is composite, the trial is much cheaper (a third to a quarter of the cost) than developing a drug for a single disease. Funding has been challenging—a billionaire lost his fortune, a foundation pulled back—but Dr. Barzilai remains optimistic that it will proceed.

Dr. Barzilai expressed deep concern about the widespread use of nutraceuticals for aging. He pointed out that we often don't know what's actually in the bottles, there are no large clinical trials, and combinations are completely unstudied. He referenced a JAMA study that followed 7 million people over 12 years and found that those taking multiple supplements had a 4% increase in mortality—despite the fact that supplement users also tend to exercise and eat better. He is working to convince the FDA to create a category for supplements that have been rigorously studied. In his view, FDA-approved drugs like metformin, SGLT2 inhibitors, GLP-1 agonists, and bisphosphonates have far more safety and efficacy data and should be considered long before any supplement regimen. He even extends this skepticism to vitamin D, stating that it only helps people with osteoporosis and that there is no evidence it benefits the biology of aging.