204 - Centenarians, metformin, and longevity | Nir Barzilai, M.D.

KEYPOINTS

• 01

  Genes matter more the further out you go.

  Nir Barzilai, an endocrinologist at Albert Einstein College of Medicine who studies centenarians, says twin studies put lifespan heritability low (around 20%), but for reaching 90 or 100 versus 70 or 80, genes play a much larger role. His cohort, begun in 1998, is mainly Ashkenazi Jews, chosen because a population bottleneck and isolation made their gene pool homogeneous and easier to study.

• 02

  Centenarians often carry 'bad' genes plus protective ones.

  Among roughly 15,000 variants studied, 44 centenarians carried variants that by textbook standards should have made them demented at 70 and dead at 80, including Alzheimer's and Parkinson's risk genes. Barzilai's interpretation: protective variants buffer the damage. With some 80,000 rare genotypes in the population and perhaps '50 ways' to longevity, you need very large cohorts.

• 03

  Reduced growth hormone/IGF-1 signaling is a major longevity theme.

  About 60% of his centenarians have variants that impair the GH/IGF-1 pathway (including FOXO3A-related genes); in one genotype, people reach normal height after puberty but keep low IGF-1 for life (about 12% of centenarians). Using UK Biobank data on about 440,000 people, they found high IGF-1 in younger people predicted outcomes differently, an example of how the 'right' level may depend on age.

• 04

  Growth hormone is a poor anti-aging drug.

  Barzilai and Attia agree that GH is unlikely to be geroprotective; people taking it often also take metformin and exercise, so observational benefits are confounded.

• 05

  APOE2, CETP and TSH variants show up repeatedly.

  APOE2, as allele frequency or homozygosity, is the most validated longevity genotype. CETP variants giving HDL as high as 130–140 mg/dL were an early finding. Centenarians also tend to have higher TSH (mild hypothyroid tendency), and Barzilai explains the thyroid feedback loop for listeners. Lp(a) is a counterexample: high levels in about 10% of the population cause damage that dwarfs other effects.

• 06

  Centenarians get sick later and die quickly.

  Their 'superpower' is delaying disease by roughly 20–25 years. In controls aged 60–80, only about 10% are disease-free at 80, while about 30% of centenarians past 100 have no disease and take no treatment. A centenarian might have a first heart attack at 101 and die six months later, a compression of morbidity rather than a long decline.

• 07

  Metformin has an unusual track record.

  Used since the 1950s–60s and approved in the US only around 1993, metformin in diabetics is associated with lower mortality than other drugs, and in the Diabetes Prevention Program both metformin and lifestyle prevented diabetes in roughly 30% of participants, a trial stopped early. Attia notes the healthy-user bias: compliant patients are healthier.

• 08

  TAME aims to make aging an FDA indication.

  The Targeting Aging with Metformin trial plans about 3,000–3,500 non-diabetic participants aged 65–79 across 14 US centers (about 250 each), looking at a composite of age-related diseases. Using a multi-morbidity endpoint means 20–50 times fewer people are needed than a single-disease trial (versus about 12,000), making it much cheaper; the effects in prior studies are consistently 20–30%.

• 09

  Biomarkers of aging are the goal.

  Barzilai wants tests to tell a 50-year-old whether they're biologically 40 or 60, for example to decide on screening. His group measured 5,000 proteins in 1,000 people to see what changes between 65 and 95, and TAME samples could validate such markers. Volatile metrics like fasting glucose (95 vs. 105 depending on last night's meal) are poor biomarkers.

• 10

  Metformin may blunt exercise gains.

  Attia, who stopped taking metformin, notes it's a weak mitochondrial inhibitor and that studies show blunted improvements in cardiorespiratory fitness; it may be net positive for some people but not for those who exercise a lot. Barzilai thinks most benefit appears in people recruited above about 50, and that senolytics probably shouldn't be used before 70–80.