175 - The biology of aging, rapamycin, and other interventions that target the aging process

KEYPOINTS

• 01

  Targeting aging itself could add far more healthy years than curing diseases one by one.

  Kaeberlein, an aging biologist at the University of Washington, notes that roughly a dozen or 15 interventions now extend mouse lifespan by 15–30%. Extrapolated to humans, that is about 20 years of life expectancy, and because all functional declines slow together, those years are spent in relatively good health. He calls the disease-by-disease approach '20th-century medicine' and contrasts it with targeting the biology of aging.

• 02

  Aging is the dominant risk factor, and it can't be offset by perfect health.

  A 70-year-old with every risk marker in their favor still has a worse 10-year mortality outlook than a 20-year-old 'train wreck'. Kaeberlein and Attia agree that any 50-year-old is functionally impaired compared with themselves at 25, which is why they argue regulators shouldn't treat typical 65–70-year-olds as 'healthy' when weighing trial risk.

• 03

  Centenarians get the same diseases—just decades later.

  Citing the centenarian studies of Nir Barzilai and Tom Perls, Attia notes that centenarians don't live longer with chronic disease; they get a 20–30-year phase shift in onset. They are more likely to carry protective variants such as APOE2 rather than APOE4. Attia's clinical takeaway: the earlier prevention starts, the more you can mimic that delay.

• 04

  Rapamycin is the best-supported longevity drug, but human dosing is guesswork.

  It extends lifespan in mice even when started late in life. Kaeberlein wouldn't start it before about age 25, and admits 'we're flying blind' on dose and frequency. In their mouse study, three months of treatment between 20 and 23 months of age produced lifespan effects roughly similar to continuous treatment in the National Institute on Aging's Interventions Testing Program (ITP).

• 05

  The Novartis vaccine studies are the key human evidence.

  Joan Mannick and Lloyd Klickstein's 2014 study at Novartis gave older adults (65+) the rapalog everolimus—placebo, 0.5 mg daily, 5 mg weekly or 20 mg weekly. Low-dose arms improved response to a flu vaccine, which Attia used to infer that a moderate weekly dose is the sweet spot. Old mice show a similar problem: only about a third respond adequately to vaccines.

• 06

  The follow-up trials were promising, then the phase 3 failed.

  A phase 2 trial combining everolimus with RTB101 (a catalytic mTOR inhibitor specific to complex 1 at the doses used) reported improved vaccine response and fewer upper respiratory infections, though the everolimus-only arm missed significance. The company, resTORbio, then tested RTB101 alone in a phase 3 against respiratory illness; it missed endpoints, was stopped early, and the company merged with a CAR-T firm. Kaeberlein calls the endpoint noisy rather than proof the approach fails.

• 07

  Side-effect fears are overstated at these doses.

  Kaeberlein argues that claims of significant side effects are 'blatantly false' at the doses tested—there's no evidence of major harm from rapamycin, everolimus or RTB101 monotherapy in healthy people—though he concedes we lack long-term controlled trials, so the true risk-benefit balance remains unknown.

• 08

  Periodontal disease would be a smarter trial endpoint.

  His lab found that eight weeks of rapamycin reverses the defining features of periodontal disease in aged mice. About two-thirds of older adults have or will get periodontal disease, which is linked to dementia, cardiovascular disease and diabetes, so a short trial with a dental exam could give a cleaner signal.

• 09

  Epigenetic clocks and telomeres are not yet useful aging measures.

  Attia finds clocks easily moved by short-term interventions of doubtful biological relevance, comparing them to glucose of 110 after a bad night's sleep versus 95 after a good one. Kaeberlein explains clocks are DNA chemical marks that track chronological age; both consider telomere length unhelpful for organism-level aging.

• 10

  mTORC1 versus mTORC2 explains some side effects.

  Rapamycin binds FKBP12 and mainly inhibits mTOR complex 1; most lifespan evidence points to complex 1. Higher or chronic doses may affect complex 2, linked to glucose-intolerance effects in mice. Yet data shared by a physician prescribing rapamycin showed triglycerides falling from about 200 to 70 mg/dL and improved glucose in prediabetic patients—uncontrolled, so caution applies.

• 11

  NAD precursors remain unproven.

  NR and NMN raise NAD and sometimes show benefits in animals, but many results—including from the ITP—don't replicate, and NR and NMN camps dispute each other's bioavailability. Because supplements can be sold without trials, Kaeberlein expects no definitive human study and would be more bullish only if NR slowed aging in dogs.