333 ‒ Longevity roundtable—the science of aging, geroprotective molecules, & lifestyle interventions

KEYPOINTS

• 01

  Healthspan and lifespan aren't a seesaw when you target aging itself.

  Miller, who runs the NIA's Interventions Testing Program (ITP), says every drug that extends mouse lifespan does so by delaying both fatal and non-fatal diseases, much like exercise or avoiding insulin resistance. Austad counters that in humans the gap between healthspan and lifespan is widening fastest in the US and in women, because medicine keeps sick people alive longer. Kaeberlein reconciles the two: slowing aging moves both together, while disease-by-disease care stretches the sick years.

• 02

  US life expectancy lags because of deaths in middle age, not old age.

  Attia notes the US spends about 80% more than peer countries yet ranks lowest among OECD nations. That's because of maternal and infant deaths, overdoses, guns and suicide. Past about 65, Americans jump to the top, reflecting 'medicine 2.0' extending life with chronic disease. With 60% of Americans having a chronic disease, many spend decades in 'sickspan.'

• 03

  Aging research gets a sliver of funding despite driving nearly every leading killer.

  Nine of the top 10 US causes of death have aging as their biggest risk factor. Yet biology-of-aging research gets about 0.5% of the NIH budget (about $350 million). Disease lobbies guard their turf: when NIA council members floated diverting a few percent of Alzheimer's money, appropriations staff called the next day. Miller's talks showing anti-aging drugs cut age-adjusted cancer in mice tenfold draw no follow-up from cancer centres.

• 04

  Calling aging a disease is the wrong framing.

  Miller calls it a 'fundamental error' because aging is a risk factor for diseases. Austad says the label is a marketing ploy for funding. Kaeberlein says the FDA doesn't require it—Austad's TAME team got metformin trial interest by framing the endpoint as multimorbidity. Austad estimates privately funded aging research now outspends public money at least 2:1.

• 05

  Consumer epigenetic age tests aren't reliable.

  Kaeberlein sent duplicate samples from one day to four companies. At age 53.7, results ranged from 42 to 63; one company's duplicates were 20 years apart. Biological aging is real—dogs age about seven times faster, and single genes like daf-2 shift the rate—but Miller and Attia say no single number beats a rich clinical picture. Life insurers don't use the tests.

• 06

  The 'hallmarks of aging' both helped and harmed the field.

  Miller says the list became 'biblically sacrosanct,' letting grant writers skip proving causation and starving ideas off the list. Kaeberlein agrees it narrowed the field prematurely—we may understand 'about 0.005%' of aging—but says it gave the field mechanistic credibility. Austad notes reviewers punish 'fishing expeditions' and breakthrough ideas.

• 07

  Speed-type aging-rate indicators could make human trials feasible.

  Biomarkers are like an odometer and change only by old age. Miller's lab found about 12 markers that shift early in every slow-aging mouse model, across drugs, caloric restriction and five gene mutants. Examples include fat macrophage shifts, UCP1, and the enzyme GPLD1, which exercise also raises and which boosts neurogenesis in mice. A new grant tests whether they stay unchanged with ineffective drugs. Austad warns that mouse findings may not carry over to humans.

• 08

  Senescent cells are hotly disputed.

  Miller argues the concept grew from Hayflick taking a lunchtime joke seriously, and that 'senescent cell' and 'SASP' lump unrelated phenomena together. The ITP found fisetin had no lifespan effect and no change on six senescence markers. His group went 0 for 7 replicating senescent-cell clearance in the Mayo genetic model. Austad and Kaeberlein point to evidence that clearing p16-positive cells improves health, and to NIH's roughly $600 million senescence network.

• 09

  Rapamycin works as cancer prevention even where it fails as chemotherapy.

  Kaeberlein: established tumours evolve around the mTOR brake, so disease-stage biology differs from aging biology. ITP rapamycin is mixed into food daily. Weekly human dosing of about 3–10 mg traces to Joan Mannick's everolimus vaccine trials, where 5 mg weekly worked best. The idea that side effects come from mTORC2 is less proven than assumed. Partridge's lab found a MEK/ERK inhibitor adds to rapamycin through a separate pathway.