171- Longevity science: caloric restriction studies, aging biomarkers & possible longevity molecules

KEYPOINTS

• 01

  Lower extrinsic danger leads to slower aging

  Austad's first aging study compared opossums on Sapelo Island, off Georgia, which has few predators, with mainland opossums. Mainland opossums, about the size of a small cat, got cataracts by around 18 months and declined fast. The island animals aged more slowly, which fits evolutionary theory: species that face less outside death evolve to age more slowly.

• 02

  The lab mouse is a strange, narrow model

  Lab mice descend from 'fancy mice' bred for odd coat colors and sizes, then inbred until every animal is genetically identical at every locus. Austad compares this to testing drugs on the same set of twins over and over, out of about 4,500 mammal species. That's why he values the Interventions Testing Program (ITP), which uses genetically heterogeneous mice at three sites.

• 03

  Calorie restriction works in lab rodents, but the effect is weaker in wild mice

  The finding dates to rat work in the 1930s, whose author never seemed to grasp its importance and later moved into high-protein bread for the military. Austad brought wild-caught mice into the lab and restricted them to 70% of normal intake. For most of their lives there was no benefit. Only the last ~20% of survivors lived longer, so he expects the effect to be much smaller than in obese, sedentary lab strains.

• 04

  The two monkey studies disagreed partly because of sugar

  The Wisconsin study used a purified diet that was about 28–29% sucrose. The NIA (Bethesda) study used natural ingredients with about 3% sucrose. Wisconsin restriction extended life compared with controls, but the NIA study's controls were healthier to start with, and restriction added little. Austad likens Wisconsin to 'three Big Macs, two monster fries and two jumbo Cokes a day' versus 70% of that: eating less toxic food will look good. He suspects the restricted Wisconsin monkeys had more diabetes than the NIA controls.

• 05

  Captive animals, including us, are obese compared with wild relatives

  Both captive monkeys and modern humans differ from their wild counterparts. Austad's conclusion is that nutrition and aging questions ultimately have to be studied in humans.

• 06

  Human calorie restriction is very hard to sustain

  The CALERIE trial aimed for about 25% restriction, but people managing their own food reached only about 11–12% over two years. Austad says only about 30% of Calorie Restriction Society members truly sustain it, with BMIs around 17–20. Those trials were also in people in their late 30s, and what's good for them may not suit people in their 60s.

• 07

  Time-restricted eating and fasting may matter more than total calories

  Mouse work suggests that going many hours a day without food may account for as much of the benefit as eating less. A short fast of two or three days before surgery sped recovery in mice in the late Jim Mitchell's work, including after an ischemia-reperfusion injury. Peter and Austad also discuss 16-hour eating windows and the five-day fasting-mimicking diet of about 750 calories a day.

• 08

  Women outlive men at every age, except when it comes to Alzheimer's

  Women survive better as infants and in their 20s, 30s and 40s, and die at lower age-adjusted rates of every major cause except Alzheimer's disease. Austad offers a 'private hypothesis' that Alzheimer's will turn out to have an autoimmune component, since women are more prone to autoimmune disease.

• 09

  Sex differences in ITP drug results may reflect dosing

  Rapamycin favors females at low doses, a gap that shrinks as the dose rises. 17-alpha-estradiol, acarbose and canagliflozin mostly help males. Austad suspects higher blood levels in females may mean they're effectively overdosed. Peter notes that the canagliflozin and acarbose results point to glucose dynamics rather than eating less.

• 10

  Validated aging biomarkers are the biggest missing tool

  The NIA put about $100 million into aging biomarkers in the 1990s without success. Austad wants markers that answer in weeks or months, across ages, so that healthy people can learn how to stay healthy without decades-long trials.