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Peter Attia MD175 - The biology of aging, rapamycin, and other interventions that target the aging process
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At a glance
WHAT IT’S REALLY ABOUT
Matt Kaeberlein and Peter Attia on Aging Biology, Rapamycin, and Biomarkers
- Kaeberlein argues that targeting the biology of aging should extend healthy life far more than curing individual diseases, citing Jay Olshansky's estimate of about three years for curing all cancers versus roughly 20 years extrapolated from slowing aging in mice, though Attia questions the actuarial magnitude.
- Both speakers review rapalog trials (everolimus and RTB101) showing improved vaccine response and fewer respiratory infections with few side effects, and Kaeberlein suspects the failed phase 3 trial was undermined by a forced endpoint change.
- They argue that regulatory and trial-design obstacles, including the lack of validated biomarkers of aging and the cost of long trials, hinder testing of geroprotective drugs, and Kaeberlein proposes endpoints such as periodontal disease and hearing.
- Kaeberlein describes the Dog Aging Project's TRIAD trial of once-weekly rapamycin in 350 middle-aged dogs with lifespan as the primary endpoint, and explains mTORC1 versus mTORC2 and why catalytic inhibitors like Torin 2 deserve testing.
- Kaeberlein is skeptical of sirtuins and NAD precursors because lifespan effects in mice have been inconsistent and hard to replicate, compared with the robust results seen for rapamycin.
IDEAS WORTH REMEMBERING
5 ideasFunctional decline often precedes disease
Kaeberlein says functional declines across organs appear long before any age-related disease is diagnosed, and he notes he has many of them at 50 despite no diagnosed disease.
Interventions may stop working once disease pathology diverges from aging biology
Using cancer as an example, Kaeberlein notes that rapamycin can prevent cancer by inhibiting mTOR but is ineffective once a mutation makes cells ignore the mTOR brake.
Targeting aging could outweigh curing individual diseases
Kaeberlein cites Olshansky's math that curing all cancers adds about three years for a 50-year-old US woman, while slowing aging as in mice could add about 20 years; Attia thinks the actuarial approach understates the biological overlap between diseases.
Low or weekly rapamycin doses appear to have few side effects in older adults
Kaeberlein says the everolimus and RTB101 trials showed improved immune responses with minimal adverse events at low or once-weekly dosing, and he calls claims of severe side effects unsupported at those doses.
The regulatory problem is about endpoints and risk tolerance
Kaeberlein disputes that regulators would block rapamycin trials, arguing instead that the challenge is choosing quantitative functional endpoints, and he suggests that typical 65–70-year-olds are functionally impaired rather than healthy.
WORDS WORTH SAVING
5 quotesFrom the perspective of what is the best strategy to keep people healthier longer, it just doesn't matter whether aging causes disease or it creates a permissive physiological state for disease.
— Matt Kaeberlein
We have a lot of biomarkers of aging. We just don't have any validated biomarkers of aging, right?
— Matt Kaeberlein
It is a progressive, chronic decline in function that at some point will lead to overt disease and with 100% probability will lead to death, right?
— Matt Kaeberlein
mTOR is head and shoulders above sirtuins when it comes to magnitude of effect.
— Matt Kaeberlein
I mean, we don't have diddly squat in the way of meaningful biomarkers of aging.
— Peter Attia
High quality AI-generated summary created from speaker-labeled transcript.
