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Peter Attia MD175 - The biology of aging, rapamycin, and other interventions that target the aging process
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CHAPTERS
- 0:02 – 4:29
Defining Aging: Molecular Hallmarks vs. Functional Decline
Peter Attia asks how to define aging, and Matt Kaeberlein explains he has moved from a molecular, hallmarks-based view toward a functional one that includes frailty. The two then try to recite the hallmarks of aging.
- •Kaeberlein's training leads him to a molecular definition built on damage and the hallmarks
- •He has gained appreciation for functional definitions such as frailty
- •Social aspects of aging matter for quality of life but are not his focus
- •Attia and Kaeberlein recall eight of the nine hallmarks, forgetting epigenetic alteration until later
- 4:29 – 15:52
How Disease Relates to the Biology of Aging
Kaeberlein argues that functional declines precede overt disease and that disease pathology can eventually diverge from aging biology. He uses mTOR and cancer as an example, and Attia adds a nutrition analogy and the point that defining disease is somewhat circular.
- •Functional declines often appear long before any diagnosis
- •Once pathology stops being an extension of aging biology, an aging intervention may no longer work
- •A cancer mutation that ignores the mTOR brake makes rapamycin ineffective
- •Attia compares this to prevention versus treatment in nutrition, such as ketogenic diets for type 2 diabetes
- 15:52 – 23:39
Targeting Aging vs. Curing Individual Diseases
Kaeberlein argues it does not matter whether aging causes disease, since age is the greatest risk factor. He contrasts disease-by-disease medicine with targeting aging, citing Olshansky's math on life expectancy, and Attia pushes back on the actuarial assumptions.
- •Age is the greatest risk factor for atherosclerosis and other major diseases
- •Attia notes that PCSK9 inhibitors lower disease risk without targeting a hallmark
- •Curing all cancers adds about three years of life expectancy for a 50-year-old woman, and about seven with heart disease
- •Mouse interventions extending lifespan 15–30% would imply roughly 20 years if extrapolated to humans
- •Kaeberlein describes 21st century medicine as targeting the biology of aging
- 23:39 – 33:34
Centenarians, Longevity Genes, and Late-Life Interventions
The conversation turns to centenarian data showing a delay in disease onset rather than protection from disease. Kaeberlein explains why strong-effect longevity variants are rarely seen in humans and why mice show that interventions can work even when started late.
- •Centenarians get chronic diseases later but are not protected once they have them
- •Genetics explains roughly 25–30% of being a centenarian
- •Strong mTOR variants are likely incompatible with development, which explains their absence in humans
- •Several interventions work in old mice, and rapamycin reverses functional declines
- •Attia says he would not start rapamycin before about age 25
- 33:34 – 39:39
Rapamycin Dosing Uncertainty and Barriers to Human Trials
Kaeberlein and Attia discuss the balance of benefit and risk in choosing a rapamycin regimen, and why trials are hard in healthy people. They cite regulatory reluctance and the lack of validated biomarkers, and Attia describes his own weekly dosing.
- •Optimal treatment balances benefits against the risk of side effects
- •Self-experimenters are coalescing around weekly dosing and on/off cycles, with little data behind it
- •Regulators are reluctant to accept risk in people without disease
- •Attia says reliable biomarkers of aging are nearly nonexistent
- •Attia bases his dose largely on the 2014 everolimus study
- 39:39 – 53:54
The Everolimus Vaccine Trial and Rapamycin as an Immune Modulator
Kaeberlein describes the mouse vaccine study and the phase two everolimus trial in older adults. He explains why the transplant-era view of rapamycin as an immunosuppressant is outdated at low, intermittent doses, and how it may calm inappropriate inflammation.
- •Rapamycin restored vaccine response in old mice to youthful levels
- •In the human trial, 5 mg weekly improved vaccine response with side effects close to placebo
- •Attia notes rapamycin was previously known mainly as a transplant immunosuppressant
- •Kaeberlein says dose and aged physiology explain the different effects
- •Aging immune dysfunction involves inappropriate activation and sterile inflammation
- 53:54 – 57:09
Inflammaging and the Shared Mechanism Across Interventions
Kaeberlein and Attia say they have become more convinced of inflammation's role in aging. Kaeberlein suggests that interventions like rapamycin and possibly senolytics converge on reducing chronic inflammatory signaling.
- •Kaeberlein was once skeptical that inflammation would be a major player
- •He now thinks inflammaging is critical to functional declines
- •The interventions he is enthusiastic about all appear to reduce inflammation in mice
- •He is not sure senolytics or reprogramming differ fundamentally from rapamycin in mechanism
- 57:09 – 1:09:59
RTB101, the Failed Phase 3 Trial, and FDA Risk Tolerance
Kaeberlein recounts the second phase two trial with RTB101 and the failed phase three trial by Restorbio. He argues regulators and society need a realistic view of normal aging when judging acceptable risk, and disputes that regulators would block a rapamycin trial.
- •RTB101 is a dirtier kinase inhibitor with a longer patent life
- •The phase three trial dropped the rapalog and had its endpoint changed to patient-reported symptoms
- •Kaeberlein thinks the drug may have worked but was hurt by the endpoint change
- •He says a typical 65- or 70-year-old is functionally impaired, not healthy
- •He believes the FDA would allow a rapamycin trial with a quantitative functional endpoint
- 1:09:59 – 1:25:07
Designing Aging Trials: Periodontal Disease and Other Functional Endpoints
Kaeberlein proposes periodontal disease as a quantitative, noninvasive endpoint for a rapamycin trial in older people and describes the planned phase two. Attia asks about secondary endpoints, and they list hearing, muscle, cognition, heart function, and reproductive function.
- •TAME is a comorbidity trial, while Kaeberlein would target a functional deficit
- •Periodontal disease in mice was reversed by eight weeks of rapamycin
- •The trial idea came from Jonathan Ahn and would be an R01-sized grant
- •Possible secondary endpoints include hearing, muscle function, cognition, and heart function
- •Reproductive decline in female mice may be delayed, but magnitude is unknown
- 1:25:07 – 1:33:20
Treatment Duration and Kaeberlein's Frozen Shoulder Experience
Attia questions whether an eight-week course is long enough, and Kaeberlein weighs the added risk of longer treatment. He shares his own use of rapamycin for frozen shoulder and discusses whether rapamycin acts as a senolytic or by quieting inflammatory signaling.
- •Longer treatment raises side-effect risk, and continuous dosing might impair responses that need mTOR activity
- •Eight weeks of weekly rapamycin appears sufficient for many functional outputs, though lifespan is unknown
- •Kaeberlein used 8 mg weekly for eight weeks and recovered range of motion in a frozen shoulder
- •He thinks rapamycin turns down chronic inflammatory signaling rather than killing senescent cells
- •Attia has stopped his on/off cycling but lacks a biomarker to guide him
- 1:33:20 – 1:47:29
Biomarkers of Aging and Epigenetic Clocks
Attia voices skepticism about telomere length and epigenetic clocks, and Kaeberlein explains how epigenetic clocks work and their limits. They discuss why validated biomarkers of aging are missing and who might build them.
- •Epigenetic clocks track DNA chemical marks that correlate with chronological age
- •Most human data come from blood, which may not reflect whole-body age
- •Kaeberlein worries about high dimensionality and pattern matching in clocks and multi-omic clocks
- •There are many biomarkers of aging but none validated
- •A preclinical multi-omic and machine learning approach is feasible in mice, with Calico as a possible candidate
- 1:47:29 – 2:04:57
The Dog Aging Project and the TRIAD Rapamycin Trial
Kaeberlein explains why pet dogs are a powerful model for aging and describes the Dog Aging Project and its TRIAD rapamycin trial. They cover the design, dosing, power, endpoints, and earlier heart function results.
- •Dogs share human environment, show diverse genetics and lifespans, and age about seven times faster
- •TRIAD is powered to detect a 15% lifespan change over three years in 350 dogs
- •Dogs receive 0.15 mg/kg once weekly, chosen partly to reduce side effects and improve owner compliance
- •Secondary endpoints include echocardiograms, activity, cognition, and the microbiome
- •In the earlier safety trial, heart function improved mainly in dogs with lower baseline function
- 2:04:57 – 2:16:52
mTORC1 vs. mTORC2 and Rapamycin's Metabolic Effects
Kaeberlein explains the two mTOR complexes and how rapamycin directly inhibits only mTORC1. He covers the model that chronic mTORC2 inhibition causes glucose intolerance, and why he thinks this may reflect a metabolic shift rather than harm.
- •mTORC1 senses nutrients and regulates autophagy, translation, and metabolism
- •Rapamycin binds FKBP12 and disrupts mTORC1, with possible chronic effects on mTORC2
- •The Sabatini/Lamming model blames mTORC2 for rapamycin's glucose intolerance
- •Kaeberlein suspects it reflects a shift toward fat metabolism and ketogenesis, and is less convinced it is bad
- •Attia describes another physician seeing improved triglycerides and glucose handling in patients
- 2:16:52 – 2:29:15
Torin 2, Catalytic mTOR Inhibitors, and Mitochondrial Disease
Kaeberlein describes Torin 2 as a catalytic inhibitor that blocks both mTOR complexes, and notes it has not been tested for aging in mice. He explains his lab's Leigh syndrome mouse work, where Torin 2 rescued mice as rapamycin did.
- •Catalytic inhibitors should inhibit both mTORC1 and mTORC2, unlike allosteric rapamycin
- •Rapamycin extends survival in the Leigh syndrome mouse model
- •Proteomics pointed to mTORC2 and protein kinase C as part of rapamycin's effect
- •Torin 2 worked about as well as rapamycin in the model without visible side effects
- •Kaeberlein knows of no one developing Torin 1 or 2 for FDA approval
- 2:29:15 – 2:49:44
Sirtuins, NAD Precursors, and Whether NR and NMN Work
Kaeberlein explains sirtuins and their NAD dependence, and says the lifespan evidence for sirtuins is far weaker than for mTOR inhibition. They discuss NR and NMN, including replication problems, and Kaeberlein says he would like to test them in dogs.
- •Sirtuins are NAD-consuming deacetylases, and NAD levels shift with age and mitochondrial dysfunction
- •Kaeberlein says mTOR's effect on lifespan dwarfs the sirtuin evidence
- •NR and NMN results often fail to replicate, including in the ITP and in his own lab
- •Attia thinks NR and NMN are safe but sees little upside beyond cost
- •Kaeberlein would like to test NAD precursors in dogs since the risk is low
