#357 ‒ A new era of longevity science: models of aging, human trials of rapamycin, biological clocks, promising compounds, and lifestyle interventions | Brian Kennedy, Ph.D.

Episode Summary

Executive Summary: Peter Attia and Brian Kennedy explore the state of longevity science, arguing that aging is better understood as a loss of resilience/homeostasis than a single broken pathway. They discuss rapamycin, mTOR, inflammation, biomarker limitations, and promising compounds like AKG, urolithin A, NAD boosters, and spermidine, while emphasizing that current interventions mostly improve healthspan and “square the curve” rather than prove lifespan escape velocity.

Main Topics: How the longevity field changed after 2017 (Priority: 5/5): Kennedy explains that interest and funding surged around 2017-2018 due to Calico, Silicon Valley attention, and a broader shift toward healthspan rather than disease-specific aging targets. Aging as resilience loss, not isolated hallmarks (Priority: 5/5): He argues the hallmarks/pillars of aging are useful descriptors but not the core explanation; aging is better modeled as declining homeostasis and resilience, with damage accumulating linearly and mortality rising exponentially. mTOR, rapamycin, and inflammatory feed-forward loops (Priority: 5/5): Kennedy frames mTOR as central to nutrient sensing, inflammation, and aging, and says rapamycin remains the strongest small-molecule candidate for geroprotection, though likely with modest human effects and timing-sensitive dosing. Why aging biomarkers and clocks still fall short (Priority: 4/5): He critiques commercial epigenetic clocks for poor reproducibility and argues clinical chemistry-based clocks may be more actionable and more useful to clinicians because they map to modifiable risk factors. Promising interventions: AKG, urolithin A, NAD, spermidine (Priority: 4/5): The conversation reviews early evidence for alpha-ketoglutarate, urolithin A, sublingual NAD, and spermidine, with Kennedy emphasizing cautious optimism, animal data, and the need for rigorous human trials. Exercise, GLP-1s, SGLT2s, and the importance of lean mass (Priority: 4/5): Both speakers stress VO2 max, strength, and muscle mass as major health predictors, while debating whether metabolic drugs like GLP-1 agonists and SGLT2 inhibitors can aid healthy people without compromising lean tissue. AI, clinics, and the next phase of translational longevity science (Priority: 3/5): Kennedy says AI is already helping analyze data and may soon suggest better questions, while longevity clinics should collaborate with academia to generate real-world safety and efficacy data instead of operating in isolation.

Key Arguments: The field of aging research accelerated because attention, capital, and philanthropy finally converged around the idea that slowing aging could prevent multiple diseases at once. Hallmarks of aging are informative but misleading if treated as independent targets; aging is network-level loss of dynamic balance and resilience. Aging likely involves a roughly linear accumulation of subtle damage or stochastic change, but mortality rises exponentially because the chance of falling into a failure state increases over time. Inflammation appears repeatedly as a central axis across aging models and may be both a driver and a readout of aging rather than a mere endpoint. Rapamycin is still the leading small-molecule geroprotective candidate, but the most likely human effect is improved healthspan rather than major lifespan extension. Many biomarkers are noisy or poorly standardized; clinical chemistry panels may offer a better, more actionable “clock” than commercial methylation tests. Exercise, sleep, and nutrition likely improve the oscillating, second component of aging risk, but probably do not fully change the underlying slope of decline. AKG, urolithin A, spermidine, and NAD-related products are promising because they may improve metabolic flexibility, mitochondrial turnover, or frailty, but the evidence is still early. Combining interventions may work better than single agents, but blindly stacking many compounds is risky because effects can cancel out or produce unknown interactions. The biggest near-term win may be “squaring the curve” by improving the final decade of life, even if maximal lifespan is not dramatically extended.

Data Points: Buck Institute faculty size: About 20 faculty - Kennedy described the institute when he became CEO in 2010. Time period of renewed longevity interest: Around 2017-2018 - He tied the field’s inflection point to Calico publicity, Silicon Valley interest, and healthspan framing. Companies started at Buck: 7 companies - Kennedy said the institute launched several ventures during his tenure. Yeast genes screened: About 5,000 genes - In the yeast deletion screen related to lifespan extension. Lifespan-extending yeast genes found: About 300 genes - Genes whose deletion made yeast live longer. Rapamycin human study sample size: About 150 to 200 subjects - Singapore trial of intermittent rapamycin in adults 40 to 60. Rapamycin dose: 5 mg once weekly - Protocol for the six-month Singapore study. Rapamycin study duration: 6 months - Planned human intervention period. AKG trial duration: 6 months with 3-month follow-up - Time-release alpha-ketoglutarate study in humans. Estimated cost of a study: About 1.5 million Singapore dollars - Kennedy estimated the cost for the kind of human trial discussed. Annual research spend: About $4 million per year - Kennedy’s combined animal and human research budget. NHANES follow-up window: 200 months - Used to model mortality prediction from clinical chemistry and methylation data. Clinical chemistry clock size: About 50 parameters - Kennedy said the clock uses standard lab markers, many already routinely measured. Biologic age impact example: 4 years - A principal component example increased biologic age by 4 years, equated to about a 50% mortality risk increase. Precondition under-treatment rate at age 65: About 20% - He said roughly one in five people had actionable abnormalities but were untreated. AKG lifespan effect in mice: About 5% to 10% - Mouse lifespan increase observed with AKG.

Pivotal Quotes: "“It’s really about your body knows how to function in a healthy way, it’s about trying to maintain that and maybe improve upon it.”" — Brian Kennedy: His core framing of aging as preserved homeostasis/resilience rather than isolated hallmarks. "“The only way to really slow aging is to keep the hill higher.”" — Brian Kennedy: His mountain-valley model explaining why declining resilience increases failure states with age. "“If anybody tells you they have the answers to that, they’re lying to you or they’re lying to themselves.”" — Brian Kennedy: On claims that science can already reverse or stop aging.

Implications: For listeners, the practical takeaway is to prioritize exercise, muscle, metabolic health, and evidence-based interventions while treating anti-aging claims skeptically. For the field, the next leap likely comes from better clocks, combination studies, and rigorous human trials.