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Brian Kennedy is a renowned biologist, leader in aging research, and director of the Center for Healthy Longevity at the National University of Singapore. In this episode, Brian shares insights from ongoing human aging studies, including clinical trials of rapamycin and how dosing strategies, timing, and exercise may influence outcomes. He presents two key models of aging—one as a linear accumulation of biological decline and the other as an exponential rise in mortality risk—and explains why traditional models of aging fall short. He also explains why most current aging biomarkers lack clinical utility and describes how his team is working to develop a more actionable biological clock. Additional topics include the potential of compounds like alpha-ketoglutarate, urolithin A, and NAD boosters, along with how lifestyle interventions—such as VO2 max training, strength building, and the use of GLP-1 and SGLT2 drugs—may contribute to longer, healthier lives.

We discuss:

• Brian’s journey from the Buck Institute to Singapore, and the global evolution of aging research [2:45];

• Rethinking the biology of aging: why models like the hallmarks of aging fall short [9:45];

• How inflammation and mTOR signaling may play a central, causal role in aging [14:15];

• The biological role of mTOR in aging, and the potential of rapamycin to slow aging and enhance immune resilience [17:30];

• Aging as a linear decline in resilience overlaid with non-linear health fluctuations [22:30];

• Speculating on the future of longevity: slowing biological aging through noise reduction and reprogramming [33:30];

• Evaluating the role of the epigenome in aging, and the limits of methylation clocks [39:00];

• Balancing the quest for immortality with the urgent need to improve late-life healthspan [43:00];

• Comparing the big 4 chronic diseases: which are the most inevitable and modifiable? [47:15];

• Exploring potential benefits of rapamycin: how Brian is testing this and other interventions in humans [51:45];

• Testing alpha-ketoglutarate (AKG) for healthspan benefits in aging [1:01:45];

• Exploring urolithin A’s potential to enhance mitochondrial health, reduce frailty, and slow aging [1:05:30];