#359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more | Eric Verdin, M.D.

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Eric Verdin is a physician-scientist and the CEO of the Buck Institute for Research on Aging whose career has centered on understanding how epigenetics, metabolism, and the immune system influence the aging process. In this episode, Eric traces his scientific journey from studying viruses and histone deacetylases (HDACs) to leading aging research at the Buck Institute, offering insights into how aging impairs immune and nervous system function—including thymic shrinkage, chronic inflammation, and reduced vaccine response—and how these changes impact lifespan. He explores the metabolic underpinnings of aging, such as oxidative stress and insulin and IGF-1 signaling, and he discusses practical tools like zone 2 cardio, ketogenic diets, and GLP-1 drugs. The conversation also covers declining NAD levels with age, the roles of NAD-consuming enzymes such as sirtuins and CD38, and what current NAD-boosting strategies (like NMN, NR, and IV NAD) can and can't accomplish. Eric weighs in on promising longevity interventions including rapamycin, growth hormone for thymic regeneration, and anti-inflammatory therapies, while also examining the promise and limitations of current biological age tests and the potential of combining epigenetic, proteomic, and organ-specific metrics with wearables to guide personalized longevity care.

We discuss:

• Eric's scientific journey from virology to the field of geroscience [2:45];
• How dysfunction in the immune system and central nervous system can drive aging throughout the body [5:00];
• The role of metabolism and oxidative stress in aging, and why antioxidant strategies have failed to deliver clear benefits [8:45];
• Other aspects of metabolism linked to aging: mitochondrial efficiency, fuel utilization, and glucose-modulating drugs [16:30];
• How inefficient glucose metabolism drives insulin, IGF-1 signaling, and accelerates aging [21:45];
• The metabolic effects of GLP-1 agonists, and the need to move beyond crude metrics like BMI in favor of more precise assessments of metabolic health [27:00];
• The case for immune health as a "fifth horseman" [36:00];
• How the innate and adaptive immune systems work together to build immune memory [39:45];
• Why vaccines lose effectiveness with age: shrinking of the thymus gland and diminished T-cell diversity [44:15];
• Exploring growth hormone, thymic regeneration, and the role of exercise in slowing immune aging [48:45];
• The challenges of identifying reliable biomarkers for immune function, and the potential of rapamycin analogs to enhance vaccine response in older adults [57:45];
• How rapamycin's effects on the immune system vary dramatically by dosage and frequency [1:03:30];
• The limitations of mouse models in aging research and the need for cautious interpretation of rapamycin's benefits in humans [1:08:15];
• NAD, sirtuins, and aging: scientific promise amid commercial hype [1:15:45];
• How CD38 drives age-related NAD decline, influences immune function, and may impact longevity [1:23:45];
• How NMN and NR supplementation interact with CD38 and NAD metabolism, and potential risks like homocysteine elevation and one-carbon cycle depletion [1:31:00];
• Intravenous NAD: limited evidence and serious risks [1:37:00];
• Interleukin-11 (IL-11) as a new target in immune aging, the dual role of chronic inflammation in aging, and the need for better biomarkers to guide interventions [1:43:00];
• Biological aging clocks: types of clocks, promise, major limitations, and future outlook [1:48:30];
• The potential of proteomics-based aging clocks for detecting organ-specific decline and frailty [2:00:45]; and
• More.

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