#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.

Episode Summary

Executive Summary: Peter Attia interviews Dr. Eric Verdin on the biology of aging, arguing that immune decline, metabolism, and NAD/sirtuin pathways are central drivers of longevity. They contrast promising interventions (exercise, GLP-1s, rapamycin in select contexts) with overhyped or insufficiently validated ones (universal antioxidants, many NAD supplements, current aging clocks), emphasizing nuance, biomarkers, and individualized risk-benefit decisions.

Main Topics: Immune aging as a rate-limiting determinant of lifespan (Priority: 5/5): Verdin argues that the immune system and central nervous system may be the most biologically rate-limiting organs in aging because they are distributed across the body and influence many tissues. He details thymic involution, loss of naive T cells, weaker vaccine responses, chronic inflammation, and rising infection/cancer risk with age. Metabolism, fuel choice, and oxidative stress (Priority: 5/5): The discussion centers on how mitochondrial leakage, oxygen chemistry, and insulin/IGF-1 signaling contribute to aging. Verdin favors zone 2 exercise, views ketones as relatively clean fuel, and sees glucose spikes and insulin peaks as key drivers of metabolic aging. Rapamycin, growth hormone, and geroprotective drugs (Priority: 4/5): They debate rapamycin’s dose/frequency-dependent effects, including the immune-enhancing results from older-adult vaccination trials, thymic regrowth attempts using growth hormone, and the difference between mouse data and human practicality. Both emphasize that benefits must be weighed against side effects and context. NAD, sirtuins, and CD38 (Priority: 5/5): Verdin explains NAD as a core redox cofactor and substrate for sirtuins and PARPs, but argues that simply adding NMN, NR, or IV-NAD may not solve the real issue. He highlights CD38-driven NAD depletion, recycling pathways, and concerns about homocysteine, SASP signaling, and potential tumor effects. Biologic age measurement and the limits of clocks (Priority: 4/5): The conversation critiques current epigenetic aging clocks for lacking clinical readiness and for being confounded by immune-cell composition changes. Verdin describes his lab’s Immune/Entry clock, and discusses a future of multi-omic and organ-specific proteomic clocks that may be more useful than single-number age estimates. Inflammation, IL-11/IL-1, and balancing immune modulation (Priority: 3/5): They discuss the appeal of blocking inflammatory pathways such as IL-11 or IL-1 while also cautioning that aging interventions may need to both suppress overactive inflammation and restore underactive immunity. The immune system is framed as a delicate equilibrium rather than a simple 'more or less' target.

Key Arguments: Aging is not driven by one pathway; it is pleomorphic, with immune dysfunction, metabolic inefficiency, inflammation, and tissue-specific decline interacting over time. The immune system and brain may be especially important because they are distributed systems whose dysfunction can propagate throughout the body. Chronic inflammation is both a consequence and an accelerator of aging; innate immune activation can repair damage but also create further harm when persistent. Oxidative stress is real, but blanket antioxidant supplementation failed because reactive oxygen species also serve essential signaling roles, especially during exercise. Metabolic health is better understood as fuel utilization and insulin dynamics than as body weight alone; glucose spikes and high insulin responses likely matter more than BMI. Zone 2 training is presented as a practical way to improve mitochondrial function and fat oxidation, potentially slowing metabolic decline. Ketones (especially beta-hydroxybutyrate) are described as cleaner fuels than glucose, and high-fat/low-carb models may not be equivalent to high-fat/high-sugar diets. Rapamycin may be context- and dose-dependent: immunosuppressive at transplant-level dosing but potentially geroprotective when pulsed, especially for vaccine responses in older adults. Growth hormone may help thymic regeneration and perceived well-being, but chronic use raises concerns about glucose intolerance and cancer risk. NAD biology is central, but supplementation may be limited by CD38-driven turnover and downstream consequences such as increased homocysteine or unwanted inflammatory signaling. Current aging clocks are not ready for routine clinical decision-making; better tools will likely combine methylation, proteomics, organ-specific signals, and wearables.

Data Points: Thymus size after age 50: Very small / often replaced by fat - Verdin describes thymic involution as a major contributor to reduced vaccine responsiveness in older adults. Age-associated vaccine response: ~30% success rate above age 70 - Verdin says many vaccinations work poorly in older adults because adaptive immunity declines. COVID mortality differential: 84-fold excess mortality above age 75 - Used to illustrate the steep increase in infection-related risk with aging. Anti-aging effect of rapamycin in mice: ~15% lifespan increase - Verdin references CD38 knockout longevity as comparable to rapamycin’s effect size. CD38 knockout lifespan effect: ~15% longer life - He cites published work showing preserved NAD and longer lifespan in CD38 knockout mice. Homocysteine increase on NMN: 7 to 15 - Verdin reports his own homocysteine rose while taking 1 g/day NMN. NMN dose self-experiment: 1 gram/day - He describes personal NMN use before stopping due to elevated homocysteine. Titer timing in rapalog vaccine trial: 4 weeks treatment + 6-week washout - Attia summarizes the Mannick trial design for older adults receiving rapamycin/rapalogs before vaccination. Rapalog dosing in vaccine trial: 1 mg daily; 5 mg weekly; 20 mg weekly - Doses compared in the older-adult vaccination study; 5 mg weekly was described as the sweet spot. Blood cell diversity: More than 500 cell populations - Verdin emphasizes the blood as a highly heterogeneous tissue complicating aging-clock interpretation. Immune aging study size: 1000 Immunome Project - Mentioned as a large human study used to identify vaccine-response biomarkers. Proteomics aging cohort: 40,000+ participants - Used in discussing a UK Biobank-based proteomic/organ-specific clock study. Sarcopenia / protein intake: No exact number stated - Verdin notes higher protein intake can help older adults preserve muscle mass.

Pivotal Quotes: "Aging is pleomorphic." — Dr. Eric Verdin: Verdin’s core framing that no single mechanism explains aging. "The immune system and central nervous system are the rate-limiting organs in terms of aging." — Dr. Eric Verdin: He explains why these distributed systems may determine whole-body decline. "I think lower is always better." — Peter Attia: Attia’s argument about blood pressure and glucose targets in longevity medicine, provided the patient is asymptomatic.

Implications: Listeners should think of longevity as systems biology, not supplement shopping. Exercise, glucose control, immune resilience, and selective pharmacology look more credible than one-size-fits-all anti-aging fixes, while biomarker-guided personalization remains the next frontier.