Peter Attia MD359 ‒ How metabolic and immune system dysfunction drive the aging process, NAD, aging clocks, & more
CHAPTERS
- 0:00 – 4:31
Eric Verdin's path from virology to geroscience
Peter Attia asks Eric Verdin what drew him to geroscience. Verdin describes his path from medical training in Belgium and Harvard, through diabetes and virology work, to cloning the HDACs and leading the Buck Institute.
- •Verdin trained as an MD in Belgium and did his last year of medical school at Harvard
- •His postdoc on diabetes led to work on viruses, HIV and autoimmunity
- •His lab cloned the HDAC family of epigenetic regulators, which turned out to matter in aging
- •His lab now focuses on epigenetics, immunology and metabolism, and he leads the Buck Institute
- 4:31 – 8:27
Immune system and central nervous system as rate-limiting organs of aging
Verdin argues that the immune system and central nervous system limit aging because both are distributed organs. He cites mouse models in which immune-specific damage accelerates aging in the whole organism, and chronic inflammation as a further driver. Attia asks whether the endothelium belongs on the list.
- •Two organs are rate limiting for aging: the central nervous system and the immune system
- •Knocking out ERCC1 or Tfam only in the immune system induced senescence across the organism in mice
- •Chronic inflammation is both caused by aging and accelerates it
- •Verdin sees barrier function (endothelium, skin, blood-brain barrier) as a key area for longevity
- 8:27 – 17:32
Oxidative stress theory and why antioxidant trials failed
Verdin explains how electron leakage in the respiratory chain produces reactive oxygen species, and why antioxidant trials failed without disproving the theory. Reactive oxygen species also play signaling roles, and Attia notes the trials may not have verified that the agents lowered free radicals.
- •Leakage from the respiratory chain generates reactive oxygen species that rises with age
- •Antioxidant trials failed, but ROS also have protective signaling roles, as in exercise
- •Attia suggests the trials may not have tested the hypothesis, since there is no good biomarker to confirm free radicals were lowered
- •Martin Brand found that inhibiting ROS at some mitochondrial sites helped and at others did not
- •Verdin warns against dismissing whole fields, such as sirtuins and NAD, after a few negative results
- 17:32 – 29:45
Fuel utilization and glucose-targeting longevity drugs
Verdin says fuel utilization is the key aspect of metabolism in aging, ranking ketones as the cleanest fuel and glucose as the dirtiest. He points to ITP drugs that target glucose metabolism and discusses why glucose might be worse, then recounts his own ketogenic diet experience.
- •Different fuels burn with different efficiency; ketones are cleanest and glucose worst, in Verdin's view
- •Several ITP-validated drugs, including acarbose, canagliflozin and metformin, target glucose metabolism
- •Attia notes that mouse high-fat diets are often high-sugar, like donuts
- •Verdin emphasizes insulin and IGF-1 as the culprits, particularly fast-absorbing glucose
- •Verdin did not feel healthy on a ketogenic diet and found it socially isolating
- 29:45 – 33:23
GLP-1 agonists, insulin and Verdin's self-experiment
Attia asks why insulin does not rise in people on GLP-1 agonists when the drugs improve beta-cell function. Verdin describes his own tirzepatide experiment, with lower A1C and insulin and a new feeling of satiety.
- •Attia lays out the GLP-1 and beta cell logic and asks why insulin doesn't rise on the drugs
- •Verdin saw his insulin fall to five and his A1C drop to 5.0 on tirzepatide
- •He lost six or seven pounds with no loss of muscle mass while exercising
- •He describes a new feeling of fullness after about two weeks
- •Verdin presents it as self-experimentation, not an endorsement
- 33:23 – 40:48
Normal ranges, adiposity and metabolic health
Verdin and Attia argue that 'normal' ranges for glucose and blood pressure are misleading and that lower is generally better. They then discuss body fat versus metabolic health, the limits of BMI, and a biochemical BMI developed by Buck colleagues.
- •Verdin was told a fasting glucose of 96 was normal, prompting his critique of ranges
- •Attia says A1C shows a monotonic relationship with all-cause mortality in non-diabetics
- •Verdin says many health measures follow a J curve with a sweet spot
- •Overweight people can be metabolically healthy, but visceral fat is highly predictive
- •Buck colleagues Nathan Price and Lee Hood published a biochemical BMI
- 40:48 – 45:09
Immune health as a fifth horseman and why COVID hit older people
Attia explains that he should have added immune health as a fifth horseman to his Four Horsemen framework. Verdin says immunology and aging research barely interact and points to COVID mortality rising steeply with age.
- •Attia says he wishes he had added immune health as a fifth horseman in his book
- •Immunology and aging fields use terms like immunosenescence differently
- •COVID showed that infection risk was not tied to age, but outcomes were, with 84-fold excess mortality above 75
- •Influenza and RSV show the same age pattern
- •Verdin attributes mortality gaps in obese and diabetic people to immune function too
- 45:09 – 54:34
Innate and adaptive immunity, memory, and vaccine decline with age
Verdin explains the innate and adaptive immune systems and how memory T and B cells make vaccines work. He says most vaccines work poorly above 70, which leads to a discussion of COVID vaccine data and herd immunity, and of thymic involution as a cause.
- •The innate system is non-specific and has no true memory; the adaptive system uses T and B cells
- •Vaccination amplifies selective clones that persist as memory cells
- •Verdin says vaccine success falls to about 30% above age 70
- •Both speakers are unsure how this fits with COVID vaccine benefit in older people and plan to check
- •Diversity of T cells comes from the thymus, which is small and fat-replaced after about age 50
- 54:34 – 1:07:00
Growth hormone, thymic regeneration and exercise for immune aging
The conversation turns to growth hormone and thymic regeneration, including the HIV trial that inspired the Fahy trial and its reliance on an epigenetic clock readout. Attia asks for a strategy against immune decline, and Verdin points first to exercise.
- •Growth hormone has been shown to reinduce thymogenesis in HIV patients
- •Verdin questions the Fahy trial's whole-blood clock readout because blood cell composition shifts
- •Verdin worries growth hormone induces glucose intolerance when used chronically
- •Verdin says exercise is the best anti-aging intervention and improves responses to infection and vaccination
- •His lab and Mark Davis seek metabolite markers predicting poor vaccine response
- 1:07:00 – 1:16:22
Immune biomarkers and the rapalog vaccine trial
Attia contrasts the strong biomarkers of cardiovascular disease with the lack of immune biomarkers. They discuss the Mannick rapalog vaccine-response trial and its dose arms, and how improvement in immune function could be measured.
- •Attia notes cardiovascular disease has excellent measurable biomarkers while immune function does not
- •The Mannick trial showed better antibody titers and protection with a rapalog before vaccination
- •In that trial, the 5 mg weekly pulse seemed the sweet spot
- •A later trial failed for what both describe as bureaucratic reasons
- •Verdin mentions Buck startup Eovien working on novel rapalogs
- 1:16:22 – 1:27:52
Rapamycin dose and frequency, immunosuppression, and the limits of mouse models
Verdin says rapamycin is immunosuppressive by itself and that its geroprotective effect depends on dose and frequency, citing his own weekly dosing. Attia challenges him with the ITP mice, and Verdin raises doubts about mouse models and the longevity quotient, and explains why he stopped rapamycin.
- •Verdin took 4 to 6 mg once weekly and noticed a pimple after each dose, which he read as transient immunosuppression
- •Attia asks how to reconcile this with ITP mice eating rapamycin in every bite
- •Verdin worries about overreliance on mice, especially Black 6, and wants primate studies
- •Steve Austad's longevity quotient suggests humans may already be optimized while mice maximize TOR activity
- •Verdin says he would not recommend rapamycin to a 40-year-old and puts exercise first
- 1:27:52 – 1:37:40
NAD, sirtuins and the commercial hype around them
Attia poses three agreed facts about NAD and asks why supplementing it wouldn't help. Verdin says it depends why NAD falls, and both criticize commercialization and resveratrol, then Verdin covers NAD's roles, the enzymes that consume it, and why sirtuins sense NAD levels.
- •NAD is essential for redox reactions, sirtuins use it, and its levels fall with age
- •Whether supplementation helps depends on whether NAD decline is from production or consumption
- •Attia says commercial proponents have not studied NAD rigorously and calls resveratrol useless
- •NAD is used by 600+ enzymes and consumed by PARPs, sirtuins, CD38 and CD157
- •Sirtuins have a narrow range of KD for NAD, making them sensors of NAD levels
- 1:37:40 – 1:41:45
CD38 and NAD decline in aging
Verdin describes CD38 as the major driver of age-related NAD decline. CD38 knockout mice keep their NAD and live about 15% longer, and Verdin suspects other mechanisms are involved. He links senescent-cell SASP to CD38 induction in macrophages and discusses its possible immune role.
- •Eduardo Chini showed CD38 knockout mice do not lose NAD with age
- •Knockout mice show no obvious deficiency and live about 15% longer
- •Verdin doubts the longevity benefit is only due to NAD
- •SASP from senescent cells strongly induces CD38 in macrophages
- •CD38 may play a suppressive role in the immune response, which must stay balanced against autoimmunity
- 1:41:45 – 2:31:46
NMN and NR supplementation, CD38 and homocysteine
Verdin explains the nicotinamide salvage pathway and how CD38 also cleaves NMN. He says NMN can drive nicotinamide methylation, which raised his own homocysteine from about 7 to 15. He also discusses NR, doses, and concerns about SASP and tumor growth.
- •Blocking the NAMPT salvage pathway drops NAD to zero within hours
- •CD38 cleaves NMN, so high NMN can increase nicotinamide methylation and deplete the one-carbon cycle
- •Verdin's homocysteine rose from 7 to 15 on about a gram of NMN and normalized after stopping
- •NR must also pass through NMN and the same pathway; Verdin compares supplementation to pouring water into a leaking sink
- •Verdin cites concerns about SASP and tumor growth but agrees the evidence is not convincing
