The Fifth Horseman: How Metabolism and Immunity Drive Aging
Peter Attia and Buck Institute president Eric Verdin argue that two distributed systems — the immune system and the central nervous system — may be the rate-limiting organs of aging, and that metabolism matters mostly through which fuel you burn and how sharply insulin spikes. They walk through NAD biology, the CD38 leak, the real risks of NMN and NR supplementation, rapamycin dose versus frequency, and why today's aging clocks remain research tools rather than personal dashboards.
Overview
This long-form conversation pairs Peter Attia with immunologist and Buck Institute president Eric Verdin, whose lab moved from virology and epigenetics into aging biology. Verdin makes the case that the immune system and the central nervous system are rate-limiting for aging because both are distributed throughout the body — damage in either propagates everywhere. On metabolism, he argues the central variable is fuel utilization: ketones appear to burn cleanest, fatty acids next, glucose dirtiest, largely because of the insulin response that fast-absorbing carbohydrate provokes.
Both men push back on the culture of 'normal ranges,' noting that for average blood glucose and blood pressure, lower is generally better within physiological limits. Verdin shares his own self-experimentation with a GLP-1 agonist — dropping A1C from around 5.5 to 5.0 with no loss of muscle mass — and his decision to stop rapamycin after seeing no measurable change. The immune half of the conversation covers innate versus adaptive defence, why vaccination efficacy falls sharply after 70, thymic involution, and the growth hormone experiments meant to reverse it.
The NAD segment is unusually candid: NAD declines with age largely because CD38 consumption rises, and simply pouring in NMN or NR may accelerate the leak, raise homocysteine and feed inflammatory signalling. The episode closes on aging clocks — why they disagree with each other, why blood composition confounds them, and why organ-specific proteomic clocks may be the more interesting next chapter.
Key quotes
5There are two organs that are rate limiting in terms of your aging, and it's the central nervous system and the immune system.
I'm convinced that it is fuel utilization. Ketones are probably the cleanest fuel to burn.
I really should have added a fifth horseman, and that is immune health.
Today we have one intervention that is very profoundly anti-aging, and it is physical activity in all of its forms.
They are not ready for prime time in terms of patient management. They are research tools.
Key ideas
9Distributed organs set the pace of aging
The immune system and the central nervous system reach every tissue, so decline in either radiates outward. Animal work shows that damaging only the immune compartment can drive senescence across the whole organism.
A hierarchy of fuels
Beta-hydroxybutyrate appears to burn cleanest, then fatty acids, with glucose the dirtiest — partly because glucose also generates energy in the cytoplasm and partly because fast-absorbing carbohydrate provokes insulin. Longevity-relevant drugs from screening programmes cluster around glucose metabolism from completely different angles.
The peaks matter more than the average
Average glucose measured by A1C predicts complications, but the intensity of glucose and insulin spikes may matter more. Continuous glucose monitoring is framed as a learning tool for discovering which foods spike you personally.
'Normal range' is not the same as optimal
In people without diabetes, lower average glucose tracks with lower all-cause mortality without an obvious floor, and blood pressure targets keep being revised downward. Both speakers argue that reference ranges built for disease detection get misread as targets for health.
Why vaccination fades with age
The adaptive immune system depends on naive T cells produced by the thymus, which is largely replaced by fat after midlife. Response rates to vaccination drop steeply after 70, which reframes infection as a genuine longevity issue rather than a footnote.
Rapamycin: the dose and the schedule are the whole story
Continuous higher dosing is immunosuppressive; weekly pulses are the pattern adopted to preserve immune benefit while limiting side effects. A landmark trial in older adults found a weekly pulse improved vaccine response — the opposite of what an immunosuppressant should do.
NAD falls because consumption rises
The enzyme CD38 climbs with age across tissues and cleaves NAD; in animals lacking it, NAD simply does not decline and lifespan extends meaningfully. The salvage pathway recycles NAD so aggressively that blocking it collapses cellular NAD within hours.
Pouring more into a leaking sink
Because CD38 also cleaves NMN, supplementing precursors can accelerate turnover rather than fix the deficit — Verdin's own homocysteine rose from around seven to fifteen on a gram of NMN daily, and normalised months after stopping. He also flags that NAD levels feed the inflammatory secretions of senescent cells.
Clocks measure the blood, not necessarily you
Blood is a shifting mixture of hundreds of cell populations with epigenetic ages differing by two decades, so a change in cell proportions can masquerade as rejuvenation or accelerated aging. Clocks built to strip out those differentiation signals stop reacting to infection — and organ-specific proteomic clocks may prove more clinically useful.
Practical takeaways
7- 1
Treat movement as the foundation, not a supplement 36:00
Both speakers agree the strongest evidence for slowing aging still sits with regular physical activity in all its forms. Optimise that before layering on anything more exotic.
- 2
Train the mitochondria you want to keep 38:00
Steady lower-intensity aerobic work is the classic way to maximise fat oxidation and, by hypothesis, mitochondrial health. It is framed as a plausible mechanism, not a proven one.
- 3
Flatten your spikes rather than eliminating carbohydrate 50:00
Verdin is explicitly not a proponent of very low carbohydrate diets, calling long ketogenic stints impractical and socially isolating. The goal he describes is smoothing the peaks, not removing a macronutrient.
- 4
Body fat percentage and visceral fat beat BMI 1:10:00
BMI serves populations, not individuals — Verdin sits at the overweight border with 11 percent body fat. Visceral fat and glucose tolerance carry the real signal.
- 5
If you use NAD precursors, watch homocysteine 2:18:00
The methylation route for excess nicotinamide can draw on the one-carbon cycle, and this showed up as a measurable rise in Verdin's own bloodwork. Any experimentation is worth pairing with tracking rather than assumption.
- 6
Be sceptical of intravenous NAD 3:16:00
NAD barely exists in plasma and is largely cleaved by the liver into nicotinamide, a cheap and widely available compound. The expensive infusion has little mechanistic case behind it.
- 7
Run from a test that sells you its own cure 3:42:00
Both speakers warn about companies selling an unvalidated marker and, in the same breath, the supplement to fix it. Order a test only when you already know how the result would change what you do.
Topics & chapters
15Opening and the path into aging biology
The themes are previewed — immune health as a missing chronic risk, fuel quality and the NAD puzzle — before Verdin traces his route from medical school in Belgium to Harvard, diabetes research, HIV virology and the epigenetic regulators that turned his lab towards aging.
The two rate-limiting organs
Why the immune system and central nervous system may govern the pace of aging, and where the endothelium and barrier function fit into that picture.
Oxidative stress revisited
Electron leakage in the respiratory chain, why blanket antioxidants failed in trials, and the site-specific inhibitor work that was abandoned too early.
Fuel utilisation and the cleanliness hierarchy
Ketones, fatty acids, lactate and glucose compared as substrates, and why longevity-relevant compounds keep converging on glucose metabolism.
Insulin, spikes and GLP-1
The role of insulin as the culprit variable, endogenous versus exogenous GLP-1, and the open question of what happens to postprandial insulin on these drugs.
Ranges versus optimal values
Verdin's self-experiment results, the argument that lower average glucose and blood pressure are generally better, and the J-curve caveat.
Body fat, visceral fat and metabolic health
Why BMI misleads at the individual level, whether metabolically healthy excess weight holds up over decades, and biochemical alternatives to BMI.
Immune health as a chronic risk
Attia's fifth horseman, the mortality gap seen with respiratory infections in older adults, and why immunology and aging research barely speak the same language.
Innate, adaptive and immune memory
How the two lines of defence work, how memory cells form after infection or vaccination, and why that machinery weakens with age.
The thymus, growth hormone and regeneration
Thymic involution after midlife, attempts to restore naive T cells, and the reasons Verdin remains cautious about growth hormone as a longevity tool.
Rapamycin: dose, frequency and the mouse problem
Why weekly pulses differ from daily immunosuppressive dosing, the vaccine-response trial in older adults, and the limits of extrapolating from laboratory mice.
Sirtuins, NAD and the CD38 leak
What NAD does across hundreds of enzymes, why sirtuins act as NAD sensors, and the evidence that CD38 drives the age-related decline.
NMN, NR and the limits of supplementation
How precursors feed the same turnover, the homocysteine signal Verdin saw in himself, and the open questions around senescent-cell signalling and tumour biology.
IL-11, inflammaging and the balance problem
Blocking an inflammatory signal extended life in mice, but the immune system is a balancing act between too little and too much response.
Aging clocks and what comes next
Why clocks disagree, how blood composition confounds them, the appeal of pace-of-aging measures, and the move towards proteomic and organ-specific clocks.