359 ‒ How metabolic and immune system dysfunction drive the aging process, NAD, aging clocks, & more

Verdin explains that NAD levels decline with age largely due to increased CD38 activity. Supplementing with NMN or NR attempts to boost NAD, but if CD38 is high, NMN is cleaved, leading to accumulation of nicotinamide. This nicotinamide is either salvaged back to NAD or methylated for excretion. The methylation pathway consumes methyl groups from the one-carbon cycle, potentially raising homocysteine. Verdin personally experienced a rise from 7 to 15 on 1 g NMN daily. He suggests that if one still wants to try precursors, a lower combined dose of NMN and NR (250 mg each) may be safer, and homocysteine should be monitored. He also notes that some people take TMG (trimethylglycine) to counteract this, but he did not try it. He emphasizes that the entire field is still uncertain, and that inhibiting CD38 directly might be a better strategy.

Verdin explains that both the immune system and CNS are distributed throughout the body, so their dysfunction can affect every organ. He cites mouse studies where inducing a DNA repair defect (ERCC1) or mitochondrial dysfunction specifically in the bone marrow (thus the immune system) caused accelerated aging and senescence in all organs. This suggests immune decline is not just a consequence of aging but a driver. He also notes that chronic inflammation, a hallmark of aging, is both caused by and further accelerates aging, creating a vicious cycle. The COVID-19 pandemic starkly illustrated the consequences: an 84-fold excess mortality in those over 75, driven by immune aging. Verdin argues that immunology and aging research have been siloed, and that bridging them is essential for developing interventions.

Verdin describes work by Eduardo Chini showing that CD38, a membrane-bound NAD hydrolase, is the main driver of NAD loss during aging. In CD38 knockout mice, NAD levels do not drop with age, and they live about 15% longer—comparable to rapamycin. CD38 is upregulated in immune cells by the SASP (senescence-associated secretory phenotype), linking cellular senescence to NAD depletion. However, Verdin suspects the longevity benefit may not be solely due to preserved NAD, because CD38 also generates signaling molecules like cyclic ADP-ribose that affect calcium signaling. He cautions that simply supplementing NAD precursors (NMN, NR) may be counterproductive if CD38 is high, because it will cleave NMN, leading to increased nicotinamide and methylation stress (elevated homocysteine). His lab is actively studying CD38's role in immune and endothelial cells.

Verdin decided to try tirzepatide out of curiosity about its effects beyond weight loss. He was not aiming to lose weight but wanted to see metabolic changes. After a few weeks, his A1C dropped from 5.4-5.5 to 5.0, and his fasting insulin fell to 5.0, which he notes is the lowest possible. This was surprising because GLP-1 agonists work by enhancing glucose-stimulated insulin secretion; he expected insulin to rise. He also experienced a profound new sensation of satiety—for the first time in his life, he felt full and stopped eating. He lost 6-7 pounds without losing muscle mass, which he attributes to continued exercise. He emphasizes this is self-experimentation, not an endorsement, but he finds the drug remarkable and believes GLP-1 agonists will emerge as geroprotectors.

Verdin took rapamycin at 4-6 mg once weekly. He noticed that every time he took a dose, the next morning he would get a pimple on his nose, which he interprets as a sign of transient immunosuppression (similar to what happens after intense exercise). He never felt any metabolic or physical benefit, unlike with the GLP-1 agonist where all numbers improved. He stopped because he couldn't tell if it was doing anything. He raises a deeper concern: mice are an outlier in longevity quotient—they live shorter than expected for their size, while humans live much longer. He suspects mice may have high basal mTOR activity to support rapid reproduction and growth, making them more responsive to mTOR inhibition. Humans, already long-lived, may have lower mTOR activity, so rapamycin might not yield the same benefits and could even be detrimental. He advises against rapamycin for young people and suggests it might only be considered for older individuals with chronic inflammation, but even then with caution.

Verdin argues that metabolism's role in aging is largely about fuel utilization. He describes the electron transport chain as leaky, producing reactive oxygen species. He believes ketones (beta-hydroxybutyrate) burn cleanest, producing the least oxidative stress. Fatty acids are intermediate, and glucose is the dirtiest, partly because it generates ATP in the cytoplasm via glycolysis, which may produce more free radicals, and because it elicits insulin secretion. He notes that the ITP (Interventions Testing Program) has identified several lifespan-extending drugs that target glucose metabolism: acarbose (blocks glucose absorption), canagliflozin (SGLT2 inhibitor), metformin (though failed alone), and he predicts GLP-1 agonists will join the list. He also mentions that mice fed a pure fat diet (no carbohydrates) lived longer, supporting the idea that avoiding glucose-driven insulin spikes is beneficial. However, he acknowledges that a ketogenic diet is socially and practically difficult, and he personally did not feel healthy on it long-term.

Verdin explains that blood is a highly dynamic organ with over 500 cell populations, each with its own epigenetic age. As we age, the proportion of naive T cells (which are epigenetically young) decreases, while memory T cells (epigenetically old) increase. This alone can make a person appear to age epigenetically. In acute infections like COVID or HIV, there is a massive expansion of memory T cells, causing a spike in epigenetic age that is not true aging. The TRIIM trial (growth hormone, metformin, DHEA) claimed rejuvenation based on an epigenetic clock, but Verdin suspects the result was largely due to a shift in T-cell subsets (increase in naive T cells) rather than true reversal of aging. To address this, his lab created an 'intrinsic clock' by removing methylation sites that change with T-cell differentiation. This clock is impervious to immune activation and does not change during COVID or HIV. It does, however, change with cancer and senescence, making it potentially more useful. He also highlights Dan Belsky's DunedinPACE clock, which measures pace of aging and seems responsive to interventions. Verdin is excited about next-generation proteomic clocks that can assess organ-specific aging, but he cautions they are early-stage and not ready for clinical use.