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

The Role of the Immune System in Aging

Verdin emphasizes the immune system as one of two rate-limiting organs in aging, alongside the central nervous system. Both are distributed systems, meaning their cells and functions are spread throughout the body, influencing overall health and longevity. The immune system's pervasive presence allows it to impact every organ, making its decline a critical driver of systemic aging.

Experimental evidence from mouse models supports this concept. For example, impairing DNA repair specifically in bone marrow cells or inducing mitochondrial dysfunction in immune cells accelerates aging and senescence across multiple organs. This systemic effect underscores the immune system's central role in maintaining organismal health. Chronic inflammation, often termed "inflammaging," is both a cause and consequence of immune aging, creating a vicious cycle that further accelerates decline.

Metabolism and Its Importance in Aging

Metabolism is another cornerstone of aging biology. Verdin discusses the oxidative stress theory of aging, acknowledging its complexity and the nuanced role of reactive oxygen species (ROS). While antioxidant supplementation has largely failed in clinical trials, this does not invalidate the theory. ROS have dual roles: damaging cellular components but also serving as important signaling molecules, especially during exercise.

Fuel utilization is a key metabolic factor influencing aging. Verdin argues that ketones, particularly beta-hydroxybutyrate, represent the cleanest fuel source, producing fewer harmful byproducts compared to glucose. Fatty acids rank next, with glucose being the "dirtiest" fuel in terms of oxidative stress and metabolic impact. This hierarchy is not just about energy yield but also about the downstream effects on insulin signaling and inflammation, which are intimately tied to aging processes.

Insulin, GLP-1, and Glucose Metabolism

The conversation delves into the role of insulin and GLP-1 in metabolic health and aging. Insulin resistance and glucose spikes are detrimental, and managing these peaks is crucial for longevity. GLP-1 agonists, such as semaglutide, improve glucose control by enhancing insulin secretion and overcoming beta-cell resistance, leading to better metabolic outcomes.

Interestingly, Verdin shares his personal experimentation with GLP-1 agonists, noting remarkable improvements in glucose control and satiety without significant muscle loss or adverse effects. This highlights the potential of these drugs as longevity interventions, not merely for weight loss but for metabolic optimization. The discussion also touches on the disconnect between insulin levels and GLP-1 treatment, where improved glucose control occurs despite lower insulin levels, a paradox that remains to be fully understood.

The Immune System's Complexity and Aging

Verdin elaborates on the immune system's two arms: innate and adaptive immunity. The innate immune system provides immediate, non-specific defense, while the adaptive system, composed of T and B cells, offers targeted, memory-based responses. Aging impairs both arms, reducing vaccine efficacy and increasing vulnerability to infections like COVID-19 and influenza.

The thymus, responsible for generating naive T cells, involutes with age, drastically reducing new T cell production. This decline contributes to immunosenescence and diminished vaccine responses in older adults. While some interventions, such as human growth hormone, have shown promise in partially restoring thymic function, the clinical relevance and safety of such approaches remain uncertain. The immune system's delicate balance between adequate defense and avoiding autoimmunity complicates therapeutic strategies.

Rapamycin and Immune Modulation

Rapamycin, a well-known mTOR inhibitor, presents a paradox in aging and immunity. While it is an immunosuppressant at high doses used in transplant medicine, low-dose or intermittent rapamycin has demonstrated immune-enhancing effects, such as improved vaccine responses in older adults. Verdin discusses the importance of dosing and frequency in achieving these benefits without immunosuppression.

Despite robust lifespan extension in mice consuming rapamycin continuously, translating these findings to humans is challenging. Differences in species longevity, metabolism, and environmental factors complicate direct extrapolation. Verdin expresses caution about widespread rapamycin use, especially in younger individuals, due to potential side effects like glucose intolerance. He advocates prioritizing exercise as the most effective anti-aging intervention before considering pharmacological agents like rapamycin.

NAD Metabolism and Sirtuins

Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme involved in redox reactions and a substrate for sirtuins, a family of proteins implicated in DNA repair and aging. NAD levels decline with age, potentially impairing sirtuin activity and metabolic health. However, supplementing NAD precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) has yielded mixed results in humans.

Verdin highlights the complexity of NAD metabolism, including the role of CD38, an enzyme that degrades NAD and whose expression increases with age, driven in part by senescent cell secretions. This creates a feedback loop exacerbating NAD depletion. Supplementation strategies face challenges such as CD38-mediated breakdown of precursors and potential side effects like elevated homocysteine levels due to methylation pathway overload. While animal studies are promising, human data remain inconclusive, and caution is warranted.

Interleukin-1 and Chronic Inflammation

The podcast touches on interleukin-1 (IL-1) and its role in chronic inflammation associated with aging. IL-1 is a pro-inflammatory cytokine produced by immune cells that contributes to "inflammaging." Blocking IL-1 or related cytokines like IL-11 in animal models has shown lifespan extension and reduced age-related pathology.

Verdin explains that chronic immune activation, while initially protective, becomes maladaptive as damage accumulates with age. Targeting inflammatory pathways may help break this cycle, but interventions must be carefully balanced to avoid impairing necessary immune functions. The immune system's complexity means that therapies modulating inflammation must be personalized and timed appropriately.

Biological Aging Clocks: Promise and Limitations

A significant portion of the discussion focuses on biological aging clocks, tools designed to estimate biological age or the pace of aging using biomarkers such as DNA methylation patterns, proteomics, or metabolomics. Verdin acknowledges their potential but stresses that current clocks are primarily research tools, not ready for clinical decision-making.

He critiques the variability and noise inherent in these measures, including circadian fluctuations and changes in immune cell populations that can confound results. Verdin's lab developed an "intrinsic clock" that accounts for immune cell composition, improving stability. While some clocks, like the "pace of aging" clock, show responsiveness to interventions, no clock yet outperforms chronological age in predicting lifespan. The field is evolving toward multi-omic approaches and organ-specific clocks, which may offer more actionable insights in the future.

Organ-Specific Clocks and Proteomics

Building on the aging clock discussion, Verdin highlights recent advances in organ-specific aging clocks derived from plasma proteomics. By identifying proteins uniquely expressed by specific organs and measuring their levels in blood, researchers can infer organ health and detect early signs of dysfunction.

This approach, exemplified by work from Tony Wyss-Coray and others, offers a promising avenue for detecting frailty points—organs or systems that limit overall healthspan. While still in early stages, such tools could revolutionize personalized medicine by enabling targeted interventions before clinical symptoms arise. However, Verdin cautions that clinical validation and understanding of false positives remain critical challenges.

The Balance of Immune Modulation and Clinical Implications

Throughout the conversation, a recurring theme is the delicate balance required in modulating the immune system and metabolism to promote healthy aging. Overactivation leads to chronic inflammation and tissue damage, while underactivation increases infection risk and cancer susceptibility. Therapeutic strategies must navigate this fine line, often requiring personalized approaches.

Verdin stresses the importance of robust biomarkers to guide interventions and avoid unintended consequences. He warns against oversimplified solutions or commercial exploitation of unvalidated tests and supplements. Instead, he advocates for rigorous science, cautious optimism, and prioritizing proven lifestyle interventions like exercise as foundational to any longevity strategy.