#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.
Dr. Eric Verdin, CEO of the Buck Institute for Research on Aging, discusses how epigenetics, metabolism, and the immune system drive aging. He explores practical interventions like zone 2 cardio, GLP-1 drugs, and rapamycin, and critiques NAD-boosting strategies and biological age tests.
Deep Dive Analysis
19 Topic Outline
Eric Verdin's Scientific Journey to Geroscience
Immune System and Central Nervous System as Rate-Limiting Organs in Aging
Metabolism, Oxidative Stress, and the Failure of Antioxidant Strategies
Fuel Utilization and Glucose Metabolism in Aging
Role of Insulin, IGF-1, and GLP-1 Agonists in Longevity
Limitations of BMI and the Need for Biological Metabolic Markers
Immune Health as a Critical Factor in Aging and Mortality
Innate and Adaptive Immune Systems: Function and Memory
Why Vaccine Effectiveness Declines with Age: Thymic Involution
Thymic Regeneration with Growth Hormone and Exercise's Immune Benefits
Rapamycin's Dual Role in Immunity and Dosage Considerations
Limitations of Mouse Models in Aging Research
NAD, Sirtuins, and the Complexity of NAD Metabolism
CD38 as a Major Driver of Age-Related NAD Decline
NMN and NR Supplementation: Metabolism, Risks, and Efficacy Concerns
Intravenous NAD: Limited Evidence and Potential Risks
Interleukin-11 and Chronic Inflammation in Aging
Current State and Future Outlook of Biological Aging Clocks
Proteomics-Based Aging Clocks and Organ-Specific Health Assessment
10 Key Concepts
Oxidative Stress Theory of Aging
This theory posits that reactive oxygen species (free radicals) generated as byproducts of oxygen-dependent metabolic reactions cause damage to proteins and fatty acids, contributing to aging. While direct antioxidant supplementation has largely failed in trials, the underlying concept of oxidative damage remains relevant.
Fuel Utilization Efficiency
Different metabolic fuels (ketones, fatty acids, glucose) burn with varying efficiency and byproduct generation. Ketones are considered the 'cleanest' fuel, while glucose is seen as 'dirtier,' potentially leading to more oxidative stress and eliciting insulin responses that accelerate aging.
Innate Immune System
This is the body's first line of defense against pathogens, comprising cells like macrophages and dendritic cells, and non-specific cellular mechanisms. It recognizes intruders broadly and activates a rapid, non-specific defense, giving time for the adaptive immune system to respond.
Adaptive Immune System
The second, highly specific line of immune defense, made up of T cells and B cells. B cells produce antibodies, and T cells kill infected cells. This system develops 'memory' after initial exposure (infection or vaccination), allowing for a faster and more effective response to subsequent encounters with the same pathogen.
Thymic Involution
The thymus, an organ behind the sternum, is responsible for generating diverse T cells. It shrinks dramatically with age, often replaced by fat after age 50, leading to a diminished capacity to produce new, 'naive' T cells and contributing to reduced vaccine effectiveness in older adults.
NAD (Nicotinamide Adenine Dinucleotide)
A critical intermediary metabolite essential for over 600 redox reactions and playing a key role in energy metabolism. NAD levels decline precipitously with age, impacting metabolic efficiency and the activity of NAD-dependent enzymes like sirtuins and PARPs.
Sirtuins
A family of seven proteins that act as NAD-dependent deacetylases, playing critical roles in DNA repair, metabolism, and gene regulation. Their activity is sensitive to NAD levels, suggesting they act as sensors of the metabolic state, and their function declines with age due to falling NAD.
CD38
A membrane-anchored protein that acts as an NAD hydrolase, cleaving NAD into nicotinamide and other byproducts. CD38 levels increase with age, especially in the immune system, and are considered a major driver of age-related NAD decline, potentially contributing to accelerated aging.
Biological Aging Clocks
Tools, primarily based on DNA methylation patterns (epigenetic clocks), that aim to estimate an individual's biological age or rate of aging. While some show promise in research, they are not yet ready for clinical patient management due to issues like variability, lack of direct biological meaning for all sites, and inconsistent predictive power compared to chronological age.
Proteomics Clocks
A newer generation of biological aging clocks that analyze changes in the proteome (the full set of proteins) in plasma. These clocks can identify proteins predictive of specific organ health or frailty, offering a more organ-specific and potentially clinically relevant assessment of aging than purely epigenetic clocks.
10 Questions Answered
The central nervous system and the immune system are considered rate-limiting organs for aging, primarily because they are distributed throughout the body and their function influences the well-being of every other organ.
While oxidative stress contributes to aging, global, non-specific antioxidant supplements have failed because reactive oxygen species also play important signaling and protective roles, and suppressing them completely can eliminate these beneficial effects.
Zone 2 cardio training, which maximizes fat oxidation, is hypothesized to improve the health and function of mitochondria, thereby potentially reducing the age-related degradation of mitochondrial function and associated oxidative leakage.
The efficiency of fuel utilization is critical, with ketones burning 'cleanest,' followed by fatty acids, and glucose being the 'dirtiest' fuel. Inefficient glucose metabolism drives insulin and IGF-1 signaling, which can accelerate aging.
Vaccinations lose effectiveness with age primarily due to the shrinking of the thymus gland (thymic involution), which reduces the generation of new, 'naive' T cells, leading to diminished T-cell diversity and a weaker adaptive immune response.
The innate immune system provides a rapid, non-specific first line of defense against pathogens, while the adaptive immune system develops highly specific responses through T cells and B cells, creating immunological memory for faster, more effective future responses to specific pathogens.
Rapamycin's anti-aging effects on the immune system, such as enhancing vaccine response, appear to be dose and frequency-dependent. Lower, intermittent doses (e.g., weekly pulsing) can improve immune function without the immunosuppressive effects seen with higher, continuous doses used in transplant medicine.
The enzyme CD38 is identified as a major driver of age-related NAD decline. As we age, CD38 levels increase across the organism, especially in the immune system, leading to increased degradation of NAD.
NMN and NR supplementation can increase nicotinamide levels, which, when shunted to methyl nicotinamide, can deplete the body's one-carbon cycle, potentially leading to elevated homocysteine levels. There are also concerns about accelerating tumor growth in animal models.
No, current biological aging clocks are not ready for prime-time patient management. They are primarily research tools with issues like circadian variation, sensitivity to cell type proportions in blood, and a tenuous link between methylation changes and specific biological functions.
20 Actionable Insights
1. Optimize Exercise First
Prioritize and optimize physical activity and exercise in all its forms as the most profoundly anti-aging intervention before considering other longevity interventions.
2. Prioritize Zone 2 Cardio
Engage in zone 2 cardio training for specific periods throughout the week to maximize fat oxidation and improve mitochondrial health and function, which may reduce degradation of function over time.
3. Aim for Lower Glucose
Strive for lower average blood glucose levels, as indicated by A1C, because in non-diabetics, a lower A1C is monotonically associated with lower all-cause mortality.
4. Aim for Lower Blood Pressure
Aim for lower blood pressure (e.g., 105/65 mmHg) as it is generally better for health outcomes, provided you remain asymptomatic.
5. Exercise for Immune Health
Engage in regular physical activity and exercise in all its forms, as it is the best anti-aging intervention and clearly benefits immune function, leading to better responses to infection and vaccination.
6. Optimize Fuel Utilization
Prioritize burning “cleaner” fuels like ketones, followed by fatty acids, as they produce fewer byproducts and less oxidative stress compared to glucose, which is considered a “dirty” fuel.
7. Use a Continuous Glucose Monitor
Wear a continuous glucose monitor (CGM) to identify foods and activities that cause glucose spikes, with the goal of mitigating intense peaks of insulin secretion.
8. Order Tests for Actionability
Only order medical tests if you are prepared to act on the potential outcomes or if the results will genuinely change your behavior or treatment decisions, rather than just for information.
9. Avoid Predatory Health Companies
Be wary of companies that sell unvalidated health tests and simultaneously offer supplements to “fix” the results, as this often indicates a lack of scientific rigor and potential exploitation.
10. Consider Risks of Over-Testing
Be mindful of the potential for over-testing, as procedures like whole-body MRIs can lead to incidental findings (e.g., thyroid nodules) that cause anxiety and unnecessary invasive follow-up without clinical benefit.
11. Maintain Scientific Open-Mindedness
When evaluating complex scientific fields like sirtuins and NAD, avoid premature dismissal due to controversy, as science is inherently messy and clarity emerges over time.
12. Consider GLP-1 Agonists
GLP-1 agonists can help mitigate peaks of insulin secretion and improve glycemic control, potentially leading to benefits like satiety and weight loss, but this is based on self-experimentation and not an endorsement.
13. Exercise with GLP-1 Agonists
If using GLP-1 agonists, ensure you are exercising to prevent loss of muscle mass, as observed in self-experimentation.
14. Avoid Impractical Diets
Do not adhere to extremely low or no-carbohydrate diets, such as a strict ketogenic diet, as they are often impractical for long-term adherence and may not be beneficial for everyone.
15. Consider NR/NMN Supplementation
For individuals aged 60 or above, consider taking 250 mg each of NR and NMN daily (total 500 mg) as a relatively safe dose, but monitor homocysteine levels as a precaution.
16. Monitor Homocysteine with NMN/NR
If supplementing with NMN (and potentially NR), monitor homocysteine levels, as high doses can increase homocysteine by depleting the one-carbon cycle, and some people take trimethylglycine (TMG) to offset this.
17. Be Aware of NAD Supplementation Risks
Be cautious with NAD supplementation, as increasing NAD levels might inadvertently increase pro-inflammatory markers (SASP) and could potentially accelerate tumor growth in individuals with early-stage cancer.
18. Be Aware of Supplement Dosing
Be aware that the doses of supplements like NR and NMN used in animal studies to show benefits are often 10 times higher than what is typically available in commercial supplements.
19. Use Multiple Epigenetic Clocks
If determined to use epigenetic clocks, use multiple different ones as they offer varied perspectives on your biological reality, but understand they are still research tools.
20. Exercise Caution with Novel Tests
Approach novel diagnostic tests with caution, especially those that report multiple abnormalities without clear clinical correlation, as they can lead to false positives, unnecessary anxiety, and further invasive procedures.
8 Key Quotes
I always tell people, you know, once you get into any field of study and you go deep and you start testing in humans, put on your seatbelt because it's not easy and there are no magic bullets.
Eric Verdin
I think living in an oxidative environment is one of the mechanisms that leads to aging. Not the only one. Aging is pleiomorphic.
Eric Verdin
The whole idea is to mitigate these peaks of insulin secretion.
Eric Verdin
The whole idea there is to, again, mitigate these peaks and either dietary or, for example, the GLP-1 agonists are playing a role in this as well.
Eric Verdin
I think longevity medicine is going to make an important impact. It's really sort of revisiting... revisiting... what is normal?
Eric Verdin
I think I'm convinced that it is fuel utilization.
Eric Verdin
The immune system is an incredibly tenuous system, which is in really delicate balance.
Eric Verdin
The problem is the activation of the immune response by itself becomes problematic because these cells, macrophages, for example, a powerful tissue remodeler. The immune system in this case is Dr. Jekyll and Mystic Hyde.
Eric Verdin