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

Link: https://youtu.be/818-8vS5JpA

Short Summary

Here's the breakdown of the YouTube video transcript:

Number One Takeaway/Action Item:

Prioritize exercise, particularly Zone 2 cardio, as it is currently the best-understood and most effective anti-aging intervention, impacting both immune function and metabolic health.

Executive Summary:

This podcast episode features a conversation about the intersection of immunology, metabolism, and aging. It highlights the critical roles of the immune and nervous systems in lifespan, the importance of fuel utilization in metabolism, and the complex and sometimes controversial landscape of interventions like NAD supplementation and rapamycin.

Key Quotes

Here are 4 quotes that I believe are particularly valuable insights from the transcript:

1. "There is data showing that there are two organs that are rate limiting in terms of your aging and it's the central nervous system and the immune system."
2. "...oxidative stress is the fact that um pretty much the main metabolic reaction are dependent on oxygen uh which gives its electron. ... these electrons reacting with oxygen can generate these um byproducts called radical oxygen species which are highly reactive."
3. "...I think ketones are probably the the cleanest fuel to burn in terms of again byproducts oxidative stress they seem to be really unique"
4. "...when you sample the blood as an iminologist I know this is a highly dynamic organ think about the blood as an organ we enumerate at this point today with the best technology more than 500 different populations of cells in the blood."

Detailed Summary

Here's a detailed summary of the YouTube video transcript, focusing on the key topics, arguments, and information discussed.

Key Topics

• Aging Hallmarks: Discussion revolves around the major contributors to aging, particularly metabolism and immunology.
• Oxidative Stress: Examination of the oxidative stress theory of aging, the role of free radicals, and the failure of broad-spectrum antioxidant therapies.
• Metabolism & Fuel Utilization: Importance of fuel utilization and efficiency. Focus on glucose, fatty acids and ketones with special attention to glucose metabolism and insulin sensitivity, and potential benefits of ketone utilization.
• Immunology of Aging: Focus on the aging of the immune system, its impact on overall health, and the challenges of addressing immune decline.
• The Thymus: Exploration of the role and diminishing function of the thymus with age, and potential for rejuvenation (growth hormone.)
• Rapamycin & Immune Function: Discussion on rapamycin's potential impact on the immune system, the nuances of its effects depending on dosage and frequency, and comparisons of mouse vs human studies.
• NAD Metabolism: Examination of NAD, its role in cellular processes, declining levels with age, and various supplementation strategies.
• CD38: Description of CD38, its role in NAD degradation, and the phenotype of CD38 knockout mice.
• Interleukin-11 (IL-11): Discussion of Interleukin 11 as a pro-inflammatory marker of the aging immune system and results blocking IL-11 expression.
• Biological Clocks: A thorough conversation regarding different types of biological clocks and their applicability.

Arguments and Information

• The Four (or Five) Horsemen: The speaker mentions his framework of the four major causes of death: cardiovascular disease, cancer, neurodegeneration, and metabolic disease. He now believes immune health should be added as a fifth "horseman" due to its significant impact on aging.
• Central Nervous System & Immune System: These two organ systems are proposed as rate-limiting factors in aging due to their distributed nature and influence on overall organ function.
• Endothelium: The importance of endothelial barrier function is highlighted, alongside skin and blood-brain barrier integrity, as a key factor for longevity.
• Oxidative Stress Theory Nuance: While antioxidant trials have largely failed, the role of free radicals is complex. They can have both damaging and signaling roles. Global suppression may be detrimental, and better biomarkers are needed.
• Exercise & Mitochondrial Health: Zone 2 cardio training can improve mitochondrial health and efficiency, promoting fatty acid oxidation and mitigating age-related mitochondrial decline.
• Fuel Utilization Hierarchy: Ketones are considered the "cleanest" fuel, followed by fatty acids, with glucose being the "dirtiest," due to byproducts and oxidative stress.
• Glucose Metabolism & Insulin: Glucose elicits insulin secretion, which may be a culprit in the aging process. Managing glucose peaks is crucial.
• GLP-1 Agonists: These drugs are predicted to be geroprotective by helping overcome insulin resistance at the beta cell.
• BMI vs. Metabolic Health: While BMI is a population-level tool, it's insufficient for individual assessment. Metabolic health is more critical. The possibility of being overweight and metabolically healthy exists.
• Vaccination Decline with Age: The efficacy of vaccinations decreases with age. COVID vaccines have shown a remarkable effect in risk reduction, but this may not be the case with all vaccines.
• Thymic Involution: Thymus shrinks with age, limiting T-cell production and reducing immune response. Growth hormone is a potential intervention.
• Naive T Cells: They're generated in the thymus and are essential for immune response and T-cell rejuvenation. The Fe trial with growth hormone, metformin and DHEA resulted in the regeneration of these.
• Impact of Exercise on the Immune System: Exercise is shown to improve immune function by improving response to infection and vaccinations.
• Rapamycin & Immunosuppression: This is a dosage/frequency question. High dose/frequency has an immunosuppressive effect, but at certain low doses and frequency, rapamycin can have gero-protective effects and improve immune response.
• Over-Reliance on Mouse Studies: There is concern about the over-reliance on ITP mouse studies in aging, and the necessity for primate interventions with drugs.
• Longevity Quotient: Steve Austad's concept is introduced, highlighting that mice live shorter than they should based on their size. Humans live longer than they should based on our size.
• CD38's Role: CD38's primary purpose is to hydralize NAD. The question is raised: does CD38 contribute to an anti-inflammatory state or a pro-inflammatory state?
• NAD Supplementation Caveats: Supplementation with NMN can increase nicotinamide, which then can shunt methylation, increasing homocysteine. NMN is cleaved by CD38, and the increase in CD38 can increase this.
• Intravenous NAD: The argument is made that NAD is largely an intracellular process, therefore IV use of NAD is not appropriate.
• I Age: Immune aging measured with serum biomarkers such as cytokines and CXC.
• Interleukin-11 (IL-11): Interleukin 11 acts as an important pro-inflammatory marker of the chronically activated immune system.
• Benefits of Blocking IL11: IL-11 plays an important role as an inflammatory marker in aging, and blocking expression of IL-11 did lead to improved outcome in a research study.
• Challenges of Multi-Target Strategies: The fine balance needed within the immune system makes interventions that hit multiple targets difficult to achieve with a predictable outcome.
• Biomarkers are Important: Discussion about a lack of biomarkers in order to make conclusions and predictions.
• Epigenetic Clocks and Validation: Epigenetic clock has a dynamic epigenome which makes biological conclusions difficult. There is a tenuous link with each change of methylation at a site and the biology.
• Blood Samples and Clocks: The distribution of cells in the blood change, therefore, a blood test might skew a clock. Clocks, therefore, need to be constructed without a variation.

This summary captures the core of the video transcript and can be used to understand the key points made by the speakers.