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

Oxidative stress, caused by reactive oxygen species (free radicals) from metabolic processes, contributes to aging by damaging proteins and fatty acids. While antioxidants failed globally in trials, selective inhibition of ROS generation points to a more nuanced role, where ROS also function as signaling molecules.

Exercising, particularly zone 2 cardio, is believed to improve mitochondrial health and function, thereby reducing the degradation of mitochondrial efficiency that occurs with aging. It is considered one of the best anti-aging interventions.

Ketones, specifically beta-hydroxybutyrate, are considered the cleanest fuel source, generating fewer byproducts and less oxidative stress compared to fatty acids and especially glucose, which is considered the 'dirtiest' fuel.

High peaks of insulin, elicited by fast-absorbing glucose, are considered detrimental to the aging process. The intensity of these insulin peaks, rather than just average glucose, is a critical factor, suggesting that mitigating these spikes is important for longevity.

GLP-1 agonists improve glucose control by increasing GLP-1 in the system, overcoming beta-cell resistance, and leading to better glucose management without necessarily increasing insulin levels. Personal experimentation showed significant improvements in metabolic markers and unexpected satiety, making them potential geroprotectors.

The J-curve indicates that for certain health metrics like A1C and blood pressure, lower values (within a healthy range, avoiding symptoms) are generally better for longevity, even if they fall below traditionally 'normal' ranges. This challenges the conventional idea of a broad normal range.

While individuals can be metabolically healthy with excess weight, there's concern about the long-term effects. Visceral fat is highly predictive of negative health outcomes. The long-term impact on metabolic health and increased risk of complications from sustained excess weight remain a worry.

The immune system plays a crucial role in aging, as evidenced by the dramatically increased mortality from infections like COVID-19 and influenza in older adults. Immunosenescence, or aging of the immune system, leads to decreased vaccine efficacy and increased susceptibility to severe outcomes.

Human growth hormone has been shown to induce thymogenesis (thymus regeneration) and increase naive T-cells, which could theoretically improve immune function. However, it also induces glucose intolerance and has been correlated with shorter lifespans in larger animal species and taller humans, raising concerns about chronic use.

Rapamycin, typically an immunosuppressant at high, continuous doses, can show beneficial, immune-enhancing effects when administered in lower, intermittent doses. Studies have shown it can improve vaccine response in older adults, though its long-term effects on immune function and broader anti-aging benefits in humans are still debated.

NAD+ is a crucial coenzyme for hundreds of metabolic and DNA repair enzymes, including sirtuins. Its levels decline with age primarily due to increased degradation by enzymes like CD38, which acts as an NAD+ hydrolase. This decline reduces metabolic efficiency and impacts DNA repair.

While NMN and NR raise NAD+ levels, they can lead to an increase in downstream metabolites like methyl nicotinamide, potentially depleting the body's one-carbon cycle (e.g., increasing homocysteine). There are also concerns about these supplementing exacerbating inflammation (SASPs) and potentially accelerating tumor growth in certain models.

Currently, aging clocks are primarily research tools and not ready for routine patient management. While some, like the Dunedin Pace clock, respond to interventions, they can be noisy and show significant variation based on blood cell composition and even time of day. New proteomics-based clocks show promise but carry risks of false positives and over-medicalization.