Advocate for targeting aging itself as a treatable condition, rather than individual age-related diseases, to prevent a cluster of diseases altogether and extend health span.
Consider metformin as a potential anti-aging drug due to rodent studies showing increased lifespan and improved health span, and human observational data linking it to significantly less mortality and reduced incidence of various cancers (excluding prostate) in diabetics.
Strive for compression of morbidity, as observed in centenarians who live longer, healthier lives with a delayed onset of chronic diseases and a quicker, less costly decline at the very end of life.
When exploring anti-aging interventions, prioritize drugs with extensive safety data, like metformin, over those with less understood long-term safety profiles or potential severe side effects, such as rapamycin.
Understand metformin’s anti-aging effects stem from its action on multiple cellular pathways, including inhibiting mitochondrial complex one, activating AMPK, decreasing mTOR activity, increasing autophagy, reducing ROS production and inflammation, and influencing epigenetic changes like histone deacetylation.
Implement cyclic fasting (e.g., water-only for a week quarterly) to profoundly and transiently reduce IGF-1 levels, which then slowly rebound, potentially offering a healthier approach than constitutive caloric restriction.
Reduce visceral fat, as studies in rats showed surgical removal of visceral fat led to significantly longer and healthier lives, even with ad libitum feeding, suggesting its critical role in aging.
Avoid exogenous growth hormone treatment for elderly women, as human and rodent studies suggest it is not beneficial and could be dangerous, though its effects in elderly men are less clear.
Exercise caution and await the results of the TAME study before taking metformin as a non-diabetic for anti-aging purposes, as its safety and efficacy in this population are not yet clinically proven.
Understand that metformin-associated lactic acidosis (MALA) is often an association with other conditions like kidney failure or heart attacks, rather than a direct causation by metformin alone, suggesting the risk might be overemphasized.
Recognize and account for sex differences in longevity research and interventions, as many findings (e.g., rapamycin efficacy, IGF-1 impact) show varying effects between males and females.
For women, consider strategies that may lead to lower IGF-1 levels, as centenarian women with the lowest IGF-1 levels lived twice as long and experienced significantly fewer cognitive problems.
Recognize that many rodent ‘caloric restriction’ studies are effectively intermittent fasting (e.g., eating all food within an hour and fasting for 23 hours), which significantly lowers IGF-1, a distinction important for human application.
Metformin may contribute to weight loss by subtly reducing hunger and improving the body’s response to satiety signals like leptin, leading to decreased food intake without conscious effort or nausea.
Consider that NMN supplementation might improve sleep patterns, specifically increasing deep sleep early in the night and REM sleep later, based on anecdotal reports and observations from researchers.
Be skeptical of the efficacy of intravenous NAD administration, as there is currently no compelling evidence to suggest it effectively delivers NAD into cells.
When studying longevity, focus on the offspring of centenarians rather than the centenarians themselves, as the latter’s current phenotype might reflect impending death rather than the genetic factors that led to their longevity.
When evaluating the risk of high LP(a), consider the individual’s CTEP genotype, as centenarians with high LP(a) often also carry protective CTEP mutations (VV genotype) that may mitigate its atherogenic effects.
Look for future NAD precursor drugs designed to bypass initial liver metabolism and directly enter the bloodstream and cells, as this may improve their efficacy.
Use metformin as a first-line treatment for type 2 diabetes, as it primarily targets hepatic glucose production and improves insulin sensitivity in the liver.
Metformin enhances glucose disposal by increasing muscle insulin sensitivity and participating in AMPK-driven, non-insulin mediated glucose uptake, which is also exercise-dependent.
Consider insulin resistance in muscle as a protective mechanism or stress response, as it can prevent excessive glucose storage in cells when saturated, redirecting it elsewhere.
Be cautious with hormone replacement, especially estrogen in older age, as studies in older animals showed it could worsen conditions like stroke, suggesting it might have opposite effects compared to young bodies.
Intuitively realize there’s a chronological age and a biological age, and observe if individuals look older or younger than their chronological age, as this difference is key to understanding aging.
Understand that specific mutations in the growth hormone receptor (e.g., deletion of exon 3) can lead to higher stature during puberty due to high growth hormone, but then result in lower IGF-1 activity later in life, contributing to longevity in some centenarians.
Recognize that metformin induces tissue-specific metabolic changes (e.g., free fatty acid metabolism in fat, pyruvate metabolism in muscle) and also alters expression of non-metabolic, aging-related genes like BRCA1, suggesting broad systemic benefits beyond direct metabolism.
Consider metformin as a foundational tool to demonstrate the principle of targeting aging, acknowledging that future advancements will likely bring more effective drugs and combination therapies.
Focus on understanding the specific timeline for autophagy activation in humans through fasting, as this knowledge is crucial for programming optimal nutrient exposure strategies.