#35 - Nir Barzilai, M.D.: How to tame aging
In this episode, Dr. Nir Barzilai, director of the Institute for Aging Research, discusses metformin's anti-aging properties, the TAME trial, and the genetics of longevity. He explores how centenarians compress morbidity, the role of IGF/GH, and the potential of NAD precursors for healthspan.
Deep Dive Analysis
13 Topic Outline
Nir Barzilai's Background and Entry into Longevity Research
Metformin's History, Mechanism, and FDA Approval Challenges
Understanding Insulin Resistance and its Paradoxical Role in Longevity
Metformin as a Potential Anti-Aging Drug: Clinical Evidence
The TAME Trial: Targeting Aging with Metformin
Mechanistic Explanation of Metformin's Anti-Aging Properties
Genetic Insights from Centenarians and Offspring Studies
The Growth Hormone-IGF Axis and its Impact on Human Aging
Sex Differences in Growth Hormone-IGF Effects on Longevity
Genetic Mutations and Protection Against Age-Related Diseases
Metformin's Non-Metabolic Effects and Tissue-Specific Changes
NAD Precursors (NR/NMN) and Reported Effects on Sleep
Ethical and Practical Considerations of Metformin Use for Anti-Aging
8 Key Concepts
Insulin Resistance (IR)
Insulin resistance is clinically defined by the inability of insulin to clear glucose, primarily through reduced glucose uptake in muscle. However, it can also be a protective mechanism, where cells become resistant to prevent over-storage of nutrients, diverting excess glucose to other tissues like fat or the liver.
Longevity Dividend
The longevity dividend refers to the immense societal benefits, including trillions of dollars in medical cost savings, that would result if people lived healthier for longer, even if overall lifespan isn't dramatically extended. This concept emphasizes extending health span and compressing morbidity.
DAF2 Model
The DAF2 model refers to a genetic manipulation in nematodes (C. elegans) where decreasing insulin sensitivity (analogous to the insulin receptor) leads to fat accumulation in intestinal cells and significantly extended lifespan, presenting a paradox for understanding insulin resistance in longevity.
AMP Kinase (AMPK)
AMPK is a nutrient-sensing enzyme that acts as a 'hormone of nutrient deprivation' or an 'exercise mimetic pathway.' Its activation signals the body to adapt to low energy states, influencing downstream pathways like mTOR and autophagy.
mTOR
mTOR (mammalian target of rapamycin) is a central regulator of cell growth, proliferation, and survival. It is downstream of AMPK, and its inhibition is associated with increased autophagy and potential anti-aging effects.
Autophagy
Autophagy is a cellular process of 'self-eating' where cells break down and recycle damaged components. It is increased by nutrient deprivation, exercise, and certain compounds like metformin, and is considered a key mechanism in cellular rejuvenation and longevity.
Growth Hormone-IGF Axis
This endocrine system involves growth hormone (GH) from the pituitary stimulating the liver to produce insulin-like growth factor 1 (IGF-1). It plays a complex role in aging, with lower IGF-1 levels often associated with increased longevity and reduced age-related diseases, particularly in women.
CETP-VV Mutation
The Cholesteryl Ester Transfer Protein (CETP) VV mutation is a longevity-associated genetic variant. Individuals with this mutation tend to have higher HDL levels, larger lipoprotein particle sizes, and lower CETP levels, offering protection against several age-related diseases, most notably cognitive decline.
9 Questions Answered
Metformin was used in Europe for decades before the U.S. FDA required extensive studies to prove its efficacy in the U.S. population and to better understand its mechanism of action, a process that took many years.
While metformin can cause a slight increase in lactic acid within the normal range, true lactic acidosis (MALA) is rarely caused by metformin alone and is more often associated with underlying conditions like kidney failure or heart attack in patients already taking the drug.
Metformin primarily targets hepatic glucose production, reducing the liver's output of glucose, and also improves insulin sensitivity in the liver, rather than directly increasing insulin secretion from the pancreas.
Studies in rodents show metformin extends lifespan and health span, and a large UK study found that type 2 diabetic patients on metformin monotherapy had 17% lower mortality than matched non-diabetics, and significantly less cancer.
TAME is a clinical trial designed to prove that aging itself can be targeted by a drug, specifically metformin, by demonstrating a delay in the onset of multiple age-related diseases (cardiovascular disease, cancer, Alzheimer's, mortality) in non-diabetic individuals aged 65-80.
Metformin enters cells via the OCT1 transporter, binds to complex I in mitochondria, altering the ADP/ATP ratio, which activates AMP kinase (AMPK). This leads to mTOR inhibition, increased autophagy, decreased ROS production, and reduced inflammation, all contributing to cellular rejuvenation.
Centenarians often exhibit genetic alterations in the growth hormone-IGF axis (e.g., IGF receptor mutations, growth hormone receptor exon 3 deletion, specific microRNAs), and mutations in FOXO3A and CETP-VV, which collectively lead to delayed onset of age-related diseases.
Based on current human genetic and animal studies, growth hormone treatment is not considered beneficial and may be dangerous for elderly women, as lower IGF-1 levels are associated with better longevity and cognitive function in females, while effects in men are less clear.
While rodent studies show promise, human clinical data on NAD precursors like NR and NMN are limited. Some anecdotal and preliminary observations suggest potential benefits, such as improved sleep patterns (more deep sleep and REM), but robust, well-controlled clinical trials are needed to confirm efficacy and optimal delivery.
28 Actionable Insights
1. Target Aging as a Disease
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.
2. Consider Metformin for Anti-Aging
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.
3. Aim for Compression of Morbidity
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.
4. Prioritize Safety in Anti-Aging
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.
5. Metformin’s Multi-Pathway Anti-Aging Effects
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.
6. Consider Cyclic Fasting for IGF-1
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.
7. Minimize Visceral Fat for Longevity
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.
8. Avoid Exogenous Growth Hormone
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.
9. Await TAME Results for Metformin
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.
10. Re-evaluate Metformin Lactic Acidosis Risk
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.
11. Acknowledge Sex Differences in Longevity
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.
12. Consider Lowering IGF-1 for 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.
13. Distinguish Intermittent from Caloric Restriction
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.
14. Metformin May Aid Weight Loss
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.
15. NMN May Improve Sleep Patterns
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.
16. Question Efficacy of IV NAD
Be skeptical of the efficacy of intravenous NAD administration, as there is currently no compelling evidence to suggest it effectively delivers NAD into cells.
17. Focus on Offspring for Longevity
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.
18. Assess LPA with CTEP Genotype
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.
19. Seek NAD Precursors Bypassing Liver
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.
20. Metformin for Type 2 Diabetes
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.
21. Metformin Enhances Glucose Disposal
Metformin enhances glucose disposal by increasing muscle insulin sensitivity and participating in AMPK-driven, non-insulin mediated glucose uptake, which is also exercise-dependent.
22. View Insulin Resistance as Protective
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.
23. Caution with Hormone Replacement in Elderly
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.
24. Consider Biological vs. Chronological Age
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.
25. Understand Growth Hormone Receptor Mutations
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.
26. Metformin’s Broad Tissue-Specific Effects
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.
27. View Metformin as Foundational Tool
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.
28. Investigate Human Autophagy Timelines
Focus on understanding the specific timeline for autophagy activation in humans through fasting, as this knowledge is crucial for programming optimal nutrient exposure strategies.
6 Key Quotes
I'm not for longevity. I'm just for health span, right? So if we can live healthy, healthy, healthy, die, that's fine with me.
Nir Barzilai
Metformin is a weak cyanide.
Nir Barzilai
The disease you get first depends on, you know, your genetics and environment. If you have a mother who's diabetic and you're obese, you'll get diabetes first, okay? But really, because we age biologically, you know, in different way, whatever it is, the next disease, you're going to get the next disease.
Nir Barzilai
The cost of dying after a hundred was third of that of dying in 70.
Nir Barzilai
The problem with HDL cholesterol is it's just such a dumbass metric. It's so useless. It's so far downstream that it doesn't tell us much.
Peter Attia
I think the prevention of aging is really a good place to be. And I think because we went from hope to promise and we have to realize the promise, I think life is going to be very different in the next decade with our advance.
Nir Barzilai