#35 – Nir Barzilai, M.D.: How to tame aging

Founding director of the Institute for Aging Research at Albert Einstein, leading the TAME trial and a significant expert in longevity genetics.

An early researcher from Leningrad who, in the 1980s, showed that Metformin extended life and healthspan in rodents, driving early interest in its anti-aging potential.

A researcher with whom Dr. Barzilai worked at Yale doing metabolism research, specifically on Metformin's mechanism of action.

A pathologist known for his extensive work on insulin response and glucose tolerance, advocating for longer sampling durations in OGTTs.

A researcher from St. Louis with proprietary patents and studies in Japan on NMN, who reports improved sleep patterns and deep sleep in his subjects, aligning with Dr. Barzilai's anecdotal experience.

Then Vice President, speaking at the Vatican conference about his cancer initiative and the complexity of treating cancer.

A prominent longevity researcher, mentioned in the context of discussions around Resveratrol's bioavailability.

A prominent researcher in lipidology, collaborator with Dr. Barzilai working on HDL efflux studies.

Filmmaker who created 'The Age of Aging,' a National Geographic movie that Dr. Barzilai describes as the best movie ever on aging.

Dr. Barzilai advises them on future planning, including questions about adding Metformin to public water supplies.

A longevity researcher, who, along with Nir Barzilai, studied Laron dwarfs in Ecuador for their potential extended lifespan and reduced disease risk.

A researcher whose paper on NAD+ tracer studies suggested that orally administered nicotinamide riboside primarily goes to the liver, raising questions about its widespread cellular bioavailability.

A researcher with whom Dr. Barzilai collaborates to study autophagy in human T lymphocytes, looking at its time course in response to interventions like fasting.

A historical figure whose conflict with the Vatican serves as a cautionary tale for the institution regarding resistance to scientific advancement, prompting their interest in modern science like aging research.

Speaking at the Vatican conference, expressing hope for a single, cheap pill to cure cancer, which Dr. Barzilai relates to Metformin's potential for preventing a range of age-related diseases.

Targeting Aging with Metformin, a prospective clinical trial led by Dr. Barzilai to test Metformin's effect on aging in non-diabetics, seeking FDA approval for aging as an indication.

A landmark clinical study referred to for showing Metformin's benefits in preventing cardiovascular disease.

A clinical study demonstrating that Metformin prevents diabetes by 30%, which the FDA used as a reference point for considering Metformin's indications.

Insulin-like Growth Factor 1, a hormone discussed in relation to longevity, growth hormone, and centenarian data, with complex and often contradictory epidemiological findings.

A hormone produced by adipose tissue that plays a role in glucose regulation and fatty acid oxidation; Peter Attia notes a Type 1 diabetic patient with unusually high levels.

A transcription factor in humans analogous to daf-16 in C. elegans, important for cellular homeostasis and identified as a common mutation in centenarians.

Glucose transporter type 4, the major glucose transporter in muscle cells, whose translocation to the plasma membrane is stimulated by insulin to facilitate glucose uptake.

An enzyme found in the liver that phosphorylates glucose, playing a key role in glucose uptake and metabolism.

A side effect noted with Rapamycin use in animals, contributing to caution about its safety for human anti-aging indications.

A nutrient-sensing enzyme activated by Metformin, leading to downstream effects on mTOR and autophagy, and considered an exercise mimetic pathway.

Magnetic Resonance Imaging, used in early research to show how caloric restriction decreases visceral fat.

Insulin Receptor Substrate 1, a protein involved in insulin signaling, expressed widely in tissues like muscle and liver.

A region in the brain that plays a critical role in controlling metabolism, including insulin and glucose regulation in peripheral tissues.

A project directed by Dr. Barzilai which studies the genetics of longevity, particularly in centenarians.

A hormone produced by the pituitary gland that stimulates IGF-1 production, also discussed for its potential role in lifespan and healthspan, with complex effects on muscle function and sex differences.

A gene in C. elegans, an analog of the insulin receptor in humans, whose attenuation leads to increased fat accumulation and extended lifespan in nematodes.

A gene in C. elegans, an analog of the FOXO transcription factor in humans, involved in longevity pathways.

A measure of average blood glucose levels over the past 2-3 months, used to assess glycemic control in diabetic patients.

An epigenetic action of Metformin, occurring independently of mitochondria, involved in gene regulation.

A form of dwarfism caused by a defect in the growth hormone receptor, studied for its association with reduced cancer and diabetes incidence, providing human evidence for the GH/IGF-1 longevity connection.

A receptor involved in regulating appetite and metabolism, whose absence in certain rat models leads to constant hunger and obesity.

Insulin Receptor Substrate 2, a protein involved in insulin signaling, expressed widely in tissues but more prominently in the liver.

A protein that binds sex hormones, also noted by Peter Attia to be remarkably high in his Type 1 diabetic patient, implying favorable metabolic health.

A cranial nerve connecting the brain to various organs, including the liver, mediating central nervous system control over peripheral metabolism, demonstrated by vagotomy experiments.

A transporter protein that Metformin uses to enter cells, influencing its distribution and specificity in different tissues.

A genetic analysis technique that searches for genetic variants associated with traits or diseases, criticized for its focus on single SNPs rather than pathways or gene-to-gene interactions.

High-density lipoprotein cholesterol, a metric for which the presenter and guest share skepticism about its clinical utility, emphasizing the need for functional assays.

A type of white blood cell, used by Dr. Barzilai's collaborators to study autophagy in humans, as they reflect autophagy in the brain.

A gene involved in DNA repair, whose expression was found to be changed by Metformin in human muscle and adipose tissue biopsies, indicating non-metabolic, aging-related effects.

A side effect noted with Rapamycin use in animals, contributing to caution about its safety for human anti-aging indications.

A cellular process of self-degradation and recycling, increased by Metformin, which is important for longevity and improved by fasting in rodents.

A microRNA found to be overexpressed in 30% of centenarians, preventing IGF-1 receptor phosphorylation and decreasing FOXO signaling, suggesting a novel epigenetic mechanism for longevity.

A gene variant strongly associated with an increased risk of Alzheimer's disease, but found in 100-year-old centenarians who did not develop dementia, suggesting protective genetic interactions.

A dietary intervention known to extend lifespan in many organisms, but with differing effects on IGF-1 depending on whether it's continuous or intermittent.

A form of intermittent fasting, practiced by Peter Attia, and discussed for its potential benefits, though with questions regarding the magnitude of nutrient deprivation in humans compared to mice.

A protein kinase whose activity is decreased by Metformin, leading to increased autophagy, a key pathway in aging.

A receptor involved in the IGF-1 signaling pathway, where clusters of mutations have been found in centenarians, implying resistance to IGF-1 and its role in longevity.

A transcription factor involved in cellular homeostasis and stress resistance, commonly mutated in centenarians worldwide, suggesting its role in human longevity.

A protein involved in reverse cholesterol transport; mutations like CETP VV are associated with higher HDL, larger lipoprotein particles, lower CETP levels, and cognitive protection, protecting against LP(a)'s negative effects.

A dietary pattern involving cycles of fasting and eating, which in rodent studies led to lower IGF-1 levels, unlike continuous calorie restriction approaches.

Nicotinamide Adenine Dinucleotide, a coenzyme involved in metabolism, referred to by Peter Attia in the context of supplements like nicotinamide riboside and n-MN for anti-aging.

A precursor to NAD+, discussed alongside NMN for its potential anti-aging effects, with questions about its bioavailability and clinical efficacy.

A sirtuin activator, sometimes paired with NAD+ precursors in supplements, but Dr. Barzilai does not use it with his NMN.

A natural polyphenol and sirtuin activator discussed for its anti-aging potential, but with questions regarding its bioavailability and effective dosing in humans.

A precursor to NAD+, taken by Dr. Barzilai, who anecdotally reports improved sleep patterns and deep sleep, sparking hope for its efficacy.

Academic institution where Dr. Barzilai works, specifically at the Institute for Aging Research.

A division of the NIH, mentioned as having a small budget relative to the burden of age-related diseases, and initially hesitant to fund the TAME trial due to its scope.

Where Dr. Barzilai completed a fellowship in metabolism.

The U.S. Food and Drug Administration, whose regulatory processes delayed Metformin's approval in the U.S. and is now the target for TAME trial's novel indication for aging.

Where Dr. Barzilai completed an endocrine fellowship.

The primary agency of the U.S. government responsible for biomedical and public health research, whose grant review process for TAME was criticized for its siloed approach to disease vs. aging.

A prestigious scientific journal where Dr. Barzilai's lab recently published a paper on the IGF receptor antibody accelerating healthspan and lifespan in female mice.

The UK's public healthcare system, which facilitated a crucial epidemiological study on Metformin by centralizing patient data from prescriptions to mortality, providing human evidence for Metformin's anti-aging effects.

Produced 'The Age of Aging,' a film narrated by Ron Howard about the science of aging.

An organization for which Steve Austad and Dr. Barzilai are scientific directors, providing philanthropic funding for the TAME trial.

A division of the NIH, which Dr. Barzilai sought to partner with for the TAME trial, hoping they would contribute funding due to Metformin's anti-cancer effects.

A cousin of Metformin, more potent but associated with higher rates of lactic acidosis, leading to its eventual consideration as unsafe.

A class of drugs that increase insulin secretion from the pancreas, compared unfavorably to Metformin due to its effects on macrovascular disease.

A pharmaceutical drug, initially for Type 2 diabetes, now being studied by Dr. Barzilai for its anti-aging properties in the TAME trial.

An immunosuppressant and anti-aging drug that causes insulin resistance but extends lifespan in rodents, mentioned as an alternative anti-aging agent to Metformin.

A neurodegenerative disease for which Metformin has shown some positive effects in mild cognitive impairment in clinical studies, particularly in memory recall.

Likely referring to Dr. Anna Lembke's book, mentioned by Peter Attia in the context of his work, though not discussed in detail by Barzilai.

Pharmaceutical company that conducted studies to get Metformin approved in the United States.

A company that sells nicotinamide riboside (NR) supplements, whose efficacy is questioned in light of research on NAD+ precursor bioavailability.

A biopharmaceutical company that developed an IGF receptor antibody for cancer treatment, which Dr. Barzilai's lab subsequently used in mouse longevity studies.

German pharmaceutical company that holds the worldwide license for Metformin and provides the drug and placebo for the TAME trial.

A company that sells nicotinamide riboside (NR) supplements, whose efficacy is questioned in light of research on NAD+ precursor bioavailability.

An experimental technique used to measure insulin secretion and sensitivity by maintaining stable high glucose levels, revealing non-insulin mediated glucose uptake.

A public archive of human variations that are observed in patients and assertions about their clinical significance, used to test the 'perfect genome' hypothesis in centenarians.

An assay technology used to measure mitochondrial action and oxygen consumption, used in understanding Metformin's effects.

A clinical test used to assess glucose metabolism and insulin sensitivity by measuring glucose and insulin responses after a glucose load.

A protein complex that controls transcription of DNA, cytokine production, and cell survival, whose activity is influenced by Metformin, contributing to its anti-inflammatory effects.

A brand of sparkling mineral water, humorously suggested by Peter Attia as a potential addition to the TAME trial, predicting it would enhance happiness.

An influential newspaper that published an article about the TAME trial, leading to a surge of volunteer inquiries, but also raising concerns about study bias.

Where Dr. Barzilai was invited to speak about aging to high-level figures, highlighting the philosophical implications of extending healthspan and preventing age-related diseases.