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Rapamycin extends mouse lifespan 9–14%
NAD+ precursors reverse aging in humans
Blue-light glasses improve sleep quality
Walking 10 min after meals blunts glucose
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#35 – Nir Barzilai, M.D.: How to tame aging — Whalespan

Content›Video›#35 – Nir Barzilai, M.D.: Ho…

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

Peter Attia2h 48m · 2020-01-07

Claims Made

243

Claims Supported

132

Support Rate

54%

Support rate

132 of 243 claims supported

132 supported111 partial / not

Claims from this content

195

◐Partially SupportedThe TAME trial tests if an intervention, like metformin, can delay the onset of a second age-related disease in individuals with one age-related disease.✓Well SupportedMetformin likely works primarily by slowing the conversion of NADH back to NAD+ through inhibiting Complex I of the electron transport chain.✓Well SupportedMetformin serves as a valuable tool to demonstrate the principle of targeting aging, paving the way for future, more effective drugs and combination therapies.✓Well SupportedTargeting the biology of aging aims to improve both healthspan and lifespan simultaneously.Partially Supported

More from Peter Attia

Peter Attia on Zone 2 Cardio

Peter Attia on Rapamycin (with Matt Kaeberlein)

Attia walks back the clinic protocol: too aggressive for healthy adults

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A. Volkovreader

4h

Bookmarking — the dossier-vs-overview split is the right call. Most of the time I want overview; sometimes I want receipts.

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◐

NAD+ precursors like nicotinamide riboside (NR) are broken down in the gastrointestinal tract, primarily into nicotinic acid (niacin), when taken orally.

✓Well SupportedThe longevity gene FOXO3 is associated with increased lifespan in model organisms and a higher chance of becoming a centenarian in humans.

◐Partially SupportedMetformin's action on mitochondrial Complex I affects the NAD+/NADH ratio, influencing cellular signaling like lactate to pyruvate conversion.

◐Partially SupportedThe TAME trial for metformin is in a preliminary state, with enrollment currently starting after securing initial funding.

✓Well SupportedA common mutation involving the deletion of exon 3 in the growth hormone receptor is present in 3-4% of the general population and 12% of centenarians.

✓Well SupportedMetformin has shown life extension effects in various animal models, with a milder effect on longevity (10%) compared to its effect on healthspan (50% improvement).

✓Well SupportedThe TAME study aims to gain FDA approval for aging as an indication.

✓Well SupportedDiabetic patients taking metformin have lower all-cause and cause-specific mortality compared to diabetics not taking metformin.

✓Well SupportedIndividuals with the CTP VV genotype exhibit higher HDL levels, larger lipoprotein particle size, and lower CETP levels.

◐Partially SupportedThe optimal range for Insulin-like Growth Factor 1 (IGF-1) is likely between the 60th and 80th percentile.

✓Well SupportedIn centenarian females, lower IGF-1 levels predict longer longevity.

◐Partially SupportedA 24-hour fast-feed cycle in mice that extends lifespan is equivalent to approximately a 5-day fast in humans.

✓Well SupportedTreatment of 18-month-old mice with mouse-Ganitumab extended female lifespan by approximately 10%.

?Limited ResearchMetformin's safety and efficacy for longevity in non-diabetic individuals has not been established.

◐Partially SupportedIntravenously administered NAD+ is likely partially broken down due to unknown cellular uptake mechanisms from the bloodstream.

✓Well SupportedMetformin acts as a weak inhibitor of mitochondrial respiration at complex I, leading to reduced ROS production and inflammation.

◐Partially SupportedPhenformin was a more powerful drug than metformin and its significant effect contributed to fear around bringing metformin to the US.

✓Well SupportedThe timing of food intake may be as important, or more important, than the composition of the diet for longevity.

◐Partially SupportedMetformin is a drug used for over 50 years in Europe and 40+ years in the U.S. as a first-line treatment for type 2 diabetes.

✓Well SupportedA 48-hour fast in humans can reduce IGF-1 levels by approximately 50%, which typically requires 5 to 7 days of fasting.

◐Partially SupportedMetformin is known to inhibit mitochondrial complex I.

◐Partially SupportedMetformin's geroprotective effects in non-diabetics may involve fundamental mechanisms beyond glucose homeostasis regulation.

✓Well SupportedThe hypothesis for the TAME trial is that aging processes continue and can be intervened upon even after the onset of the first disease.

✓Well SupportedDecreasing IGF-1 and growth hormone levels in mice, worms, and flies leads to a 50% extension in lifespan, while overexpressing them reduces lifespan by 50%.

✓Well SupportedInsulin resistance in muscle can lead to fat accumulation in the liver, resulting in fatty liver disease.

✓Well SupportedMetformin use in people with type 2 diabetes is associated with significantly less breast cancer, regardless of diabetes status, obesity, or hyperinsulinemia.

✓Well SupportedAMPK activation by metformin leads to downstream inhibition of mTOR activity and increased autophagy.

✓Well SupportedCentenarians have lower medical costs in the last two years of life compared to 70-year-olds.

✓Well SupportedNir Barzilai's sleep quality has improved since starting NMN, with more deep sleep and REM sleep.

✓Well SupportedAging is the primary risk factor for cardiovascular disease, cancer, and Alzheimer's.

◐Partially SupportedOffspring of centenarians exhibit significantly better health than controls, with substantially less heart disease.

✓Well SupportedMutations that reduce growth hormone or IGF-1, or result in dwarfism, are associated with increased lifespan in some animal models.

◐Partially SupportedCentenarians delay the onset of chronic diseases like cancer and heart disease by 20-25 years.

◐Partially SupportedIndividuals with a deletion of exon 3 in the growth hormone receptor have lower IGF-1 levels.

◐Partially SupportedThe concentration of Lp(a) gene in centenarians does not flatline after age 80, requiring further investigation.

✓Well SupportedPreventing aging can prevent many age-related diseases and has a significant, low-cost impact.

◐Partially SupportedIn Zucker rats, the absence of visceral fat prevented diabetes development, but once visceral fat regrew, diabetes developed.

◐Partially SupportedMetformin may enable individuals to dispose of glucose with lower insulin levels by activating AMPK, especially when combined with intense exercise.

◐Partially SupportedMetformin's primary mechanism of action is liver-focused, unlike sulfonylureas or TZCDs.

◐Partially SupportedThe clinical definition of insulin resistance is solely based on the ability of insulin to clear glucose from the blood into muscle.

✓Well SupportedNir Barzilai suggests the term 'geroprotection' for interventions that protect against aging.

✓Well SupportedHuman dwarfs with Laron syndrome have less cancer and diabetes.

◐Partially SupportedMetformin, rapamycin, and NAD+ precursors (NR, NMN) are frequently inquired about by patients and friends regarding longevity.

◐Partially SupportedNir Barzilai is conducting a study on metformin but is not promoting it to individuals due to scientific neutrality.

?Limited ResearchOral doses of NR or NMN in commercial supplements may not significantly increase intracellular NAD levels in a physiologically meaningful way.

◐Partially SupportedThe concentration of the CTP VV genotype increases significantly after age 80, with 8% of the population having it at age 55 and 20% at age 100.

◐Partially SupportedLpa levels drop by half until age 80 and then increase in centenarians, suggesting a protective role in aging.

✓Well SupportedInsulin resistance is a protective mechanism where cells stop taking in excessive glucose to prevent overload.

◐Partially SupportedCETP inhibition reduces LDL by upregulating liver LDL receptors and clearing LDL particles more efficiently.

✓Well SupportedThe minimum time required to induce autophagy through fasting is difficult to determine in humans due to challenges in obtaining tissue biopsies.

◐Partially SupportedMetformin may reduce the risk of Alzheimer's disease and cognitive deterioration in individuals with MCI.

✓Well SupportedMetformin's functional benefit is shutting down inappropriate gluconeogenesis in the liver of insulin-resistant individuals, thereby blocking hyperglycemia.

✓Well SupportedPatients taking metformin experienced a 46% reduction in head/neck cancers and a 55% reduction in stomach cancers.

?Limited ResearchThere is no clear data to support or refute whether prescribing growth hormone shortens lifespan, despite theoretical arguments for potential harm.

◐Partially SupportedIn type 2 diabetes, metformin lowers glucose and leads to better outcomes, while insulin-raising drugs with similar glucose lowering have different macrovascular outcomes.

◐Partially SupportedDrugs that are NAD+ precursors and can enter cells outside the liver are a promising area for NAD+ research.

◐Partially SupportedThe TAME study will randomize participants 1:1 to receive either 2 grams or 1500mg of metformin, or a placebo.

✕Not SupportedNIH reviewers questioned the concept of targeting aging with a single drug, suggesting separate studies for each disease.

◐Partially SupportedThe precise impact of each aging pathway in humans is not yet fully understood, with most current data derived from animal studies.

✕Not SupportedValter Longo is not enthusiastic about working with rapamycin due to concerns about blocking central cellular metabolism and potential side effects like hyperglycemia, testicular degeneration, and cataracts.

◐Partially SupportedReduced insulin receptor signaling (daf-2 model in C. elegans) leads to increased visceral fat accumulation and extended lifespan.

◐Partially SupportedNicotinamide riboside (NR) or other NAD+ precursors are frequently asked about by patients and the public as potential longevity interventions.

◐Partially SupportedMetformin, a chemical derived from the French lily, may function as a plant defense chemical not beneficial for humans.

✓Well SupportedStarting metformin at a lower dose (e.g., 500mg qhs) and gradually increasing it leads to less nausea and less weight loss compared to starting at a high dose (2.5g/day).

◐Partially SupportedAdipocytes release free fatty acids into the blood via hormone-sensitive lipase, which impacts insulin sensitivity or resistance.

?Limited ResearchThe data on growth hormone receptor is disproportionately from men, and it is difficult to definitively state that giving growth hormone is bad.

◐Partially SupportedMany non-AMPK activities of metformin require higher doses than those needed for AMPK activation.

◐Partially SupportedMetformin may be effective for longevity by moderately modulating multiple pathways at a 'B+' level.

✓Well SupportedMetformin can prevent diabetes by 30% in pre-diabetic individuals.

◐Partially SupportedCentenarians have a higher prevalence of mutations predicted to cause disease, suggesting these mutations are not necessarily detrimental to longevity.

✓Well SupportedOptimal health and longevity strategies should address multiple physiological markers and pathways simultaneously.

✓Well SupportedSupercentenarians often have loss-of-function mutations in genes like IGF-1 and growth hormone, leading to proteins that work less effectively than normal.

◐Partially SupportedIndividuals with homozygosity in the growth hormone receptor gene live longer.

◐Partially SupportedMuscle contraction can stimulate insulin-independent glucose uptake by moving glucose transporters to the muscle cell surface.

◐Partially SupportedChecking IGF-1 is usually sufficient to assess adequate growth hormone and IGF-1 levels.

◐Partially SupportedThe three main factors impacting IGF-1 are amino acid intake, insulin levels, and exogenous growth hormone.

◐Partially SupportedOnly about 100 out of 20,000 human genes are deterministic, meaning they guarantee a specific disease if mutated.

✓Well SupportedRestricting proteins in caloric-restricted individuals decreases IGF-1 levels.

✓Well SupportedAkkermansia muciniphila can extend lifespan and improve healthspan in nematodes.

◐Partially SupportedCyclic fluctuations in IGF levels through fasting and refeeding may be healthier for longevity than constant caloric restriction.

◐Partially SupportedMetformin has billions of patient-years of safety data, making it a low bar for FDA approval, and is interesting for longevity studies.

◐Partially SupportedStudying metformin's effects in non-diabetics via randomized clinical trials is justified despite the high cost and ambition.

✕Not SupportedThere is insufficient data and lack of well-controlled clinical studies to definitively support the efficacy of NAD+ precursors like NMN or NR.

◐Partially SupportedThe median IGF-1 level for individuals over 65 is approximately 100 ng/dL.

◐Partially SupportedAdministering insulin, glucose, IGF, or leptin to the hypothalamus can affect peripheral tissues.

◐Partially SupportedMerck provides metformin and placebo for the TAME study, and generic metformin is considered equally efficacious to branded versions.

✓Well SupportedRapamycin should be dosed selectively, not daily, to avoid interfering with mTORC2.

◐Partially SupportedThe TAME trial's statistical design must avoid significant findings in any single disease to prevent premature study stoppage, except for mortality.

◐Partially SupportedInsulin signals muscles to bring glucose transporters to the cell surface for passive glucose uptake.

◐Partially SupportedEstrogen can be beneficial in younger animal models by reducing stroke size when administered after ovariectomy, but it can worsen stroke outcomes in older animals.

◐Partially SupportedWomen with the lowest IGF-1 levels exhibit significantly less cognitive decline than those with the highest levels.

✓Well SupportedAn IGF-1 level of 129 ng/mL is not a concern and is considered valuable.

◐Partially SupportedThe FDA does not consider aging a disease and therefore does not prioritize research or approval for aging as a condition.

◐Partially SupportedMetformin binds to mitochondrial Complex I, influenced by Oct1 transporter concentration and distribution, especially in the liver.

◐Partially SupportedMetformin affects genes beyond metabolism, including BRCA1 and myofibrillar genes, suggesting broader anti-aging effects.

✓Well SupportedMetformin is associated with weight loss, which may be partly explained by reduced appetite due to nausea.

✓Well SupportedCentenarians exhibit compression of morbidity, living longer and healthier lives before a rapid decline.

?Limited ResearchThere is no clear dose equivalence established between metformin and rapamycin/rapalogs for achieving equivalent mTOR inhibition.

◐Partially SupportedMetformin can lower insulin levels and inflammatory factors, potentially by fixing cellular aging.

◐Partially SupportedThe APOE4 genotype is present in centenarians who are not demented or deceased at older ages.

◐Partially SupportedAn IGF receptor antibody tested in humans could potentially be indicated for aging but requires another indication for commercialization.

◐Partially SupportedHormone replacement therapy was not a primary focus of Nir Barzilai's early work on aging.

◐Partially SupportedRapamycin causes insulin resistance and animals treated with it live longer.

◐Partially SupportedThe long-term cost burden of diabetes is substantial, making prevention interventions valuable.

◐Partially SupportedIndividuals with IGF receptor resistance have higher IGF-1 levels but are shorter.

◐Partially SupportedJoseph Kraft samples glucose and insulin for 2-5 hours to research insulin resistance.

◐Partially SupportedA 120-minute glucose tolerance test threshold may not be sufficient to capture the full insulin response in elderly individuals.

◐Partially SupportedInsulin resistance in muscle is defined as a fixed amount of insulin producing fewer GLUT4 transporters.

◐Partially SupportedThe clinical world rarely measures insulin in type 2 diabetic patients, and measuring it may not be useful.

◐Partially SupportedResveratrol trials may be inconclusive because they do not administer sufficient amounts in the correct biological context.

◐Partially SupportedHigher IGF-1 levels are associated with lower mortality from heart disease and diabetes, but higher mortality from cancer.

◐Partially SupportedMetformin can exert epigenetic effects, such as histone deacetylation, independent of mitochondrial function.

◐Partially SupportedThe FDA rejected metformin for pre-diabetes despite data showing it prevents diabetes by 30%.

◐Partially SupportedMetformin may cause weight loss in individuals who are not overweight, potentially due to reduced hunger or improved leptin response.

◐Partially SupportedIn 1980s studies, metformin administration increased lactic acid within the normal range without changes in pH or anion gap.

✕Not SupportedThe Women's Health Initiative (WHI) study was flawed due to its use of oral conjugated equine estrogens and synthetic progestins, rather than actual progesterone, and its focus solely on women.

◐Partially SupportedIn rats, caloric restriction without visceral fat accumulation provides about half the lifespan benefit compared to caloric restriction with visceral fat.

◐Partially SupportedFOXO 3a acts as a housekeeper gene, regulating cellular homeostasis by controlling the influx of beneficial substances and other processes.

◐Partially SupportedA composite outcome measure combining multiple disease endpoints is appropriate for studying interventions targeting aging.

◐Partially SupportedGenetic analysis should focus on pathways rather than individual SNPs to understand complex multifactorial diseases and traits.

◐Partially SupportedEndocrinology is a relevant field for studying aging because hormonal changes are associated with the aging process.

◐Partially SupportedA standard oral glucose tolerance test should measure glucose and insulin at baseline and at 30, 60, 90, and potentially 120 minutes.

◐Partially SupportedRats fed ad libitum that did not accumulate visceral fat maintained weight later in life and showed improved healthspan and insulin levels compared to those that did.

◐Partially SupportedElderly individuals may have insufficient insulin to stimulate glucose uptake in muscle, leading to glucose intolerance.

◐Partially SupportedNir Barzilai's hypothesis is that the primary driver of aging is the insulin resistance syndrome, characterized by visceral fat accumulation.

◐Partially SupportedInsulin resistance can be induced rapidly in rats by administering glucose, free fatty acids, and other substances.

◐Partially SupportedSome animals with insulin resistance live longer, while highly insulin-sensitive animals have shorter lifespans.

◐Partially SupportedInsulin resistance can lead to faster development of macrovascular disease and potentially diabetes.

◐Partially SupportedTransgenic animals (PT P1A) that are highly insulin-sensitive have half the lifespan of wild-type animals.

◐Partially SupportedMicro RNA 142 may be a better therapeutic approach than an IGF receptor antibody for decreasing IGF receptor in cancers.

✕Not SupportedThe overemphasis on single genetic SNPs in research is akin to the 'drunk in the streetlight' problem.

✕Not SupportedThe phenotype of centenarians may reflect impending death rather than healthspan.

◐Partially SupportedRemoving visceral fat in rats on an ad libitum diet provided approximately half the lifespan benefit of caloric restriction.

◐Partially SupportedThe liver's primary role is glucose production, and its failure would lead to rapid death from hypoglycemia.

◐Partially SupportedIn female mice treated with an IGF receptor antibody, inflammatory markers decreased with aging, and the drug further reduced them, while in males, inflammatory markers increased with treatment.

◐Partially SupportedPreliminary data suggest metformin is associated with diseases, and a small study showed it improved outcomes in 15 older adults compared to placebo.

◐Partially SupportedMetformin's effects on metabolic parameters in older adults may be more pronounced in individuals who start metformin before placebo in crossover studies due to insufficient washout periods.

◐Partially SupportedMetformin, rapamycin, and resveratrol can improve various biological markers.

◐Partially SupportedMetformin affects aging pathways like AMPK and mTOR in a tissue-specific manner.

◐Partially SupportedIn vitro studies show metformin can sensitize muscle to insulin.

◐Partially SupportedGene-to-gene interactions, such as the combination of Lp(a) genotype, CTP level, HDL level, and HDL particle size, may explain why some individuals with high Lp(a) do not develop premature heart disease.

◐Partially SupportedUnderstanding the non-virulent Lp(a) phenotype in centenarians could lead to better risk stratification for the general population with elevated Lp(a).

◐Partially SupportedSurgical removal of visceral fat depots in rats after puberty, even with ad libitum feeding, led to significantly longer lifespan (20% increase) compared to sham surgery controls, though not as much as caloric restriction.

◐Partially SupportedA patient requiring a higher insulin level (e.g., 90 IU) to clear glucose compared to another patient (e.g., 30 IU) may be at higher risk of developing hyperinsulinemia and future struggles with glucose disposal.

◐Partially SupportedAn IGF receptor antibody used in a mouse study did not cross the blood-brain barrier.

◐Partially SupportedThe FDA focuses longevity studies on cardiovascular disease, cancer, and Alzheimer's mortality, not diabetes as a primary outcome.

◐Partially SupportedIn Sprague Dawley rats, the primary causes of death were kidney disease and cancers, regardless of visceral fat removal or feeding regimen.

◐Partially SupportedThe development of subsequent diseases is influenced by genetics and environment, but aging is the underlying biological process.

◐Partially SupportedMany interventions, including those related to NAD+, are not based on clinical studies, highlighting the need for such trials to avoid guesswork.

◐Partially SupportedApproximately 30% of centenarians exhibit overexpression of microRNAs that can modulate signaling pathways.

◐Partially SupportedLesioning the ventral hypothalamus in animals increases food intake and alters peripheral physiology.

✕Not SupportedHDL cholesterol is a poor metric for cardiovascular health.

◐Partially SupportedInsulin receptor substrates (IRS) 1 and 2 are present in multiple tissues, including muscle and liver.

◐Partially SupportedIGF-1 levels are not associated with better or worse muscle function in males or females.

◐Partially SupportedSelective hepatic vagotomy negates metabolic effects achieved through hypothalamic intervention, indicating the necessity of the vagus nerve.

◐Partially SupportedThe liver uses a constitutively expressed glucose transporter (GLUT2) that is not significantly stimulated by insulin, making glucose uptake primarily gradient-driven.

◐Partially SupportedCentenarian data reveals an 'U' shaped mortality curve with the lowest mortality between the 60th and 80th percentile of all-cause mortality.

◐Partially SupportedIncreased growth hormone is associated with decreased lifespan in some animal models.

◐Partially SupportedLPA may be protected by homozygous CTP mutations, which are associated with longevity.

◐Partially SupportedNir Barzilai is currently taking a preparation of NMN.

◐Partially SupportedIndividuals with the CTP VV genotype have higher HDL, larger lipoprotein particle size, and lower CTP levels, a phenotype protective against age-related diseases, notably cognitive decline.

◐Partially SupportedEpidemiological data suggests growth hormone and IGF may be detrimental, but dose, age, and gender require nuanced understanding.

◐Partially SupportedIndividuals with hyperinsulinemia may be at increased risk for heart attacks or stroke due to insulin resistance affecting atherotic plaque development.

◐Partially SupportedHigh growth hormone levels are associated with high activation and proliferation in lymphocytes.

◐Partially SupportedInsulin resistance is characterized by hyperinsulinemia and elevated glucose levels, often associated with obesity.

◐Partially SupportedThe TAME study is planned to enroll 3,000 subjects aged 65-80, with enrollment potentially starting in early 2019.

✕Not SupportedGrowth hormone treatment may be dangerous for elderly people, particularly women.

?Limited ResearchThe effectiveness of companies selling nicotinamide riboside plus pterostilbene (like ChromaDex and Elysium) is uncertain in light of studies questioning NR's cellular uptake.

◐Partially SupportedThe human analog of C. elegans DAF-2 is the insulin receptor, and DAF-16 is a transcription factor.

◐Partially SupportedA UK study followed patients prospectively for five years, but the duration of metformin use prior to the study was unknown.

◐Partially SupportedMetformin use in patients with kidney failure or heart attack is associated with lactic acidosis, rather than metformin directly causing it.

◐Partially SupportedThe average dose of metformin in the UK study was approximately 1000 milligrams, with average usage around 1500 milligrams.

◐Partially SupportedMetformin has a known and established dose and frequency, unlike rapamycin and resveratrol for which optimal dosing is still being determined.

?Limited ResearchLow IGF or growth hormone may be beneficial in males, but this has not been demonstrated in rodent or human studies.

◐Partially SupportedThere are multiple types of autophagy, including macroautophagy and chaperone-mediated autophagy, which can be measured.

◐Partially SupportedInterventions targeting any of the nine interconnected pillars of aging can lead to improvements in other pillars.

◐Partially SupportedAging is a universal biological process across all animals, affecting similar systems like skeletal structure and frailty.

◐Partially SupportedThe FeedB device may work better than the Oura ring for measuring sleep.

◐Partially SupportedVisceral fat removal in mammals generally leads to increased insulin sensitivity.

✕Not SupportedAging research has historically focused on males, potentially missing sex-specific effects.

✕Not SupportedFocusing on clusters of functional mutations is more effective for longevity research than GWAS.

◐Partially SupportedCaloric restriction decreases visceral fat.

◐Partially SupportedIn rats, removal of visceral fat after puberty did not lead to re-accumulation of visceral fat or significant changes in subcutaneous fat.

◐Partially SupportedEarly rodent studies suggested metformin could extend lifespan and improve healthspan, with initial hypotheses exploring anti-cancer effects.

✕Not SupportedThe FDA declined to approve metformin for pre-diabetes due to a narrow definition of indications.

◐Partially SupportedThe liver utilizes the GLUT2 glucose transporter for glucose uptake, which is not translocated.

◐Partially SupportedA type 1 diabetic patient with strict diet and high exercise requires 6-8 units of insulin daily to maintain A1c below 6%.

◐Partially SupportedThe Seahorse assay measures mitochondrial action, showing relationships between oxygen consumption and polarity, and is sensitive to drugs affecting mitochondrial activity.

◐Partially SupportedThe TAME study has secured approximately $35 million in philanthropic funding, with the remaining half of the $70 million budget expected from other sources.

◐Partially SupportedMetformin may have already saved more patient lives from cancer than all other cancer drugs combined.

◐Partially SupportedMutations in the growth hormone and IGF-1 system are common genomic alterations found in centenarians.