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Weekly · Sunday Morning

Five longevity claims.
Worth your time.
Every Sunday.

Last Sunday

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
Verdict change — caffeine half-life downgraded

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How to slow down aging! A conversation with David Sinclair PhD — Whalespan

Content›Video›How to slow down aging! A co…

How to slow down aging! A conversation with David Sinclair PhD

Paul Saladino1h 54m · 2019-11-05

Claims Made

204

Claims Supported

144

Support Rate

71%

Support rate

144 of 204 claims supported

144 supported60 partial / not

Claims from this content

170

✓Well SupportedRegenerative agriculture practices benefit the animal, the soil, and the overall ecosystem.✓Well SupportedThe Information Theory of Aging posits that aging is caused by the deregulation of genes over time.✓Well SupportedDavid Sinclair has practiced time-restricted feeding by not eating breakfast since his teenage years.✓Well SupportedRestricting methionine for longevity is unnecessary; providing sufficient glycine is an alternative approach.◐Partially Supported

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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 SupportedDNA damage is a foundational piece of aging, and sirtuins, PARP enzymes, and NAD+ are involved in DNA repair.

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

✓Well SupportedDNA breaks leave lasting epigenetic scars consistent with The Information Theory of Aging.

✓Well SupportedmTOR is a nutrient-responsive kinase that aligns with calorie restriction data for lifespan extension.

✓Well SupportedGenetics account for approximately 16% of lifespan, while lifestyle factors account for 40% or more.

◐Partially SupportedSome plant compounds can be detrimental to certain individuals.

✓Well SupportedDavid Sinclair has been taking resveratrol since 2003 without apparent harm and reports a heart that appears 20 years younger on MRI.

✓Well SupportedSirtuins are enzymes that regulate genes and perform cellular functions including DNA repair, telomere maintenance, mitochondrial health, and inflammation control.

✓Well SupportedLongevity genes and pathways, such as sirtuins and mTOR, communicate with each other.

✓Well SupportedDavid Sinclair's information theory of aging challenges the status quo.

✓Well SupportedSirtuins are NAD-dependent enzymes that consume NAD+ during their activity.

✓Well SupportedAncestral Supplements produces grass-fed, grass-finished organ complex supplements using low-temperature dehydration.

✓Well SupportedBeta-hydroxybutyrate affects gene transcription, suggesting ketones have epigenetic effects.

◐Partially SupportedThe hallmarks of aging include mitochondrial dysfunction, loss of stem cells, senescence, nutrient deregulation, and telomere shortening.

✓Well SupportedDisrupting information in mouse cells led to aging and the manifestation of hallmarks of aging, supporting the hypothesis that information loss is a major cause of aging.

✓Well SupportedIncreased copies of genes for Sirtuins are associated with better DNA repair and longer lifespan.

◐Partially SupportedSulforaphane from various sources can have side effects.

✓Well SupportedMetformin activates AMPK by activating complex one involved in mitochondrial energy production, which lowers cellular ATP levels and triggers mitohormesis.

✓Well SupportedDavid Sinclair has trained his liver to produce sufficient sugar, eliminating hunger, by drinking liquids or nibbling on nuts if necessary.

✕Not SupportedResveratrol has failed in human trials for conditions like non-alcoholic fatty liver disease and metabolic syndrome, and in the latter, it worsened dysglycemia.

✓Well SupportedThe PARP enzyme consumes NAD+ by cleaving off the nicotinamide molecule to create ADP-ribose polymers on DNA, serving as a signal for repair.

✓Well SupportedIncreased sirtuin activity is a major area of longevity research.

✓Well SupportedThe ratio of NAD+ to NADH and absolute NAD+ levels are important for sirtuin function.

✓Well SupportedKetones act as signaling molecules that strengthen the body during stressful periods like food scarcity.

◐Partially SupportedNAD+ is consumed by sirtuins and PARPs as a cofactor, and sirtuin consumption cleaves it into nicotinamide and ADP-ribose.

✓Well SupportedKetosis can increase NAD+ levels and potentially activate longevity pathways similar to caloric restriction and exercise.

✓Well SupportedActivating mTOR is necessary for muscle building and maintaining muscle mass, which is important for longevity, insulin sensitivity, and avoiding sarcopenia.

✓Well SupportedActivating all seven sirtuins and replenishing NAD+ levels may be more effective than activating a single sirtuin.

◐Partially SupportedMolecules previously thought to affect only one longevity pathway also have connections to other pathways.

✕Not SupportedHigh doses of nicotinamide should be avoided unless the patient has cancer, as it inhibits sirtuins.

✓Well SupportedSirtuins require NAD to deacetylate lysine residues, which is important for DNA integrity and managing oxidative stress.

✓Well SupportedUnhealthy user bias and healthy user bias consistently confound observational studies examining the link between red meat and colon cancer.

✕Not SupportedNicotinamide may inhibit sirtuin activity.

✓Well SupportedAs individuals age, sirtuins increasingly prioritize DNA repair over epigenome control.

✓Well SupportedCalorie restriction activates longevity genes, specifically sirtuins, which fight aging and age-related diseases when the body is hungry.

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

✓Well SupportedCaloric restriction's beneficial effects are mediated through sirtuins, suggesting sirtuin activators could be therapeutically significant.

✓Well SupportedAltering mTOR signaling in the right way may slow aging in humans, though human data is not fully validated.

✓Well SupportedThe critical factor for longevity benefits from time-restricted feeding is the period of not eating, rather than the satiety from eating.

✓Well SupportedTwice daily 500 mg resveratrol for 60 days decreased fasting blood sugar, hemoglobin A1c, and malondialdehyde in patients with type 1 diabetes.

✓Well SupportedResveratrol was the best molecule found in a screen for Sirt-1 activators, increasing activity 13-fold.

✓Well SupportedActivation of AMPK leads to increased mitochondrial production, providing long-term health benefits.

✓Well SupportedHigh doses of resveratrol can ameliorate type 2 diabetes or fasting blood sugar levels, particularly in severely obese individuals with high blood sugar.

◐Partially SupportedCold exposure turns on sirtuins, including SIRT3, which is involved in brown fat production.

◐Partially SupportedFor individuals with insulin resistance or elevated fasting insulin (above 5 or 8 micro IU/mL), a ketogenic diet can be very helpful in the short term.

✓Well SupportedIt is beneficial to cycle mTOR inhibition.

◐Partially SupportedA ketogenic carnivore diet, combined with leucine signaling, can provide precise and short-term mTOR activation with less carryover effect.

✓Well SupportedNicotinamide acts as a feedback inhibitor of sirtuins, slowing NAD+ production.

◐Partially SupportedCurcumin has anti-inflammatory effects, potentially via prostaglandin pathways, but can also negatively affect DNA topoisomerase II and the HERG potassium channel.

◐Partially SupportedMetformin can reduce muscle size, but this effect is not as detrimental as it sounds because muscles remain equally strong.

◐Partially SupportedNicotinamide is not sufficiently effective on its own for boosting NAD levels.

◐Partially SupportedGenes like FoxO3 and PGC-1 alpha are turned on by sirtuins and AMP kinase and may control NAMPT, positively affecting aging, epigenetics, and longevity.

✓Well SupportedInducing DNA breaks in mice over three weeks can result in mice that are 50% older.

◐Partially SupportedKetones replicate partial fasting state physiology, which conserves NAD+ and benefits DNA repair and telomere lengthening via sirtuins.

✓Well SupportedOral supplementation with 250mg each of NR and NMN (total 0.5g) is relatively safe if homocysteine levels are monitored.

◐Partially SupportedAn animal-based or carnivorous diet is beneficial for human health.

✕Not SupportedThe negative effects of phytochemicals like turmeric and resveratrol are often ignored in favor of perceived benefits.

✕Not SupportedHigh doses of nicotinamide or niacin derivatives can deplete methyl groups, leading to anxiety.

✓Well SupportedSirtuins are among the first proteins to respond to a broken chromosome, with SIRT1 recruiting HDAC1 to remodel chromatin for repair proteins.

◐Partially SupportedmTOR should be cycled on and off through fasting, ketogenic diet, or consuming animal proteins rich in leucine.

✓Well SupportedOverexpressing NMPT leads to higher NAD levels and better survival from toxins.

◐Partially SupportedNAMPT is found in the bloodstream and acts both inside cells and as a blood factor regulating body and brain health.

✓Well SupportedResveratrol acts as an accelerator pedal for sirtuins, while NAD+ provides the necessary 'gas' for the enzyme's function.

✓Well SupportedResveratrol inhibits mTOR by blocking the interaction between Deptor and mTOR.

◐Partially SupportedAMPK and mTOR function antagonistically.

✓Well SupportedRelative changes in metabolic state through intermittent fasting used intermittently (2-3 times/week) provide more benefits than daily application.

✓Well SupportedIncreased DNA breaks may lead to the loss of epigenetic coding and information, acting as an arbiter of aging.

✓Well SupportedDNA damage from external factors accelerates the loss of epigenetic information.

◐Partially SupportedHistone methylation can silence a gene, while acetylation can activate it.

◐Partially SupportedHigher altitudes and space environments increase DNA breaks due to higher radiation.

◐Partially SupportedMaintaining high mitochondrial NAD+ levels may help cells survive severe injury by preventing cell death.

◐Partially SupportedColostrum contains antibodies and may benefit gut issues by reducing inflammation.

◐Partially SupportedNAD+ can be synthesized from tryptophan, which feeds into the nicotinic acid pathway.

◐Partially SupportedXeno-hormetic molecules like resveratrol are plant compounds produced by plants under stress that can confer hormetic benefits to humans.

◐Partially SupportedThe type and cause of DNA breaks may differ in their impact on aging and repairability.

◐Partially SupportedDavid Sinclair plans to work out for three hours tomorrow, incorporating hot and cold exposure, endurance, and weightlifting, and will not avoid meat or take metformin.

✓Well SupportedKetogenic diets result in low insulin, low IGF-1, and suppression of mTOR due to moderated protein intake.

◐Partially SupportedFactors that cause DNA breaks, such as sunlight, ambient radiation, chemotherapy drugs, and X-rays, can accelerate aging.

✕Not SupportedChemotherapy drugs can accelerate aging.

✕Not SupportedThe historical theory that free radical damage and DNA damage are the primary causes of aging is not well-supported by current data.

◐Partially SupportedIt is possible to activate longevity pathways and achieve optimal antioxidant status without consuming fruits and vegetables.

✓Well SupportedResveratrol was most effective in mice when administered every other day.

◐Partially SupportedBetaine (TMG) or a combination of methylfolate and methyl B12 can be used to ensure adequate methyl group supply.

✓Well SupportedFasting periods may impact longevity more than specific food choices, provided the diet is not a standard American diet.

◐Partially SupportedThe water usage of ruminant animals is significantly less than often portrayed by vegans.

✓Well SupportedA person on a ketogenic, calorie-deprived diet might have low-normal IGF-1, potentially requiring a higher growth hormone dose to achieve optimal levels.

◐Partially SupportedCertain food molecules, including isothiocyanates, cocoa polyphenols, and chlorogenic acid, can cause DNA breaks.

◐Partially SupportedMice unable to have SIRT1 activated by resveratrol live longer on a high-fat diet.

◐Partially SupportedResveratrol may activate Sirt1 and AMPK, and inhibit mTOR by blocking the interaction between mTOR and Raptor.

◐Partially SupportedTime-restricted feeding, but not changing the ratio of macronutrients, affected lifespan in a study in mice.

◐Partially SupportedThe body requires rest and recovery, similar to how one should not exercise intensely every day.

✓Well SupportedTime-restricted feeding may activate longevity genes like sirtuins.

◐Partially SupportedNusir claims leucine directly activates SIRT1, similar to resveratrol.

◐Partially SupportedDavid Sinclair's book details family practices, supplements, science behind interventions like cold exposure and diet, and provides extensive references.

◐Partially SupportedNAD+ is a carrier of hydrogen atoms between proteins, with NAD+ being converted to NADH, which carries the hydrogen.

◐Partially SupportedThe enzyme NAMPT recycles nicotinamide back to NMN, and its function appears to be regulated by inflammation.

◐Partially SupportedResveratrol requires dissolution in a lipophilic medium to be absorbed effectively.

◐Partially SupportedResveratrol has been found to worsen glycemic control in some trials involving patients with metabolic syndrome.

◐Partially SupportedOver-the-counter niacin is typically sold as nicotinic acid, which is converted to nicotinamide during the detoxification process.

◐Partially SupportedSirtuins are conserved enzymes across species that act as epigenetic regulators, controlling gene silencing.

◐Partially SupportedSirtuins are one of three major types of longevity genes.

◐Partially SupportedNiacinamide differs from NMN by lacking the sugar and phosphate components necessary for NAD synthesis.

◐Partially SupportedTime-restricted eating is being experimented with.

◐Partially SupportedThe benefit of caloric restriction for lifespan in mice may be due to time-restricted feeding rather than calorie reduction alone.

◐Partially SupportedThe aging process in mice can be induced by disrupting DNA loops and packages, not by directly altering methyls, mitochondria, or telomeres.

◐Partially SupportedSome plant toxins may create DNA breaks, similar to chemotherapy drugs.

◐Partially SupportedKetones, such as butyrate, are relevant to the epigenome because histones can be butyrolated.

?Limited ResearchResveratrol may act as an endocrine disruptor and have negative side effects.

◐Partially SupportedStressors such as heat and low food availability can stimulate the body's production of NAD+.

◐Partially SupportedSirtuins, NAD, NR, and NMN are related to DNA repair, PARP enzymes, and NAD partitioning within the cell.

◐Partially SupportedNAD+ is synthesized from vitamin B3, specifically nicotinic acid or nicotinamide, which are converted to ADP-ribose and then NMN, before finally becoming NAD+.

◐Partially SupportedA ketogenic carnivore diet with leucine signaling may lead to more precise and shorter mTOR activation compared to a carbohydrate-rich diet.

◐Partially SupportedSirtuins downregulate inflammation and compact DNA by deacetylating NF-kappaB and histones.

◐Partially SupportedInsulin is a stronger trigger for mTOR signaling than leucine in human myotubes.

◐Partially SupportedInsulin and IGF-1 receptors are located downstream of the mTOR pathway.

◐Partially SupportedLKB1 is a kinase that regulates and boosts AMPK activity.

◐Partially SupportedNAD+ is composed of nicotinamide and ADP-ribose.

◐Partially SupportedA ketogenic diet may provide health benefits that negate the need for xenohormetics.

◐Partially SupportedSauna, cold stress, exercise, and ketosis can activate similar gene expression patterns that promote longevity.

◐Partially SupportedDNA breaks occur constantly, with an estimated twenty trillion breaks per day in the human body.

◐Partially SupportedHigh NAD+ levels activate the LKB1, AMPK, and sirtuin pathway, increasing mitochondrial activity and ATP production.

◐Partially SupportedSirtuins act as 'traffic cops' in cells, regulating genes as silencers and controlling proteins involved in DNA repair, telomeres, mitochondria, and inflammation.

◐Partially SupportedEpigenetic information systems tell cells which genes to read to maintain cell identity and this information is lost during aging.

?Limited ResearchThere are questions regarding whether humans should be in a constant state of ketosis.

◐Partially SupportedThe benefits of caloric restriction may be achievable by compressing the feeding window with the same total calorie intake.

◐Partially SupportedSirtuins activate transcription factors like FoxO3 and PGC-1 alpha, which are important for cellular defense and metabolism.

◐Partially SupportedThe paper 'NAD in Aging Metabolism and Neurodegeneration' by Eric Ford in Science (December 4, 2015) is recommended for understanding NAD metabolism.

◐Partially SupportedDavid Sinclair produces a significant amount of glucose from his liver upon waking.

◐Partially SupportedA ketogenic diet can increase NAD stores and reduce inflammation, supporting NAMPT enzyme function for NAD regeneration.

◐Partially SupportedA leucine-resveratrol combination has shown synergy in clinical trials, increasing insulin sensitivity, controlling glucose in pre-diabetic patients, and promoting weight loss.

◐Partially SupportedMice fed a high amount of branched-chain amino acids become hungrier, fatter, and die younger, but caloric restriction negates this lifespan reduction.

◐Partially SupportedAnimal proteins are not inherently detrimental; insulin drives negative metabolic effects and mTOR should not be constantly activated.

✕Not SupportedPlant molecules may have negative collateral side effects, and their benefits can likely be achieved through ketosis alone.

◐Partially SupportedBeta-hydroxybutyrate has epigenetic roles, acting as an HDAC inhibitor and potentially affecting FoxO3 and NAMPT.

◐Partially SupportedKetosis increases the NAD+/NADH ratio and provides benefits for learning and memory in mice.

◐Partially SupportedSirtuins are a conserved family of seven genes in humans, found across various organisms like yeast, mice, and fruit flies.

◐Partially SupportedAMPK is connected to PGC-1 alpha, which regulates mitochondrial biogenesis.

◐Partially SupportedFoxO3 may regulate NAMPT, connecting hormesis and ketone mechanisms.

◐Partially SupportedSirtuins remove acetyl or acyl groups, and NAD+ may control inflammation.

◐Partially SupportedChanging NAD+ levels in a cell can alter its reactivity, power, and sirtuin activity.

?Limited ResearchSupplementing with NR or NMN to increase NAD+ may deplete methyl groups through the excretion of methyl nicotinamide.

◐Partially SupportedResveratrol may act as an endocrine disruptor, decreasing androgen precursors in a prostate cancer trial.

◐Partially SupportedInsulin, not animal proteins, is the primary driver of mTOR activation, and mTOR should be cycled.

◐Partially SupportedKetosis may stimulate the same longevity pathways as caloric restriction and exercise.

✕Not SupportedDavid Sinclair worries about the collateral side effects of plant molecules when their beneficial effects can be achieved through healthy living.

?Limited ResearchAging is likely influenced by more than just sirtuins, and fully understanding the players and DNA methylation changes in response to this process will take another decade.

✕Not SupportedBeyond Meat has a worse carbon footprint than regular meat and significantly worse than regenerative agriculture practices.

✕Not SupportedPaul Saladino believes he can regenerate NAD from food and a ketogenic diet without NR or NMN.

◐Partially SupportedAging involves epigenetic factors like methylation on DNA.

◐Partially SupportedMost land used for cattle is not farmable land, and cattle can be raised using rotational grazing to avoid land destruction.

◐Partially SupportedAlmonds use significantly more water than cows.

◐Partially SupportedMarks on DNA, such as methyls, and changes in DNA looping are lost over time, contributing to the loss of epigenetic information during aging.

◐Partially SupportedThe genetic information in old bodies contains the instructions to be young, as evidenced by cloning.

◐Partially SupportedThe body may naturally produce an endogenous molecule that resembles resveratrol.

◐Partially SupportedSirtuins, acting as deacetylases on chromosomes, influence gene expression.

◐Partially SupportedmTOR activation is beneficial for growth but chronic activation is detrimental to longevity.

◐Partially SupportedThere is no known blood test that serves as a reliable proxy for mTOR activation.

◐Partially SupportedWhen sirtuins are active with high NAD+ levels, they perform DNA repair, gene silencing, and regulate FoxO3.

?Limited ResearchResveratrol's benefits are uncertain, and ketosis may offer similar benefits.

◐Partially SupportedSirtuins and NAD+ should be kept as active as possible at all times.

◐Partially SupportedNAD+ can be synthesized in the body from Vitamin B3 (niacin) through a pathway involving ADP-ribose and NMN.

✕Not SupportedX-rays and CT scans can break DNA and should not be used frivolously.

◐Partially SupportedAncestral Supplements' liver and pancreas supplements are beneficial for digestive enzymes.

◐Partially SupportedIn aging yeast cells, DNA breaks distract sirtuins from protective roles, leading to gene dysregulation, which is proposed as a model for aging.

◐Partially SupportedEating animal products nose-to-tail, including connective tissue, provides glycine and supports a healthy methionine-glycine ratio.