Dr. Peter Attia: Supplements for Longevity & Their Efficacy

Longevity Approaches

• Dr. Attia categorizes longevity approaches into four categories: essential behaviors, exogenous molecules, targeted disease processes, and a "do everything" approach.
• Essential behaviors include eating, sleeping, and moving, which can be done in ways that promote or erode health.
• Exogenous molecules are substances taken to impact these systems, such as caloric restriction, rapamycin, and NAD precursors like NR and NMN.
• Targeted disease processes focus on delaying the onset of chronic diseases like cardiovascular disease, cancer, and neurodegenerative diseases.
• The "do everything" approach encompasses a wide range of interventions, including high doses of polyphenols, time-restricted feeding, red light therapy, and platelet-rich plasma.

Dr. Attia's Personal Supplement Regimen

• Dr. Attia takes several medications, including a PCSK9 inhibitor, bidic acid, an SGLT2 inhibitor, and rapamycin.
• He believes that the SGLT2 inhibitor may also have geroprotective effects, citing the success of canagliflozin in the Interventions Testing Program (ITP).
• Dr. Attia takes 8mg of rapamycin once a week, but has to take breaks due to side effects like mouth sores.
• He views these side effects as a positive sign, indicating that the rapamycin is working as intended.
• Dr. Attia takes Huperzine A as a supplement, believing it may improve cognitive function, particularly in individuals with mild cognitive impairment (MCI). He acknowledges that the evidence is not overwhelming but considers the potential benefits to outweigh the risks.
• He also takes vitamin D despite spending time outdoors, as his levels remain surprisingly low. He takes 5,000 IU daily, raising his levels from around 30 to 50. He acknowledges the ongoing debate about optimal vitamin D levels.
• Dr. Attia takes methyl folate and methyl B12 to lower homocysteine levels. He explains that elevated homocysteine is associated with negative health outcomes, potentially impacting vascular health through its effect on nitric oxide synthesis. He believes that lowering homocysteine may improve vascular health.
• He avoids supplementing with vitamin B6 due to concerns about potential nerve damage.
• Dr. Attia takes magnesium in three forms: magnesium L-threonate, magnesium glycinate, and magnesium oxide. He believes magnesium is crucial for bowel function and muscle health, citing his lack of cramps despite intense exercise.
• He takes electrolytes through the company Element, in which he is an investor.
• He also takes creatine monohydrate, AG1, and Pendulum probiotic. He believes Pendulum is the only probiotic with a meaningful effect on the body due to its anaerobic bacteria content.
• Dr. Attia takes three products from Pendulum: Glucose Control, Polyphenol, and Acromania. He explains that Pendulum is a unique supplement company that adheres to pharmaceutical GMP conditions due to the anaerobic bacteria they produce.
• He also takes AG1, a daily multivitamin and adaptogen blend, to supplement his diet and support gut health.
• Dr. Attia emphasizes the importance of quality fish oil, aiming for over 1 gram of EPA per day, and takes a high dose of vitamin D3, adjusting the dosage based on blood tests.
• He also takes methyl B12, Tongkat Ali for testosterone optimization, and green tea capsules for a stimulatory effect.
• Dr. Attia uses NMN and NR in powder form for their potential benefits, and utilizes Element MH as an electrolyte supplement.
• He takes 10 grams of creatine monohydrate daily for muscle health and cognitive function.
• Dr. Attia previously experimented with nicotine gum but stopped due to its stimulating effects and potential for dependence.
• Before sleep, he takes magnesium 3 and 8, apigenin, and theanine for relaxation and sleep quality.
• He uses a high-quality whey protein as a protein replacement and has experimented with other supplements like Shilajit, but has not found consistent long-term benefits.
• Dr. Attia is interested in supplements that provide sustained energy without caffeine and uses yerba mate and coffee for his caffeine intake.
• Dr. Attia's supplement regimen includes caffeine in tablet form, alpha-GPC, and garlic.
• He emphasizes that behavioral factors like sleep, exercise, nutrition, and sunlight have a much greater impact on healthspan and lifespan than any single supplement.
• He views supplements as an insurance policy or an augmentation to mental and physical health, but not as essential.

NAD and Longevity

• The episode focuses on the NAD pathway, a potential target for improving lifespan, and explores various molecules and approaches to increasing NAD levels.
• The discussion includes a comparison of NR, NMN, direct infusions, and oral NAD in terms of their ability to enter cells and their potential efficacy for longevity and healthspan.
• Dr. Attia discusses NAD and longevity, focusing on four categories of approaches to living longer.
• The first category is "dos and don'ts," which includes getting enough exercise, eating right, and understanding your genetics.
• The second category is "calories, glucose, insulin, etc.," which all relate to mTOR (mammalian Target of Rapamycin), a molecule that plays a crucial role in cell growth and development.
• Dr. Attia argues that the period from infancy to puberty is one of the most rapid phases of aging, as evidenced by the significant physical changes that occur during this time.
• He uses his daughter's annual birthday photos as an example, highlighting the dramatic changes in her appearance and size during her first ten years of life.
• Dr. Attia categorizes interventions for longevity into three main categories: behaviors, disease-targeting molecules, and geroprotective molecules.
• Behaviors encompass lifestyle choices that promote health and longevity, such as diet, exercise, and sleep.
• Disease-targeting molecules are medications that directly address specific diseases, such as Metformin for diabetes, SGLT2 inhibitors for heart disease, and PCSK9 inhibitors for high cholesterol.
• Geroprotective molecules target the fundamental processes of aging, aiming to slow down the aging process itself.
• Rapamycin is an example of a geroprotective molecule that targets a specific hallmark of aging, mTOR signaling.
• Dr. Attia discusses the potential of activating sirtuins for longevity.
• He mentions that overexpressing sirtuins in yeast has been shown to increase lifespan in some strains, but this finding is not consistent across all strains.
• The speaker then explores whether this effect translates to other species, such as flies, worms, and mammals.
• He notes that there is one transgenic mouse experiment where overexpressing SIRT6 resulted in a 10-15% increase in lifespan for male mice, but not for female mice.
• The speaker clarifies that a transgenic mouse is one that has been genetically modified to express a specific gene, in this case, SIRT6, at higher levels than normal.
• He emphasizes that this is just one study and that more research is needed to confirm the effects of SIRT6 overexpression on lifespan in mammals.
• The speaker concludes by stating that there is evidence suggesting that overexpressing sirtuins in yeast and in one transgenic mouse model can increase lifespan, but further research is necessary to understand the mechanisms involved and to determine if these findings can be translated to humans.
• Ceru activators are believed to improve mitochondrial biogenesis, increase DNA repair, and reduce the soluble products of senescent cells (SASP). These are all beneficial effects for longevity.
• DNA repair is a crucial aspect of aging, as DNA damage accumulates over time. This damage can lead to cancer and other age-related diseases.
• The relationship between DNA damage and aging is complex. It is not simply a matter of more mutations occurring with age. The immune system's ability to detect and repair damage also plays a role.
• NAD is a key substrate for DNA repair. As we age, NAD levels decline, potentially contributing to reduced DNA repair capacity.
• Ceru activators may help to increase NAD levels. This could be a mechanism by which they promote DNA repair and longevity.
• The most famous ceru activator is resveratrol. It is considered the "heavyweight champion" of ceru activators.
• Resveratrol, a compound found in grapes, gained popularity about 20 years ago due to a single study suggesting it increased lifespan in mice.
• The study's authors claimed Resveratrol activated sirtuins, which are proteins linked to improved mitochondrial function, reduced inflammation, and enhanced DNA repair.
• However, numerous subsequent studies failed to replicate these findings, except for one experiment using a specific mouse model with severe fatty liver disease.
• In this particular model, Resveratrol seemed to improve survival by preventing the fatty liver from encroaching on the chest cavity and hindering breathing.
• Despite this outlier, the Intervention Testing Program (ITP), a rigorous scientific program funded by the National Institutes of Health, found no evidence that Resveratrol extended lifespan in mice.
• The ITP conducted its experiments in triplicate across three independent labs, using the same dosage and methodology as the original study.
• The ITP's findings suggest that Resveratrol, while potentially beneficial in specific circumstances, does not have a significant impact on lifespan in general.
• The discussion revolves around the role of NAD and NADH in the aging process and their potential as longevity supplements.
• NAD levels decline with age, particularly in the skin, while NADH levels increase.
• NAD is crucial for energy production in the mitochondria, where it facilitates the transfer of chemical energy from food to electrical energy.
• NADH is the electron acceptor in the electron transport chain, which is a key process in energy production.
• The text highlights the importance of NAD and NADH in maintaining life, as they are essential for converting chemical energy from food into ATP, the energy currency of the body.
• NAD levels decline with age, but the total amount of NAD and NADH remains the same.
• The decline in NAD levels is actually a reduction in redox potential, which is the ability of NAD to convert chemical energy into electrical energy.
• This reduction in redox potential is likely due to mitochondrial dysfunction, which is a common consequence of aging.
• Red light and near-infrared light therapy has shown promise in improving mitochondrial function in the eye, potentially by reducing reactive oxygen species.
• While NAD supplementation is a popular approach to combat aging, the relationship between NAD levels and aging is complex and not fully understood.
• The pathway leading to NAD involves NR, NMN, and NAD, with each molecule being a precursor to the next.
• There is currently no definitive evidence that increasing NAD levels through supplementation can slow down aging.
• The discussion about NAD supplementation is still in its early stages, and more research is needed to determine its efficacy and safety.
• Dr. Attia emphasizes the importance of critical thinking when it comes to supplements, particularly those marketed for longevity. He argues that many supplements lack scientific justification and are based on leaps of faith.
• He acknowledges taking NMN and NR himself, but emphasizes that his personal experience is anecdotal and doesn't necessarily translate to scientific evidence.
• Dr. Attia highlights the lack of evidence supporting the idea that raising NAD levels will directly improve healthspan or lifespan. He points out that while NAD levels decline with age, there's no proof that increasing them will correct any underlying problems.
• He discusses the various methods of supplementing NAD, including intravenous administration and oral intake of precursors like NR and NMN. He believes there's little difference in their effectiveness, as they all ultimately increase NAD levels in the blood.
• Dr. Attia shares his personal experience with intravenous NAD, describing the uncomfortable side effects he experienced, including chest pressure, leg cramps, and nausea. He criticizes the tendency to equate unpleasant sensations with effectiveness, arguing that discomfort doesn't necessarily indicate a positive physiological effect.
• Dr. Attia has tried both NAD infusions and sublingual NMN. He found that both methods made him feel better, but it's difficult to determine if this is due to a placebo effect or the actual effects of the substances.
• Dr. Attia prefers sublingual NMN because it is more cost-effective than NR. He takes 1.5 grams of NMN daily and has noticed increased energy, faster hair and nail growth, and a laxative effect.
• Dr. Attia acknowledges that there is more scientific evidence supporting NR as a more effective precursor to NAD than orally ingested NMN. However, he believes that the cost difference makes NMN a more practical option.
• Dr. Attia suggests that a study comparing the effects of oral NR and sublingual NMN on NAD blood levels would be valuable.
• Dr. Attia notes that NAD infusions are expensive and the benefits are unclear. He emphasizes the need for rigorous testing to determine the efficacy of these interventions.
• Dr. Attia mentions the Interventions Testing Program (ITP) as a valuable tool for testing the efficacy of various molecules. He encourages listeners to refer to his previous discussions with Rich Miller for more detailed information on the ITP.
• The Interventions Testing Program (ITP) is a rigorous program that tests the effects of various molecules on lifespan in non-inbred mice.
• The ITP has tested over 50 molecules, and only a few have shown to extend lifespan.
• Nicotinamide Riboside (NR) was tested at a high dose (500-1000 mg/kg) but did not extend lifespan, improve healthspan, or show any significant changes compared to a placebo.
• Rapamycin (Rapa) has been shown to extend lifespan in mice, even when administered late in life.
• Canagliflozin, an SGLT2 inhibitor, and acarbose, a drug that inhibits glucose absorption, both extended lifespan in mice without causing weight loss. This suggests that tight glycemic control, independent of weight, may be a longevity benefit.
• 17α-estradiol extended lifespan in male mice, highlighting the potential sex-specific effects of certain interventions.
• A study involving NR and a product called Tertill Bean, believed to be a ceramide activator, was conducted on humans with fatty liver disease.
• The study, involving approximately 100 participants, found no significant improvement in hepatic fat index, a measure of fatty liver disease, in those taking NR and Tertill Bean compared to those taking a placebo.
• The study on NR (nicotinamide riboside) found no significant difference in hepatic fat, body weight, inflammatory markers, glycemic markers, or liver function tests between the high-dose and low-dose groups.
• A subanalysis, which is not a primary outcome, showed a statistically significant reduction in liver fat in the low-dose group for individuals with a hepatic fat score below 27%. However, this finding may not be clinically significant.
• The study on NMN (nicotinamide mononucleotide) found a statistically significant increase in glucose disposal with insulin infusion in the NMN group compared to the placebo group. However, this increase was very small and considered clinically insignificant.
• The speaker emphasizes the importance of distinguishing between statistical significance and clinical significance, noting that a statistically significant result may not necessarily translate to a meaningful improvement in health outcomes.
• Dr. Attia and Andrew discuss the debate surrounding NMN and NR supplements, noting that the FDA has not authorized NMN for sale as a supplement, while NR is considered generally recognized as safe (GRAS).
• Dr. Attia believes the debate is primarily commercial, with little scientific basis for favoring one over the other.
• While acknowledging some studies showing minor benefits, Dr. Attia considers them insignificant and clinically irrelevant.
• The only study he found with a potential signal involved a reduction in basal cell and squamous cell carcinomas (skin cancers) by 60-80% in individuals taking either NMN or NR.
• Dr. Attia emphasizes that this study needs to be replicated, but if confirmed, it could justify taking these supplements for individuals at high risk of these skin cancers, particularly those with sun-sensitive skin or occupations involving prolonged sun exposure.
• Dr. Attia discusses a study on a type of skin cancer that showed a significant reduction in NAD levels in the skin. He wonders if this could explain why there is a potential benefit to NR and NMN supplementation for skin health.
• He acknowledges that NAD infusions are expensive and may not be the most effective way to increase NAD levels.
• Dr. Attia suggests that spending time exercising and eating healthy food could be a more beneficial and cost-effective way to improve health than NAD infusions.
• He mentions that research has shown that exercise, particularly resistance training, can enhance the rewarding properties of food, making it taste better.
• Dr. Attia discusses the similarities and differences between NR and NMN, noting that NR is more readily taken up by cells and converted to NAD.
• He cites research by Josh Rabinowitz, who has shown that the liver is likely the primary site of NAD uptake, followed by blood.
• Dr. Attia mentions that some companies claim NR is 25% more effective than NMN at raising blood NAD levels, but he emphasizes that this claim is based on milligram-for-milligram comparisons and that the impact on cellular NAD levels is unclear.
• He expresses trust in Josh Rabinowitz's research on NAD flux, as Rabinowitz has no financial stake in the supplement industry.
• The speaker expresses uncertainty about the effectiveness of NMN and NR supplements, questioning whether they actually increase intracellular NAD levels significantly.
• He argues that even if they do increase NAD levels, it's unclear whether this has a meaningful impact on lifespan or healthspan.
• The speaker criticizes the marketing of these supplements, suggesting that they are often promoted with exaggerated claims about their benefits.
• He highlights the difficulty of conducting longevity experiments in humans, making it challenging to definitively prove the efficacy of these supplements.
• The speaker mentions the FDA's recent decision to classify NMN as a drug due to ongoing clinical trials, which effectively prohibits its sale as a supplement.
• He compares this situation to the previous case of N-acetylcysteine (NAC), which was also reclassified as a drug, potentially due to lobbying efforts from pharmaceutical companies.
• The speaker suggests that the strongest argument for taking NMN might be its potential to reduce the risk of basal cell and squamous cell carcinoma, but emphasizes that this needs further research.
• He concludes by questioning the need for clinical trials on supplements that are marketed without specific health claims, arguing that rigorous testing is necessary for drugs but not for supplements.
• There have been concerns about NR (nicotinamide riboside) potentially increasing cancer risk, but experts like Charles Brenner have argued that the studies supporting this claim were not well-conducted.
• Dr. Attia acknowledges that the field of longevity research lacks the rigor found in pharmacotherapy, and he believes Charles Brenner does good work in this area.
• Dr. Attia doesn't believe Charles Brenner would argue that NR increases lifespan, but rather that it may have positive effects on NAD levels, leading to anti-inflammatory benefits.
• Dr. Attia agrees with the notion that there's no logical connection between caloric restriction and NR, calling it a "shell game."
• Dr. Attia believes there's better research on rapamycin because there's no commercial interest in the drug itself, as it's off-patent and inexpensive.
• While rapamycin is not cheap, it's significantly less expensive than some other medications.
• The commercial interest lies in rapalogs, which are analogs of rapamycin being investigated for new indications, particularly in immune function.
• Dr. Attia highlights a 2014 study by Joan Mannick and Lloyd Klickstein using everolimus, a rapalog, which showed enhanced immunity in response to an influenza vaccine in 65-year-olds.
• This study was a turning point for Dr. Attia, shifting his perspective on rapamycin from a curiosity to a potential therapeutic agent.
• The study demonstrated that intermittent dosing of rapamycin can improve immune function, suggesting it's an immune modulator.
• Dr. Attia believes future research should focus on developing drugs that are more specific to mTOR complex 1, which rapamycin is not, but intermittent dosing can mitigate this issue.
• He emphasizes the need for research on rapamycin's efficacy in areas other than longevity, as lifespan cannot be tested in humans.

The Importance of "Vigor" and "Well-being"

• Dr. Attia questions the value of biological aging tests, citing his own experience with a movement test that showed him to be 20 years old in terms of movement ability. He believes that such tests are unreliable and that chronological age is a better predictor of remaining lifespan.
• Dr. Attia acknowledges that he is 49 years old and that, based on actuarial tables, his life expectancy would be around 37 more years.
• Dr. Attia shares that he has a chart that tracks his lifespan in weeks and his subjective level of vigor, which he rates on a scale of 0 to 10.
• Dr. Attia explains that his vigor was lower in his 20s and 30s due to excessive work hours and poor lifestyle choices. He has seen an increase in vigor since his 40s and now tracks it every two months, adjusting for stressors and positive life events.
• Dr. Attia's goal is to identify the behavioral factors that contribute to his vigor and longevity.
• Dr. Attia emphasizes the importance of maintaining "vigor" and "well-being" as we age, acknowledging that achieving this may require more effort in later years.
• He highlights the value of visualizing our lifespan through a chart, as it helps us grasp the reality of our mortality, something our brains often try to avoid.
• Dr. Attia discusses the concept of "actuarial age" versus "biological age," using the example of a 49-year-old male with a predicted lifespan of 88-91 years.
• He questions the reliability of biological age tests, arguing that a younger biological age doesn't necessarily translate to a longer lifespan.
• He points out that biological age measurements are often noisy and influenced by various factors, making it difficult to interpret their significance.
• Dr. Attia uses the example of triglyceride levels to illustrate the variability of biological measurements, emphasizing the need for standardization and context.
• He concludes by expressing skepticism about the reliability of biological age tests, suggesting that they may not be as precise or meaningful as they seem.
• Dr. Attia discusses the difficulty of accurately sequencing the epigenome, highlighting that companies currently offering epigenetic testing may not be providing truly accurate data.
• He compares the radiation exposure from airport scanners and flights to other sources like CT scans and living at higher altitudes, emphasizing that the amount of radiation received from these sources is relatively low compared to the recommended annual limit.
• Dr. Attia mentions that people working in nuclear plants, who receive significantly higher radiation exposure, do not seem to have an increased risk of cancer, suggesting that the concern about radiation from everyday sources might be overblown.
• He believes that the work we do in our 50s and 60s is crucial for setting the stage for maintaining vitality in our later years, emphasizing the importance of building a strong foundation for longevity.
• The period between 50s and 70s is crucial for longevity because aging starts to become more apparent during this time.
• Dr. Attia and the speaker acknowledge that they are not as resilient as they used to be, and they need to prioritize self-care, including sleep, diet, and recovery from workouts.
• The goal during this period is to build up as much physiological reserve as possible, as compounding effects of healthy habits make a significant difference.
• It is still possible to gain muscle mass in your 50s and 60s, but it becomes increasingly difficult in your 70s.
• Power declines faster than strength, and muscle mass declines even slower.
• Maintaining muscle mass is important because it acts as a glucose sink and contributes to overall health.
• It is crucial to avoid injuries during this period, as recovery becomes more challenging with age.
• The decline in energy levels with age is a common observation, but the exact reasons are not fully understood.
• Ben Baris, a friend of Dr. Attia and the speaker, used to ask about the decline in energy levels as he aged.
• The speaker acknowledges that the decline in energy levels is a complex issue and there is no definitive answer.
• Dr. Attia observes that children, especially young boys, have an abundance of spontaneous energy, which he describes as "kinetic desire." He notes that this energy level significantly decreases as children transition into teenagers.
• Dr. Attia wonders if NAD supplementation could be a factor in maintaining energy levels, but he acknowledges that while he takes NMN and NR, he hasn't experienced a significant boost in energy that would allow him to replicate the spontaneous energy of children.
• He emphasizes that good sleep, exercise, and nutrition are crucial for energy levels and vitality, but acknowledges that these are challenging to prioritize for adults with busy lives.
• Dr. Attia shares his personal preference for healthy food and his belief that exercise, particularly when completed before 9:00 a.m., can increase energy levels throughout the day. He suggests that this could be a factor in promoting both healthspan and lifespan.
• Dr. Attia believes that the timing of exercise can significantly impact energy levels throughout the day. He hypothesizes that this is related to the change in body temperature that occurs during exercise and throughout the day.
• He suggests that exercising early in the morning, after the lowest temperature phase of the circadian rhythm, can lead to increased energy levels throughout the day.
• Dr. Attia notes that many high-achieving individuals, including Joo Wilink, Eddie Chang, and Stanford School of Medicine administrators, are early morning exercisers.
• He acknowledges that there could be a reverse causality, where high-energy individuals are more likely to exercise early in the morning.
• Dr. Attia shares his own experience with early morning exercise, noting that it has a significant impact on his energy levels.
• He encourages people to experiment with the timing of their workouts to find what works best for them.

The Hubman Lab

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