NMN, NR, Resveratrol, Metformin & Other Longevity Molecules | Lifespan with Dr. David Sinclair #4

Kicking Off Episode Four: Longevity Molecules (00:00:00)

• Dr. David Sinclair, professor at Harvard Medical School and expert on aging, and his co-host Matthew LaPlante start the episode focusing on longevity supplements.
• They emphasize that they are not medical doctors and advise listeners to consult their physicians before trying new supplements.
• The episode aims to answer common questions about supplements like NMN, NR, Metformin, and how they can potentially slow or reverse aging.

An Additional Boost Beyond Adversity Mimetics (00:04:46)

• The concept of 'adversity mimetics,' like fasting and exercise, is discussed, but these may not be enough for modern lifestyles.
• David Sinclair has been using an additional supplement regimen since his early thirties to enhance wellness and long-term health.

Drugs vs. Supplements and Highlight Points (00:05:52)

• The episode clarifies the difference between drugs regulated by the FDA and supplements that are generally recognized as safe (GRAS).
• Discussion on the importance of being cautious with supplements, especially regarding the liver and the potential need for medical supervision.
• A shortlist of the most popular and promising molecules aiding health spans and lifespans is introduced, including NAD boosters, Metformin, berberine, rapamycin, spermidine, resveratrol, fisetin, and quercetin.
• References and show notes are provided to allow listeners to explore the topics discussed in greater detail.

Longevity Molecules Target the Survival Circuit (00:09:54)

• Longevity pathways, like sirtuins, AMPK, and mTOR, are framed as the focus for understanding how various supplements function.
• These survival pathways are responsive to environmental conditions and can interact with each other in complex ways.
• New research further elucidates how molecules thought to affect only one pathway can impact others as well.

NAD Boosters (00:11:33)

• NAD is crucial for cellular energy transfer and overall bodily function; a decline in NAD levels can impede the body's ability to combat aging.
• NAD levels are naturally depleted with age, even with exercise and a healthy diet.
• Supplements like NMN and NR can potentially restore NAD levels akin to those of younger people, thus supporting the sirtuins' defensive response against aging.

Nicotinamide Riboside (00:13:32)

• Nicotinamide riboside (NR) is the most well-known and studied NAD booster, used since 2014 either alone or in combination with other molecules.
• It's considered a safe molecule, with studies indicating that doses of 250 mg to 1 g per day can raise NAD levels in blood with little to no side effects.
• NR activates the sirtuin pathway in yeast (as discovered in the early 2000s), mirroring the effects of caloric restriction and increasing lifespan by about 30%.
• NR is taken up by cells and converted to NMN (nicotinamide mononucleotide), which is then assembled into NAD.
• In mice, NR supplementation led to a 9% lifespan increase when given late in life, along with health improvements such as increased mitochondria, athleticism, and reduced inflammation.
• NR enhances oxidative metabolism in animals, resulting in fat loss and potential diabetes prevention through increased oxygen consumption.
• Human studies on NR have shown mixed results; some benefits like lower inflammation and minor changes in body composition have been observed, but improvements in blood sugar, insulin sensitivity, and mitochondria observed in mice are unconfirmed in short term human studies.
• A combination of NR and a resveratrol-like molecule showed improvement in ALS patients' daily function, indicating potential but inconclusive results on NR's long-term effects.

Nicotinamide Mononucleotide (00:21:26)

• Research community is divided into team NR (Nicotinamide Riboside) and team NMN (Nicotinamide Mononucleotide).
• NMN is the focus of Sinclair's lab; it appears to work better than NR in empirical studies, although it's unclear why.
• NMN is more expensive to produce than NR due to the additional phosphate molecule.
• There's a specific transporter, SLC128A, that may take NMN into cells.
• Animal studies show NMN enhances insulin sensitivity, restores NAD levels, and may improve lifespan by 10-15%, particularly in females.
• Human studies on NMN are less common, but increasing, with early results showing improved insulin sensitivity; larger doses are being tested in clinical trials.
• There's anticipation for more extensive human clinical trial results in 2022 to compare with animal study outcomes.
• Other more effective NAD boosting molecules (new chemical entities, or NCEs) are being developed for future human studies.

NAD Intravenous Drips (00:29:22)

• Intravenous NAD is being used outside of clinical trials, claimed to improve mood and energy, treat addiction, depression, and hangovers.
• NAD is a coenzyme needed by alcohol dehydrogenase, which detoxifies alcohol, and taking NMN or NR may replenish NAD and alleviate hangovers.
• Despite anecdotal evidence, there's no definitive proof from placebo-controlled trials regarding the efficacy of NAD IVs.
• The focus in research started with smaller precursors like NMN and NR because NAD itself does not efficiently enter cells.
• NMN has a transporter protein that significantly facilitates its uptake into cells, potentially making it more effective than NAD or NR for increasing intracellular NAD levels.

Bioavailability of NAD Boosters (00:32:45)

• Swallowing NR and NMN capsules or powder is sufficient to raise NAD levels by two to three fold.
• Sublingual versions and injections are also options, but there is no strong evidence suggesting they are superior to oral ingestion.
• Simply swallowing the supplement has been shown to effectively boost NAD levels.

NAD and Cancer (00:33:40)

• Concerns about NAD boosters potentially stimulating cancer growth due to studies in mice.
• One study indicated that reduced NAD levels can slow the growth of brain tumors in mice.
• A 2019 study suggested that NMN might promote cancer growth in mice predisposed to pancreatic cancer by affecting the tumor suppressor gene P53.
• However, NMN has been fed to normal mice, leading to longer and healthier lives, suggesting predisposition may be a factor.
• It's important for people considering NAD boosters to consult their physicians due to potential cancer risks.

Resveratrol (00:35:33)

• Resveratrol activates Sirt-1, which controls other proteins linked to longevity.
• Discovered as a Sirt-1 activator, resveratrol gained attention because it is found in red wine.
• Red wine sales increased significantly due to the association with resveratrol, although consuming adequate resveratrol through wine alone is impractical.
• A dose of 250 milligrams per day of resveratrol is the minimum seen to be effective in human studies, with some taking up to 2000 milligrams.
• Resveratrol should be mixed with fat for proper absorption as it does not dissolve in water.
• Animal studies showed resveratrol protected against high-fat diets and mimicked caloric restriction.
• Human studies have yielded mixed results but include benefits such as reduced fasting glucose, increased insulin sensitivity, lower cholesterol, and better kidney function.
• Resveratrol has a background in cancer suppression, with various studies indicating its effectiveness against cancer, and benefits to body composition, metabolic rate, and mitochondrial function.

Red Wine and The French Paradox (00:42:26)

• The French paradox refers to low rates of cardiovascular disease despite a high-fat diet, possibly mitigated by moderate red wine consumption.
• Long-term, cumulative effects of drinking red wine, along with the presence of other polyphenols besides resveratrol, might contribute to the French paradox.

Fisetin and Quercetin (00:43:08)

• Fisetin and quercetin were initially identified as potential sirtuin activating molecules along with resveratrol.
• Both are classified as senolytics, which means they assist in eliminating senescent cells (zombie-like cells that cause inflammation and cancer).
• Research in mice has shown that fisetin can significantly extend lifespan and health, even when administered late in life.
• Fisetin has been found naturally in foods like strawberries and is available for purchase online.
• Quercetin, combined with dasatinib (a leukemia drug), has shown remarkable effects in reducing inflammation and fatty liver in human clinical trials.
• Fisetin is currently being tested in humans at 20 milligrams per kilogram of body weight to determine its safety and efficacy.

Rapamycin and Rapalogs (00:47:09)

• Rapamycin is an mTOR inhibitor and has a history of discovery on Easter Island, initially found on a statue.
• It is currently used for immune suppression and cancer treatment but is being researched for its potential to extend lifespan.
• Low doses of rapamycin have been shown to extend life span across various organisms without immune suppression.
• Rapalogs are drugs that aim to mimic rapamycin's effects without its potential toxicity.
• By inhibiting mTOR, rapamycin and its analogs stimulate the body's autophagy process, recycling old proteins.

Spermidine (00:49:10)

• Spermidine promotes autophagy, similar to rapamycin, and has a historical connection to sperm crystals observed under a microscope.
• In recent studies, spermidine has extended the lifespan of yeast, flies, worms, and mice, improving heart function and other youthful capacities.
• Human studies focusing on memory enhancement have shown spermidine's potential in cognition improvement.
• Spermidine is now sourced from wheat germ and soy products and is no longer obtained from sperm.

Sirtuin Activators

• The discussion of fisetin and quercetin ties back to the broader category of sirtuin activators, which includes compounds known to impact aging and longevity by activating sirtuin pathways.

Metformin (00:51:27)

• Metformin, used since the 1950s to manage type 2 diabetes, excites interest for its potential in longevity.
• It operates by activating AMPK, influencing the mitochondrial energy-making process, and promoting mitohormesis.
• Metformin triggers energy production, better insulin signaling, and also raises NAD levels, impacting multiple aging pathways.
• Originating from the French lilac plant, Metformin has been shown to increase lifespan in animals and improve various health markers.
• In humans, Metformin can lower the risks of age-related diseases such as cancer, heart disease, and Alzheimer's.
• Metformin is inexpensive and off-patent, making funding for extensive longevity studies challenging.
• There's a shift towards doctors prescribing Metformin off-label for anti-aging benefits.
• The drug's side effects include gastrointestinal upset and potentially lactic acidosis, but it generally has a safe profile.
• The "tame" study aims to provide evidence to FDA that Metformin can decelerate aging.
• Some practitioners advise taking Metformin on non-exercise days due to its impact on energy levels during workout.

Berberine (01:00:27)

• As an alternative to Metformin, berberine activates AMPK and shares several metabolic benefits.
• Found in plants, berberine can promote mitochondrial function and improve insulin sensitivity.
• Berberine dosage in clinical studies can range up to two grams per day, showing positive health effects.
• It can cause similar side effects to Metformin, including digestive issues.
• As a natural compound, berberine is readily available for trial, but consultation with a healthcare provider is recommended.

Dr. Sinclair’s Protocol for Longevity Molecules (01:02:43)

• Dr. David Sinclair has been taking about a gram of resveratrol daily since 2004, which must be mixed with fat to be effective.
• He ingests resveratrol in the morning with yogurt or dissolved in olive oil, which also activates sirtuins.
• Sinclair also takes a gram of NMN in the morning, which does not require food to be absorbed and has been shown to double NAD levels in human studies.
• The specific timing for taking NMN and resveratrol in the morning is based on their role in the body's natural rise in NAD and Sirt-1 activity, which are part of a 24-hour clock.
• He takes 800 milligrams of Metformin at night to simulate fasting and stimulate repair pathways.
• Sinclair adjusted his regimen over the years, adding spermidine, fisetin, and quercetin to target different cellular pathways and improve his biochemistry.
• He periodically skips Metformin before days he plans to exercise, mentioning stomach discomfort and potential impacts on exercise benefits.
• Dr. Sinclair advises a spermidine supplement company and takes a gram of it as part of his own regimen.
• For maintenance, he takes half a gram each of fisetin and quercetin daily, which are being studied for their effects on senescent cells in clinical trials.

Wrap-up and Next Week’s Episode: Interventions on the Cutting Edge (01:08:51)

• The conversation on longevity molecules was recognized as comprehensive but not exhaustive, with a potential for deeper exploration in future episodes.
• Sinclair emphasizes the importance of consultation with physicians and regular monitoring, such as liver function tests, when trying new supplements or drugs.
• The next episode of the podcast is set to discuss non-supplement interventions that are considered more cutting-edge, like testosterone, growth hormone, exosomes, and peptides.