NMN, NR, Resveratrol, Metformin & Other Longevity Molecules

NAD Boosters

• Popular and promising for healthspan and lifespan
• Includes NR (Nicotinamide Riboside) and NMN (Nicotinamide Mononucleotide)
• Work on sirtuins, one of the three longevity pathways

Metformin

• Regulated by the government, not in the food supply
• Has potential side effects, needs to be discussed with a doctor
• Works on AMPK, one of the three longevity pathways

Berberine

• Natural compound, can be found over the counter
• Works on AMPK, one of the three longevity pathways

Rapamycin

• Regulated by the government, not in the food supply
• Has potential side effects, needs to be discussed with a doctor
• Works on mTOR, one of the three longevity pathways

Spermidine

• Natural compound, can be found over the counter
• Works on autophagy, a cellular process related to longevity

Resveratrol

• Natural compound, can be found over the counter
• Works on sirtuins, one of the three longevity pathways

Pterostilbene and Quercetin

• Natural compounds, can be found over the counter
• Have potential health benefits related to longevity

Important Notes

• Always consult with a physician before trying supplements or changing your diet
• Supplements and medicines can have different effects on individuals
• David Sinclair does not sell supplements and actively avoids conflicts of interest

• Scientific references and further information can be found in the podcast’s show notes
  Survival Pathways and NAD Boosters

• Survival pathways respond to our environment

  • Exercise, fasting, drugs, or supplements can activate them
  • They communicate with each other in a network
• NAD boosters are a class of molecules that work on these pathways 
  • NAD (Nicotinamide Adenine Dinucleotide) is essential for life
  • Needed for energy production and activating defensive enzymes (sirtuins)
  • NAD levels decline with age, leading to a decreased ability to fight off aging and diseases

Nicotinamide Riboside (NR)

• Most well-​​known and well-​​studied NAD booster
• Safe to take with little to no side effects
• Raises NAD levels in blood tests
• In animal studies, NR has shown to: 
  • Extend lifespan (9% in mice, 30% in yeast)
  • Improve health (more mitochondria, less inflammation, more athleticism)
  • Enhance oxidative metabolism (burn more fat, stave off diabetes)
• In human studies, NR has shown to: 
  • Raise NAD levels (takes about 9–10 days to reach peak levels)
  • Lower inflammation
  • Cause minor changes in body composition
  • However, improvements in blood sugar, insulin sensitivity, and increased mitochondria have not been proven in short-​​term studies

Effectiveness of NR

• Taking vitamin B3, a precursor to NR, does not raise NAD levels as effectively as NR
• NR may not be as effective as NMN (Nicotinamide Mononucleotide), another NAD booster

• Longer-​​term exposure to NR may be needed to see more significant health benefits in humans
  NR and NMN in Research and Human Studies

• NR and NMN have similar effects in animals:

  • Lengthening lifespan
  • Restoring mitochondrial activity
  • Restoring NAD levels
  • Enhancing insulin sensitivity
• Human studies on NR have not always confirmed the same effects as in animals
• Human studies on NMN are more limited, but some early results show promise: 
  • Yeshino et al. (2021) — 10-​​week study showed increased insulin-​​stimulated glucose disposal
  • More research needed to determine if NMN has similar effects on endurance, organ protection, and wound healing as seen in animal studies
• NAD boosters in development, called new chemical entities (NCE), may be even better than NMN; human studies expected in the next year

NAD IVs

• Some people are trying NAD IVs for various reasons: 
  • Addiction treatment
  • Depression
  • Hangovers
• NAD IVs are done under medical supervision, but there is a lack of placebo-​​controlled trials to determine their effectiveness

• Alcohol dehydrogenase, an enzyme that detoxifies alcohol, needs NAD; taking NMN or NR could potentially help with hangovers by raising NAD levels and improving liver function
  NAD Boosters and Resveratrol

• NAD boosters and resveratrol are both studied for their potential longevity benefits

• NAD boosters work on increasing NAD levels, while resveratrol activates SIRT1 protein

NAD Boosters and Cancer Concerns

• Two main studies in mice have raised concerns about NAD boosters and cancer growth 
  • One study found that lowering NAD levels in brain tumors slowed tumor growth
  • Another study found that NMN increased the number of senescent cells and made them more inflammatory, potentially leading to cancer growth in mice predisposed to pancreatic cancer
• More research is needed to understand the relationship between NAD boosters and cancer

Resveratrol

• Found in red wine, resveratrol is a SIRT1 activator
• Studies have shown positive effects on yeast, rodents, and humans
• In rodents, resveratrol protected against high-​​fat diets and mimicked the effects of caloric restriction
• In humans, resveratrol has been shown to reduce fasting glucose, increase insulin sensitivity, lower cholesterol levels, and improve kidney function

Resveratrol Bioavailability

• Resveratrol is not easily absorbed by the body when taken in water
• Mixing resveratrol with food, such as yogurt or olive oil, can improve its absorption
• Studies have used doses ranging from 250 mg to 2000 mg per day

Resveratrol and Cancer

• Resveratrol has been studied for its potential anti-​​cancer properties
• A 1999 study showed that resveratrol reduced the size of skin cancers in mice when applied topically

• Further research is needed to understand the relationship between resveratrol and cancer prevention
  Red Wine and Resveratrol

• Drinking red wine over 30 years could have a cumulative effect

• Red wine contains more than resveratrol, also has xenohormetic polyphenols
• Combination effect could contribute to health benefits

Fisetin and Quercetin

• Identified in early experiments with yeast
• Both are sirtuin activators and senolytics (kill senescent cells)
• Senescent cells accumulate over time, secrete inflammatory factors and cause cancer
• Fisetin and Quercetin show potential in extending lifespans in model organisms
• Human studies show potential health benefits, but more research needed for safety

Rapamycin and Rapalogs

• Discovered on Easter Island, inhibits mTOR (mimics fasting)
• Extends lifespan in various organisms, but could be toxic
• Not currently available for general use

Spermidine

• Stimulates autophagy (like rapamycin) and stabilizes changes to the epigenome
• Human studies show potential for enhancing memory and dealing with memory loss
• Found in wheat germ and soy products

Metformin

• AMPK activator, used since the 1950s for type 2 diabetes
• Activates complex one in mitochondria, leading to mitohormesis
• Inhibits mTOR and improves insulin signaling

• Comes from the French lilac plant, which produces guanidines
  Metformin and Berberine

• Metformin: a drug used to treat type 2 diabetes

  • Derived from a natural compound found in plants
  • Extends lifespan in animals and worms
  • Reduces risk of cancer, heart disease, Alzheimer’s, and frailty in humans
  • Currently being studied in the TAME (Targeting Aging with Metformin) trial
  • Some doctors are prescribing it off-​​label for anti-​​aging purposes
  • Potential side effects: lactic acidosis, upset stomach, muscle loss
• Berberine: a natural alternative to metformin 
  • Found in plant bark and roots
  • Mimics the effects of metformin by activating AMPK and increasing mitochondrial energy
  • Extends lifespan in mice and fruit flies
  • Dosage: 1–2 grams per day
  • Potential side effects: diarrhea, constipation, gas, upset stomach

David Sinclair’s Personal Anti-​​Aging Regimen

• Started taking resveratrol in 2004

  • Dosage: 1 gram per day, mixed with fat (e.g., yogurt or olive oil)
  • Resveratrol is a natural compound found in plants, known for its anti-​​aging properties
  • Works by activating the AMPK pathway and increasing mitochondrial energy
  • Extends lifespan in animals and worms
    David Sinclair’s Supplement Regimen

• Resveratrol: 1 gram in the morning with yogurt or olive oil

• NMN: 1 gram in the morning
• Fisetin and Quercetin: Half a gram in the yogurt
• Spermidine: 1 gram in the morning (currently testing its effects)
• Metformin: 800 milligrams in the evening (if not working out the next day)

Note: This regimen is specific to David Sinclair and should not be followed without consulting a physician. Individual needs and responses to supplements may vary.

Importance of Monitoring and Consultation

• Consult with a physician before starting any supplement regimen
• Monitor the effects of supplements on the body, especially liver function (ASD and ALT levels)
• Regularly check blood biochemistry and other health markers to ensure optimal results and avoid potential harm