NMN, NR, Resveratrol, Metformin & Other Longevity Molecules
Sinclair and LaPlante discuss drugs and supplements reported to combat aging. They share the latest data on NAD boosters (NR, NMN, NAD IV drips and shots), resveratrol, fisetin, quercetin, rapamycin, spermidine, metformin, and berberine. Special focus is given to NAD precursors and associated mechanisms, limitations, and side effects.
Key Takeaways
Protocols
Source
We recommend using this distillation as a supplemental resource to the source material.
Full Notes
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
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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
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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
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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
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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
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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
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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
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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