Dr. David Sinclair on The Theory of Aging, NAD+ Boosters (NR and NMN), Sirtuins, and More – FoundMyFitness with Dr. Rhonda Patrick

Check out the FoundMyFitness Episode Page & Show Notes. Watch the interview here.

For the most comprehensive take on all of David Sinclair’s recommendations and the best ideas on optimizing healthspan, check out The 5 Pillars to Optimize for Increasing Healthspan and Living Your Best Life

Key Takeaways

  • Sirtuins are a class of proteins that protect organisms from deterioration and disease by regulating gene expression (turning genes on/off)
    • Sirtuins need NAD+ to function properly
  • As we get older, our NAD+ levels drop
    • By the time you’re 50, your NAD levels are about half what they were when you were 20
    • “You could argue NAD+ is the most important molecule in the body, maybe with the exception of ATP. But without either of them, you’re dead in about 30 seconds.” – David Sinclair
  • NR and NMN are NAD+ precursors you can supplement with – both have been shown to raise NAD+ levels
    • You can also raise NAD+ levels with fasting and exercise 
  • If sirtuins are the car, and NAD+ is the fuel, resveratrol is the accelerator pedal
    • Resveratrol also seems to improve cardiovascular health as well as stimulate autophagy pathways
  • The primary cause of aging is a loss of epigenetic information (the pattern to which genes are turned on/off)

Products & Supplements Mentioned

  • The two best NAD+ precursors:
    • NR
      • For us at Podcast Notes, based on their unmatched quality standards and our personal experience, we strongly recommend Elysium Basis (use the code “podcast45” at checkout to receive $45 off a semi/annual subscription)
    • NMN
      • David supplements with 1 gram of capsulized NMN every morning (he doesn’t disclose his preferred brand)
  • Resveratrol is also thought to have a beneficial effect on sirtuins
    • David supplements with ~1 gram of powdered resveratrol every morning, mixed in with some yogurt (once again, brand not disclosed)
      • Why yogurt? – It’s essential to take the resveratrol with fat to increase absorption
  • Rhonda has multiple Phillips Hue Light Bulbs placed around her home
    • They’re programmable by phone – the idea is that you change them to emit red light at sunset (thus limiting the amount of blue light you’re exposed to in the evening)

Intro

Sirtuins

  • Sirtuins (SIR for short) are a class of proteins that protect organisms from deterioration and disease by turning other genes on/off (AKA regulating gene expression)
    • (We have 7 sirtuins, identified as SIR1, SIR2, etc.)
    • David and his team at MIT discovered that if you mutate these sirtuin proteins in a specific way (specifically SIR4), yeast cells live longer
    • Later research found that an extra copy of SIR2 added to yeast cells caused them to live 30% longer
      • Why? – It mimics calorie restriction (which has been shown across species to extend lifespan)
  • Sirtuin pathways respond to how much we’re eating (sirtuins are activated when you’re hungry)
    • In 2005, David and his team showed that the levels of SIR1 were increased ~5-10 fold in the liver and muscle tissue of a calorie-restricted rat
      • David then repeated this experiment in a Petri dish, growing cells in serum from animals that had been calorie-restricted – this was also sufficient to stimulate a boost of sirtuin production
        • The primary reason for this? – Low insulin and IGF-1 levels (when adding these into the Petri dish, sirtuin levels dropped)

NAD+ (Nicotinamide Adenine Dinucleotide)

  • Sirtuins are regulated by NAD+
    • For example, when you’re fasting, sirtuins are activated due to a rise in NAD+ levels (the same thing happens during exercise)
  • NAD+ levels fluctuate daily depending on the time of day and your food intake (they drop after a big meal)
    • We don’t yet know how the macronutrient composition of diet (fat vs. protein vs. carb intake) affects NAD+ levels
  • David has personally noticed that intravenous NAD+ dramatically reduces the adverse effects of jet lag
    • We need more data, but this seems to point to the fact that NAD+ can be used to reset the body’s internal clock
      • “What’s interesting about this is that NAD+ isn’t being driven by the clock, the clock is driven by NAD+”David Sinclair

What is NAD+ important?

  • “You could argue NAD+ is the most important molecule in the body, maybe with the exception of ATP. But without either of them, you’re dead in about 30 seconds.”David Sinclair
  • NAD+ is essential for:
    • Sirtuin activation
    • Metabolizing fatty acids/glucose
    • ATP (energy) production (cells that have high energy demands, like activated immune cells, are thought to require even more NAD+)
    • Activating DNA repair enzymes (specifically PARPs)
      • As DNA damage accumulates, you need even more NAD+ – it’s a vicious cycle!

NAD+ Levels Decline with Age

  • Without adequate NAD+, sirtuins can’t function properly
    • By the time you’re 50, your NAD+ levels are about half what they were when you were 20
  • By raising your NAD+ levels:
    • “What I think is going on, based on the animal work we’ve been doing for many years now, is that it’s tricking the body into thinking it’s young again… This allows the sirtuins to do their job the way they once did.” – David Sinclair

The Information Theory of Aging

  • Sirtuins are one of the first proteins to get to arrive at a broken chromosome
    • Sirtuins (specifically SIR1) help remodel DNA so it’s ready for the DNA repair proteins to come in and do their job
      • “Without SIR1 getting there, these other repair proteins are inefficient” – David Sinclair
  • The accumulation of DNA damage distracts sirtuins from their other (perhaps more important) job of regulating gene expression
    • So, when DNA needs repairing, sirtuins will move away from the genes that they should be silencing, and in turn, those genes are temporarily turned on
      • In theory, sirtuins should find their way back back to the genes they came from, but this doesn’t always happen. Over time, these sirtuins get mis-localized, and certain genes get silenced that shouldn’t.
        • Because of this, cells start losing their functionality and basically their identity (so you’d get a liver cell behaving as a neural cell) – THIS is why we age

Horvath’s Methylation Clock

  • What is it?
    • On letter C of DNA (remember – DNA consists of 4 letters: A, C, T, and G), there are chemical modifications (AKA methyls, or the presence of methyl groups) that change in very linear and predictable ways
      • Reading these chemical modifications allows one to determine biological age AND the age at which you’re likely to die
  • By reading this clock, you’re essentially able to “send proteins back to where they came from”
    • Therefore, you might be able to redirect sirtuins back to the genes they originated from, thus returning gene expression back to normal, and silencing genes that were turned on in error (and reversing aging)

Genetic Reprogramming

  • David and his team have, using a set of genes known as reprogramming factors (AKA Yamanaka factors), been able to repair eyesight in mice
    • (It sounds like these reprogramming factors reset the methylation clock mentioned above, thus reversing the age of the cell, as well as redirecting sirtuin proteins to their origin, and by doing so returning gene expression to normal)
    • How? – They put a set of the reprogramming genes into a benign virus and inject it straight into the mouse’s eyeball (the virus is just a way to get the genes into the cells)
      • The genes are then turned on with an antibiotic 
    • David started a company centered around making this possible in humans
      • The process will first be used to treat glaucoma and, if proven safe, eventually repair eyesight loss associated with old age
  • If put into an adult skin cell, these reprogramming factors cause it to reverse in age to a much more primitive version (specifically to a pluripotent stem cell)
    • That pluripotent stem cell can then be grown into a neuron, eye cell, whatever you wish! 
  • The best way to sum the above up: “Your genome can be reset… Aging isn’t a one-way street.”David Sinclair

How does fasting affect aging and the epigenetic clock?

  • We don’t quite know yet
    • “I suspect fasting can help, but it’s probably not enough to do what these powerful genes [reprogramming factor] are doing” – David Sinclair
  • BUT – fasting definitely activates sirtuin proteins by raising NAD+ levels
    • “Do we slow down aging by fasting and running? Absolutely. No question.”David Sinclair

NAD+ Boosters | NR and MNM

  • For background, humans make NAD+ from a variety of natural molecules. However, you can also supplement with NAD+ precursors (and it might be a good idea to as NAD+ declines with age).
    • (Why not just supplement with NAD? – It’s too large of a molecule and cells won’t uptake it)
    • NR (nicotinamide riboside) is one example of an NAD+ precursor
      • “It’s just a smaller version of NMN [discussed below] without a phosphate, so there’s no phosphorus on there. If you take NR, your body has to first put on a phosphorus before making NAD+.” – David Sinclair
        • In simple terms: NR is first converted to NMN and then NAD+
      • For us at Podcast Notes, when it comes to a brand of NR, we can’t recommend Elysium Basis enough (use the code “podcast45” at checkout to receive $45 off a semi/annual subscription). Elysium is the only brand we know of that’s conducted pharmaceutical-level clinical trials, wholly own their own supply chain (no bad stuff is getting in), and have all safety & quality rigor you want but don’t get from most supplements.
    • NMN (nicotinamide mononucleotide) is another NAD+ precursor
      • David calls it “the immediate precursor to NAD+”
      • “If you give a cell NMN, it will be taken up by a transporter… and it’s then converted in one step to NAD+ in the cell… That step is carried out by an enzyme called NAMPT, which goes up under stress and calorie restriction.” – David Sinclair
      • David supplements with 1 gram of capsulized NMN every morning (he doesn’t disclose which brand)
  • “Make sure your NR and NMN is kept in the cold. If it’s just on the shelf, and not in a stabilized form, it will degrade into nicotinamide, which is something you don’t want to take high doses of.”David Sinclair
    • Why? – Nicotinamide actually inhibits sirtuins, thus interfering with DNA repair
    • fun fact from Podcast Notes: Elysium Basis does continued stability testing (other brands don’t). So if there is a break-down, they know which lots and can quickly recall it.

Let’s Dig Into the Science

  • Supplemental NR and NMN have both been shown to raise NAD+ levels in humans 
  • NMN and NR have shown to beneficial to the brain (boosting NAD+ levels in the brain improves memory and slows cognitive decline)
  • In mice, NMN was found to improve blood flow (in this way, supplementing with it mimics exercise)
  • One study found that oral NR supplementation (200 mg per kg of body weight) only raised NAD+ levels in the liver, not muscle
    • Note that this is a small dose. In his studies, David uses an NMN dose of 400 mg per kg of body weight.
  • A study showed that supplementing with ~1,000 mg/day of Elysium Basis increased NAD+ levels
    • However, no effect was seen on overall endurance

Comparing NR and NMN | Which is better?

  • Simply put, we don’t have enough data – we need more studies
  • In mice, however, at the same dose (~200 mg), NMN has been to increase endurance, while NR did not
  • David & his team are working on BETTER molecules than NR and NMN – he calls them “super NAD+ boosters”
    • “We have ones that work far better than NMN. These are timed-release… Those are what I’m excited about for medicines of the future.” – David Sinclair
    • They’re currently running a clinical trial with one of them: MIB-626, made by MetroBiotech

Resveratrol

  • Think of sirtuins as a car – NAD+ is the fuel and resveratrol is the accelerator pedal
    • “NAD+ makes it work, but resveratrol comes along and makes it work even faster”David Sinclair
  • Resveratrol, and other beneficial plant molecules, known as xenohormetics, are produced in plants under stress
    • By eating stressed plants, we obtain these useful molecules and activate our own stress response pathways (helping us fight aging)
  • Resveratrol can be found in nuts and grapes, but its concentration is highest in red wine (however, the best way to get adequate amounts is by supplementing)
  • David supplements with ~0.5-1 gram of powdered resveratrol every morning, and has been doing so since 2003, mixed in with yogurt (once again, he doesn’t mention a specific brand)
    • Why yogurt? – It’s essential to take the resveratrol with fat to increase absorption
      • In David’s studies (in both humans and mice), if resveratrol was not given with fat, absorption was 5-fold less
    • Resveratrol is also light-sensitive – it degrades over time when exposed to light
      • Keep it in a dark/cold environment
    • There are two forms of resveratrol: trans and cis
      • David prefers trans-resveratrol – he says it works much better in terms of sirtuin activation
  • Resveratrol also seems to improve cardiovascular health
    • How so? – It activates SIR1, which plays an important anti-inflammatory role in the lining of blood vessels and endothelial cells
    • In mouse studies, resveratrol supplementation reduced arterial levels of oxidative stress
  • A few studies on Alzheimer’s patients have shown that supplemental resveratrol (ranging from 500-1000 mg) reduces levels of amyloid-beta 42 in cerebral spinal fluid and improves cognitive function
  • Resveratrol also seems to stimulate autophagy pathways
    • One of the critical signals for autophagy activation is a decrease in protein deacetylation (and sirtuins are histone deacetylases – remember, resveratrol accelerates sirtuin function)

The Importance of Sleep

  • David typically gets ~7 hours of sleep/night. He travels a ton and often works until 11 PM, but he’s found ways to make sure he falls asleep quickly:
    • He wears blue light blocking glasses a few hours before bed (Use PodcastNotes10 for 10% at checkout for True Dark glasses)
    • He’ll sometimes take a VERY small amount of Ambien when switching time zones
  • Rhonda has been wearing a continuous glucose monitor for a few months now
    • She’s noticed that when she wakes up in the middle of the night (because of her son), her morning fasting blood glucose level and postprandial (post-meal) blood glucose levels the following day are 15-20 units higher
  • “If you take a rat and deprive it of sleep, it’ll get diabetes within a matter of a month or so” – David Sinclair
  • On the lack of sleep that comes from having children (David has three kids, Rhonda has one):
    • “I could see my age changing when I had young kids” – David Sinclair
    • “Absolutely, I’ve aged for sure. I can see it.” – Rhonda Patrick
  • Rhonda has several Phillips Hue Light Bulbs placed around her home
    • They’re programmable by phone – the idea is that you change them to emit red light after sunset (thus limiting the amount of blue light you’re exposed to in the evening)
      • Related: Young children seem to be more sensitive to blue light in the evening than adults (their melatonin levels are more adversely affected)
  • For more on sleep, check out the Podcast Notes from Rhonda’s chat with Why We Sleep author Dr. Matthew Walker
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