David recently garnered attention with his appearances on the Rhonda Patrick and Joe Rogan podcasts. Using his moment in the spotlight to raise awareness for life extension research.

Despite being 50 years of age, David looks much younger. Given that his focus is on tackling aging and he appears to exemplify this work – it’s natural to ask – what’s his secret?

One thing David is fast to point out is that he’s a researcher – not a medical doctor, and doesn’t give health recommendations. Respecting that, this article will only look at what David does, noting that he isn’t recommending others do the same.

David Sinclair Takes:

  • Resveratrol – 1g/daily – mornings with yogurt (see where to buy)
  • Nicotinamide Mononucleotide (NMN) – 1g/daily – mornings (see where to buy)
  • Metformin (prescription drug) – 1g/daily in the evenings – except on days when exercising
  • Statin (prescription drug) – taken since his early 20s due to family history of cardiovascular disease
  • Multivitamins? Only vitamin D3 with K2, he aims to get the rest from his diet

– Started taking resveratrol in 2003, and added NMN & Metformin approximately 3 years ago
– Resveratrol, NMN & Metformin doses come via David’s recently released book; Lifespan
– David’s 2018 blog post mentioned 0.5g Metformin, but in his Lifespan book; 1g Metformin

Below, a tweet by David on taking resveratrol in the morning, with a spoon of homemade yogurt (more on his yogurt here):

His studies showed that without fat, resveratrol absorption was 5x lower. So consumption with yogurt (or another fat source) is important. David clarified on the recent podcast with Rhonda Patrick that the NMN doesn’t need to be taken with a fat source – he specifically mentions taking his NMN in capsules, downed with a glass of water in the morning.

What do Resveratrol & NMN do in relation to living longer?

David describes resveratrol and NMN as critical for the activation of sirtuin genes. Sirtuins play a key role in functions that help us to live longer – such as DNA repair.

He describes resveratrol as the “accelerator pedal” for the sirtuin genes (increasing their activation), and NMN as the fuel. Without “fuel”, resveratrol won’t work. The reason that resveratrol won’t work effectively without NMN, is that sirtuin activation requires youthful NAD levels, but by 50 years old, we have about half the level of NAD we had in our 20s (NAD being a molecule that is essential to energy production in our cells).

So in effect, you take resveratrol to increase activation of the sirtuin genes, and NMN to ensure the sirtuins have enough energy to work properly.

What else is David doing to stay healthy?

  • Intermittent fasting – skipping breakfast and/or lunch where possible. Helped by lots of green tea
  • Running 1-2x/week low impact and high intensity (using a curved treadmill such as Woodway)
  • Weight lifting (ideally!) 2-3x/week
  • Sauna weekly
  • Coffee in the morning (once per day), then green tea after that

Below we’ll dig deeper into the 3 longevity supplements David takes; NMN, Resveratrol & Metformin.

Resveratrol

Resveratrol is a molecule that’s found (in small amounts) in the skin of foods like grapes, blueberries, raspberries, mulberries, and peanuts. If you remember the “hype” some time ago around red wine being healthy, part of that came because it contains tiny amounts of resveratrol. Unfortunately all foods sources contain tiny amounts, so we need to take it in a concentrated supplement form for it to be useful.

There’s actually a fair amount of controversy around the potential benefits of resveratrol. For example this 2019 literature review is quite critical of the health claims:

Whereas this paper (admittedly co-authored by David Sinclair), points to benefits:

In that paper they hypothesize that resveratrol acts a “caloric restriction memetic”, which activates beneficial cellular pathways.

Given that there are scientists much smarter than me on both sides of the fence, I find it hard to draw a conclusion. But certainly it’s interesting that a scientist like David has taken it since 2003 – and continues to do so to this day.

Left pic = 2009 (source), right pic = 2019 (source)

Resveratrol – Where to buy?

Whilst David’s resveratrol comes from excess product leftover from lab experiments, not all of us have this luxury! Therefore we are forced to look online. If you pop resveratrol into an Amazon search, you’ll find a host of different options, many of (potentially) dubious quality.

The first thing to note is that we should be looking for trans-resveratrol, not cis-resveratrol.

From David’s studies, cis-Resveratrol did not activate the sirtuin enzyme, but trans-Resveratrol did.

To get closer to the quality that David is likely taking, we can look at research published by an old company of his; Sirtris (who were sold to GSK for $720 million). In this paper they were doing clinical tests on a formulation of resveratrol they call SRT501. Noting that:

Due to the poor aqueous solubility exhibited by resveratrol, digestive absorption is greatly influenced by drug dissolution rate. In an effort to increase absorption across the gastro-intestinal tract and thus systemically available parent compound, there has been considerable interest in the pharmaceutical manipulation of resveratrol. Decreasing the particle size of such chemicals can improve their rate of dissolution and thus their absorption. Therefore, the aim of this clinical study was to investigate whether consumption of SRT501, a micronized resveratrol formulation designed by Sirtris, a GSK Company is safe and generates measurable and pharmacologically active levels of parent agent in the circulation and in the liver.

That’s a wordy quote from the paper, but in essence, they were testing a micronized resveratrol formulation against a non-micronized version. Their study found that levels of resveratrol in the blood were 3.6x greater when using the micronized formulation, and other markers they were comparing also improved.

They find this with other molecules too, such as curcumin, whose absorption can be greatly improved by micronizing the particles. So this makes sense.

Searching Amazon for “micronized resveratrol” suddenly shrinks the options to just a few, including MegaResveratrol. However, I noticed something on the page for the Rich Roll interview with David Sinclair. He lists a micronized resveratrol by RevGenetics. This was interesting because during the interview Rich asks David where to get the supplements he takes, and David told him they’d talk about it after the podcast. Maybe RevGenetics was a brand that David mentioned post interview (possible), or perhaps it was just a brand Rich “plucked” from a Google search. Impossible to know without further info.

That said, I looked into RevGenetics a little more, and they certainly seem legitimate. They focus on longevity molecules and have been selling resveratrol since 2006. They offer a micronized resveratrol that comes in powder form, and thus could be taken in the morning with yogurt, as David does. It’s named M98 Super Micronized Resveratrol. At 1g/day their 25g tub should last 25 days, at just over $2 per daily dose.

Resveratrol – Storage

David mentions in his interview with Rhonda Patrick a few nuances around the storage of resveratrol:

  • Resveratrol is light sensitive, and when left exposed to light it turns brown. They found that brown resveratrol no longer works correctly.
  • Ideally resveratrol should be kept in the cold and dark – for example, in a sealed container in the fridge.

Homemade Yogurt

As mentioned above, David takes his resveratrol in the morning, mixed into a spoon of homemade yogurt, in order to increase its bioavailability. Of course you don't need to make your own yogurt, a store bought version will work adequately. However, if you're interested to make your own version - read on.

David has so far only touched on his yogurt making process, saying that he:

  • Takes a couple sachets of un-named greek yogurt starter culture (likely similar to these)
  • Combines them with grass fed whole milk in a mason jar
  • And puts the jar in the oven overnight on a low heat

Of course, he mentions this in passing, and so it's worth elaborating on a few details:

  • The core yogurt making process is combining yogurt bacteria with milk, and keeping the liquid at around 115°F for 5-10 hours (often overnight). During this period, the yogurt bacteria ferments the milk, turning the lactose sugars in the milk into lactic acid - causing it to thicken and change in taste.
  • A common step prior to this is to heat the milk to 180°F in order to sterilise both the milk and your storage container. David doesn't mention this part, but it's good practice in yogurt making to avoid unwanted bacteria multiplying later on.
  • After the milk has reached 180°F you can then cool it down to around 115°F (a milk thermometer makes this much easier; either analogue or digital), and then add your yogurt starter culture.
  • Next you want to store your yogurt mixture for 5-10 hours, keeping it at close to 115°F. David mentions leaving it in the oven, which is ok if your oven can maintain this temperature - worth checking on yours to see if it can do so. You want to avoid the oven getting too hot, and then killing all the bacteria!
  • Alternatives to the oven are 1) Wrap your container in a blanket and place it in a warm part of your house. Whilst it won't stay at 115°F all night, it should hopefully stay warm enough to ferment and turn into yogurt - it's a very common method 2) Use a dedicated yogurt maker, or a slow cooker (both have thermostats to maintain the correct temperature).

This YouTube video gives a nice (but slow) example of the homemade yogurt making process.

 

NMN – Nicotinamide Mononucleotide

NMN falls into a category of supplements, along with Nicotinamide Riboside (NR), referred to as “NAD boosters” – which have become increasingly popular.

NAD is required for every cell of our body to help facilitate energy production. As we age, the amount of NAD our cells produce declines, and less NAD = reduced cellular function. According to David, at 50, you have about half as much NAD as at age 20.

The hope is that by supplementing precursors we can boost the cellular level of NAD closer to youthful levels.

There’s little to no doubt in the research community that we need to restore NAD function; but the jury is still out on what the best method will be. Currently David has his eggs in the basket of NMN.

NMN – Where to buy?

Again, as with the resveratrol, David’s NMN comes from excess product leftover from lab experiments. This is good to know, but doesn’t help us when it comes to sourcing some. Below we will look at various possible buying options.

Whilst nicotinamide riboside has a clear “brand leader” (Chromadex Niagen), there isn’t yet a clear leader in the space for NMN.

One name I’ve heard some discussion around is Alivebynature, who make a 12g and 36g powdered version.

Then there’s an NMN powder made by the same company who make MegaResveratrol (mentioned above); called SuperNMN.

RevGenetics (also mentioned above) make a bulk powder version of NMN called Advanced NMN – which comes in 10g and 25g versions.

With the bulk powder versions of NMN, you could then put it into capsules yourself at home, using a cheap, but handy, capsule filling machine. Emulating the method David uses to take his NMN; in capsules swallowed with a glass water.

NMN Price & Bioavailability

One thing that’s worth acknowledging is that NMN is currently a very expensive supplement, especially if you wanted to emulate David Sinclair’s dosage of 1g/day.

There are a few possible workarounds:

  1. It may be possible to use lower doses, perhaps 0.25 or 0.5g per day. Given that NAD levels decline with age, this approach of taking a lower dose may be more viable the younger you are – on the basis that if you’re younger, you might need less NMN to raise your NAD back to youthful levels. However, this is all theory, we need studies to test the dose dependent effect, and which dose thresholds work for different age groups.
  2. An idea being discussed by the brand “Alivebynature” is sublingual dosing. Essentially you put the powder in your mouth, under your tongue, and let it dissolve fully before swallowing. With the intention that it’s absorbed by the capillaries into the bloodstream, bypassing the liver, and increasing the amount that makes it to the bloodstream. If you can increase the absorbtion, you can potentially decrease the quantity needed per dose. Sublingual dosing is described in more detail on their site. Having read their description, it’s evident that sublingual dosing is not a science backed approach (yet) – it’s still speculative. David actually wrote a blog post about sublingual dosing, saying that we still don’t have any evidence if this works, and that whilst he doesn’t tell anyone what to do, or give health advice – he doesn’t personally take NMN sublingually.
  3. The key molecular difference between NMN and NR is that NMN contains an extra phosphate. Phosphate chemistry is expensive, and even David’s lab ends up paying 10’s of thousands of dollars per KG of NMN. In the pursuit of boosting NAD levels, whilst staying within budget, it may be worth looking to NR (Nicotinamide Riboside), another precursor of NAD, as a more cost-effective NAD boosting solution.

What does David think of Nicotinamide Riboside (NR)?

David states in his book that his lab finds:

  • NMN a more stable molecule than NR
  • NMN is able to do some things in mice studies that NR can’t

That being said, he isn’t against NR, he’s just more optimistic on NMN being the better molecule for raising NAD in the long run. He notes in a blog post on NMN & NR that:

  • The science is further along for NR, but it’s too early to say which is better for humans.

Currently there are no human studies on NMN – but they are taking place!

NR – Where to buy?

 

As we discussed above, NMN is an expensive molecule, especially to take at the doses David is using (1g/day). A commonly used alternative is NR, and the brand leader in the space is Chromadex’s Niagen (pictured above). Amongst Chromadex’s scientific advisors is Charles Brenner, who first discovered NR, and showed it could extend the life of yeast cells.

It’s worth noting that Tru Niagen’s recommended serving size is 300mg (2 capsules)- which may be less efficient at raising NAD levels than 1g of NMN.

NR & NMN Storage

In David’s recent interview with Rhonda Patrick, he discussed details around storage, saying:

  • NR and NMN need to be kept cold (fridge or freezer) because they don’t have a long shelf life.
  • If they are kept on a shelf, and are not in a stabilized form, they can degrade into nicotinamide. This is sub-optimal because Nicotinamide can have the opposite of the desired effect, and actually inhibit the sirtuins1. He didn’t elaborate further on what a “stabilized form” means in this context, which would be interesting to know.
  • If NMN gets wet, or gets a bit of humidity in the bottle, its only a short time before it’s degrading. This may be the case with NR too (because it applies to many supplements), but when David explained this he was explicitly talking about NMN.

This was all interesting to note, because currently, NR & NMN are not stored and shipped cold by any suppliers that I’m aware of. They are however sold in sealed bottles that block light and contain moisture absorbing sachets, so it’s possible this is adequate for the short term, depending on how long the bottles have been on the shelf. Perhaps with third-party testing we could learn more about whether any of these supplements on the market have degraded by the time they reach consumers.

Metformin

Metformin is actually a relatively old drug, first discussed in medical literature in 1922, and studied in humans in the 1950s. It is derived from a plant called the French Lilac. It’s primary use in medicine is for the treatment of diabetes, thanks to its ability to decrease blood glucose levels in patients.

Because Metformin has been used for years, and has an established track record of safety, this makes it more attractive as a longevity drug. Molecules that are discovered today will need years of testing before they can even come close to rival the amount of data and “patient years” accumulated by metformin.

It’s thought the longevity benefits are at least in part derived from activation of the AMPK cellular pathway. This has a host of knock-on effects (visualized below), some of which are involved in beneficial processes like mediating inflammation and increasing autophagy (cellular cleanup).

AMPK pathway activation (image via this paper)

Metformin – Where to buy?

Metformin is a prescription drug, and thus needs to be acquired through a doctor’s prescription, at least in most countries. It isn’t (yet) considered a drug that can help improve healthspan or lifespan, and so you may need to find a forward thinking doctor if you want it prescribed for general health. Typically doctors only prescribe Metformin for blood sugar control issues (type 2 diabetes).

How often to take?

Typically Metformin is taken daily – both by diabetics, and by people using it for healthspan extension. However, on the latest interview with Joe Rogan, they discussed a 2018 paper which showed metformin inhibits mitochondrial adaptations to aerobic exercise training. David explained that this makes sense, and its exactly metformin’s inhibition of mitochondrial function that leads to some of the health benefits. Specifically, they cause the cell to think it’s in a nutrient restricted state, and it turns on pathways typically reserved for times of scarcity. The function of these pathways is hypothesized to lead to better healthspan outcomes.

With this in mind, David opts to take metformin at night, so that come the morning, the mitochondrial inhibition is lessened. He also opts not to take it on days when he has been exercising.

How to (big picture) think about the molecules David takes?

We can attempt to summarise the function of the molecules David takes using 2 categories; 1) molecules that emulate fasting 2) molecules that boost existing function.

1) Molecules that emulate fasting

Both resveratrol and metformin can be described as molecules that trigger cells to exhibit characteristics similar to when fasting. Metformin activates AMP-Kinase, Resveratrol activates SIRT1 and AMP-Kinase.

Why is this beneficial?

Cells have evolved to operate in 2 main states; fed and unfed. In times of plenty, they will grow and multiply, and in times of scarcity, they will hunker down and focus on maintenance. Part of maintenance includes things like:

  • DNA repair
  • Removing and re-using non-functioning or superfluous cellular contents (autophagy)
  • Removing toxins

These are all important tasks, and it’s possible that when we exist in a constantly fed state, they don’t get done as much as could be optimal.

Thus when David takes resveratrol and metformin, and undertakes intermittent fasting, he’s allowing for these fasting dependent processes to take place.

There may be other things going on too – but this is a big chunk of what’s happening.

2) Molecules that boost existing function

Whilst metformin and resveratrol are primarily aimed at preserving existing function, we have NMN which is taken to boost our NAD back to youthful levels.

Fasting can actually boost NAD levels too, but the intention is that using NAD precursors like NMN raises NAD higher and for longer than can be achieved otherwise.

To Conclude…

  • David is a longevity researcher who is certainly aging gracefully

Left pic = 2009 (source), right pic = 2019 (source)

  • He doesn’t give medical advice and doesn’t endorse any brands, however, he’s open to sharing what he does for himself
  • We looked at what he does to stay youthful, and what supplements he takes. Covering:
  • How resveratrol works and where to buy
  • How NMN works and where to buy
  • How metformin works (noting that it’s prescription only)
  • We discussed how Nicotinamide Riboside (NR) is potentially a more affordable method of boosting NAD than NMN
  • Lastly, we looked at a simple way to categorically think about how these 3 molecules work

—-

Currently research is further ahead with nicotinamide riboside than nicotinamde mononucleotide. NMN has only been tested in animals so far, but human studies are in progress currently. I've listed some of the more interesting nicotinamide riboside studies below:

Nicotinamide Riboside

  • 2019 (August), a 12 person study, taking 1g/day nicotinamide riboside. Showed elevated NAD+ metabolome in skeletal muscle, which I take to mean there was greater metabolic function, which they evidenced by greater NAD and nicotinamide clearance products (need to look into what this means in more detail!) Also showed reduced level of circulating inflammatory cytokines. This was a placebo controlled, randomized, double blind crossover trial - study link
  • 2019, 32 person study in ALS patients, taking what they called EH301. EH301 is another name for Elysium's supplement; Basis. 2 capules (1 dose) contains 250mg Nicotinamide Riboside and 50mg Pterostilbene. Participants took 4 capules, twice daily, for a total of 1,000mg NR and 200mg Pterostilbene. The results showed disease modifying benefits for ALS patients - study link
  • 2017, An 8 person, non randomized, open label trial in healthy volunteers. Dose = titrated up to 1,00mg on day 9. No adverse effects. NAD+ was 2x baseline on day 9. - study link
  • 2016, 1 person study, showed that NR raises NAD+ by as much as 2.7x in human blood with a single oral dose of 1000 mg - study link

 

Any questions or comments, please leave them below.

If you liked this post, you may also find these interesting:

  • For more discussion on lifestyle modifications (intermittent fasting, foods to eat, optimizing sleep) – see my post on Dr Rhonda Patrick’s Diet
  • David Sinclair recently wrote an article on his blog around what his 80 year old father does to stay healthy
  • David Sinclair also wrote an article on his blog comparing NR to NMN – which I also linked to above.
  • Dr Peter Attia recently wrote a post on metformin and how it appears to blunt (positive and desirable) muscle and mitochondrial adaptations to exercise – raising questions on whether super healthy people want to be taking metformin if they’re exercising regularly

See Post Sources Below:

  1. Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1 – Bitterman et al (2002)
Alex

Posted by Alex

16 Comments

  1. Avatar

    “The reason that resveratrol won’t work effectively without NMN, is that sirtuin activation requires youthful NAD levels, but by 50 years old (..)”

    If your NAD levels are still high when you’re younger.. form what age onwards does it make sense to start taking NMN?

    Im thinking of starting taking resveratrol.. but from what age onwards do you really need to start taking NMN in order for resveratrol to still work?

    Probably a question that doesnt have an exact answer, but it would be cool if some one with a but more knowledge than i do, could comment on this..

    Reply

    1. Alex

      Hi Melanie – totally agree – that’s an interesting question. Seems aspirational to try and answer, but unlikely to be possible at this stage.

      On a related note, found a study in PLOS that plots NAD levels from pelvic tissue samples, for people of different ages – link. Found it interesting for getting an idea of change over time.

      Reply

  2. Avatar

    Hi Alex, do you have more info on taking NMN with fat?

    I’ve listened to several David Sinclair podcasts and he seems to make the distinction that Resveratrol needs fat for absorption but not NMN. I’ve seen this in several other places as well. That one twitter reference is the only thing I’ve seen/heard of him saying NMN needs fat. If I recall correctly in their test mice were given NMN in their water.

    Anecdotally, I’ve used ABNs sublingual and really noticed a difference when taken in small doses throughout the day.

    But I haven’t tried taking it with fat, so I’m curious about that method. But seems like if David Sinclair takes it that way it’s mostly for the convenience rather than the actual need for fat in absorption.

    Great article and thanks for putting it together!

    Reply

    1. Alex

      Hey Aaron! Thanks for the message. So yes – David made it very clear on the recently released podcast with Rhonda Patrick – that the need for a fat source (in his case yogurt) is to help absorb the resveratrol, and isn’t necessary for the NMN. In other discussions he hadn’t said it so clearly, so I’d interpreted it as the fat source helped absorb both. Will update the post to reflect this 🙂

      Reply

  3. Avatar

    Should NMN and/or Resveratrol be taken when fasting. I’m talking about a true 48 or 72 hour fast, rather than intermittent fasting of skipping 1 or 2 meals a day. Or should I skip taking either during the days I’m fasting?

    Reply

    1. Alex

      Hi Glen. That’s an interesting question – thanks for noting you mean extended fasting rather than intermittent fasting. Whilst I don’t think I can answer it perfectly, I can certainly share some thoughts around it.

      So firstly, with the NMN, the goal is to increase NAD levels, which boosts (or restores) cellular metabolism. Its been observed that fasting also boosts NAD levels – for example this paper models that scenario in mice. So even without your NAD precursor, you’ll get an uptick in NAD whilst fasting. Whether or not it’s worth trying to boost that further via NMN? It’s an open question.

      Then with regards to resveratrol, which can be characterised as a fasting mimetic drug – increasing expression of pathways such as AMP-Kinase – a pathway that is also expressed when cells are nutrient deprived. What happens when you’re already fasting… does resveratrol help or hinder? I’m not sure the answer. If you’re already fairly disciplined with how often you take it, it could be worth cycling off for your extended fast, and then resuming once you start eating again. Or maybe even a few days after you resume eating, in order to let the body naturally recover from the fast, without simulating nutrient scarcity so quickly after real nutrient scarcity.

      Reply

      1. Avatar

        Thanks Alex. I just started taking NMN and Resveratrol. Unfortunately, I started it the same time I also did a 72 hour fast. I think it makes sense to cycle off NMN and resveratrol during prolonged fasts as I felt that I had less energy than in the past when I did 48 and 72 hour fasts alone w/o taking any other supplements.

        I’m currently doing a 48 hour fast and have not taken NMN and resveratrol and feel more energetic overall. Moving forward, I think I’m going to take these supplements only when I’m actually eating.

        I currently take a supplement that has both 250 mg of NMN and 250 mg of reseveratrol combined. I think I’m going to get separate supplements so I can try taking one and/or the other depending on what I’m doing w/ my fasting regimen.

        Reply

  4. Avatar

    But how can the average person get Metformin? It is prescription only.

    Reply

    1. Alex

      You would need to seek out a doctor who is willing to prescribe metformin to you “off-label”, and then work with you to ensure it’s a good fit. I don’t have a list of doctors who will do this.

      Reply

  5. Avatar

    Really good job summarizing all this info, much appreciated.

    Reply

  6. Avatar

    Yes, great post, Alex, bringing many of the details together about these three supplements and David’s research on and use of them.

    Big help, thank you.

    Reply

    1. Alex

      Hey, appreciate the feedback, glad the article helped!

      Reply

  7. Avatar

    What about the NAD+ IV regimen?

    Reply

    1. Alex

      Intravenous NAD? That’s not something David is using. Although he did mention trying it out of curiosity. For more information on that, you’re best off looking to other people/researchers.

      My reservation with intravenous NAD (assuming the science shows that it indeed works, which hasn’t yet been proven) would the frequency of administration. You ideally want to boost NAD levels daily, and supplements will facilitate this more easily than infrequent IV doses. More research is needed to clarify on these questions.

      Reply

  8. Avatar

    thank you! Great post, you saved me a lot of time on research.

    Reply

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