David recently garnered attention with his appearance on the Joe Rogan Experience podcast. Using his moment in the spotlight to raise awareness of life extension research taking place.

Despite being 50 years of age, David looks much younger than his years. 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 with yogurt (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 ~12 years ago, and added NMN & Metformin ~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

David, on taking NMN & resveratrol in the morning, with a spoon of home-made yogurt:

His studies showed that without fat, resveratrol absorption was 5x lower. So consumption with yogurt, or another fat source, is needed.

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

David describes resveratrol and NMN as critical for the function of the 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:

• Resveratrol: Twenty Years of Growth, Development and Controversy

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

• Therapeutic potential of resveratrol: the in vivo evidence

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 for 12 years – and continues to do so to this day.

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.

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.

N.B. October 12th – a reader informed me that RevGenetics M98 resveratrol is temporarily out of stock – perhaps in part due to the increased demand since David’s book Lifespan launched.

NMN – Nicotinamide Mononucleotide

NMN falls into a category of supplements, along with Nicotinamide Riboside, 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 (powder being important if you want to emulate David’s method of mixing it into a spoon of yogurt).

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.

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.

One solution is to use lower doses, perhaps 0.25 or 0.5g per day. With a lower dose, you want to ensure you’re maximizing bioavailability – such that none is wasted.

David’s approach is to mix the powder with a fat source (yogurt) – and that may be enough.

Another approach that’s being pushed by 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.

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. However it’s under active research, so could be worth keeping an eye on.

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.

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).

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, plus uses 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 appears to be aging gracefully.

• 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 young, and what supplements he takes. Covering:
• How resveratrol works and where to buy.
• How NMN works and where to buy.
• How metformin works and noted that it’s prescription only.
• We discussed how Nicotinamide Riboside (NR) is a potentially more affordable method of boosting NAD than NMN.
• Lastly, we looked at a (hopefully simple) way to categorically think about how these 3 molecules work

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Hopefully the above is useful, if you have any questions or comments, please leave them below.

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