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 its natural to ask whats his secret?
David doesnt give health recommendations or endorse brands, but he does share his personal supplementation:
Davids Daily Supplement Regimen:
After touching on Davids diet & exercise routines below, well look in detail at his use of NMN, resveratrol and metformin.
Davids Diet:
Davids Exercise routine:
Davids Lifestyle Choices:
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 particularly DNA repair.
He describes resveratrol as the accelerator pedal for the sirtuin genes (increasing their activation), and NMN as the fuel. Without the fuel, resveratrol wont be as effective.
The reason that resveratrol wont work effectively without NMN, is that sirtuin activation requires youthful NAD levels, but by 50 years old, David says, 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.
Graph showing NAD+ decrease with age via PLOS paper
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.
Below well dig deeper into the 3 longevity supplements David takes; NMN, Resveratrol & Metformin.
First well look at the sirtuin activator David takes; Resveratrol.
Resveratrol is a molecule thats found (in small amounts) in the skin of foods like grapes, blueberries, raspberries, mulberries, and peanuts.
If you remember the hype some years ago around red wine being healthy, part of that was due to it containing tiny amounts of resveratrol.
Unfortunately, all food sources contain tiny amounts, so we need a concentrated supplement in order to see benefits!
Resveratrol is though to act as a caloric restriction mimetic, which activates beneficial cellular pathways. Studies have pointed to benefits such as:
Whilst Davids 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, youll 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 Davids studies, cis-Resveratrol did not activate the sirtuin enzyme, but trans-Resveratrol did.
Next, the purity of the trans-resveratrol is important, were looking for 98%+. David mentions this at 1:17:54 of his Ben Greenfield interview, noting that 50% purity can even give diarrhea, because theres other stuff that comes along with the molecule. He also confirms that Polygonum cuspidatum (Japanese Knotweed) is a good source for the resveratrol.
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.
Thats 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.
We see this with other molecules too; where reducing particle size increases bioavailability. For example with curcumin, whose absorption can be improved through micronization (for example Theracurmin). So this makes sense.
Micronized resveratrol options include:
Note: Whichever source of trans-resveratrol you take, according to David, you will increase its bio-availability if you take it with a fat source.
David takes it on an empty stomach in the morning, so mixes it with a bit of yogurt. However it should also be possible to take it with a meal containing fat.
David mentions in his interview with Rhonda Patrick a few nuances around the storage of resveratrol:
David takes his resveratrol in the morning, mixed into a spoon of homemade yogurt (using the Bravo starter culture), in order to increase its bio-availability.
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 doesnt 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.
Of course you dont need to make your own yogurt, a store bought version will work adequately. However, if youre interested to make your own version expand the box below to learn more.
David has described his yogurt making process as so:
David has specifically mentioned Bravo as the brand of yogurt culture he uses, for example at 1:12:28 of his interview on the Ben Greenfield podcast. Proponents of Bravo yogurt tout it as having a very high amount of gut friendly bacteria, when compared to other similar products. Bravo seems like a fairly expensive product to me, however, once nice trick with yogurts is that you can make a new batch using a small amount from the old batch. Removing the need to use fresh starter sachets again
In terms of further details on the yogurt making process, Ive summarized some of the key points below:
This YouTube video gives a nice (but slow-paced) example of the homemade yogurt making process.
We talked above about the sirtuin activator Resveratrol, now lets talk about NMN, which helps provides the fuel for the sirtuins to work.
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 discussed above, by age 50 you have about half as much NAD as at age 20!
The intention is that by supplementing precursors we can boost the cellular level of NAD closer to youthful levels.
Theres 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.
Davids NMN powder comes from excess product left over from lab experiments. This is good to know, but doesnt help us when it comes to sourcing some. Below we will look at various possible buying options.
Potential considerations when buying include:
Assuming all the above are ok, the last crucial question is:
What Ive done below is put some of the more highly reviewed options (within USA) into a table, calculated the approximate price per gram, and added links to any 3rd party analysis certificates the companies display.
The above table provides a start, but for a detailed analysis table see this post, which also includes options for UK buyers.
Price per gramThe average price per gram appears around $4-$6. For products noticeably cheaper, it would be worth exercising caution around their authenticity.
Capsulating the PowdersWith the bulk powder versions of NMN above, you could put them into capsules yourself at home, using a capsule filling machine.
This emulates the method David uses to take his NMN; in capsules swallowed with a glass of water.
Using size 00 capsules, it takes 3 capsules to capsulate 1g of NMN. Depending on how tightly you fill them you may be a marginally over or under 1g, but it wont be by much. With enough powder, most machines can fill 100 capsules per time which would be 33 days (~1 month) supply.
TestingThere are two main types of tests companies will do. The first is third party testing on the purity of their NMN. The second is contaminant testing, for things such as heavy metals. Its a positive indicator if they can provide both.
Nicotinamide Riboside is a precursor to NAD, similar to NMN. David states in his book that his lab finds:
That being said, he isnt against NR, hes 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 brand leader in sales of Nicotinamide Riboside is Chromadexs Niagen (pictured above). Amongst Chromadexs scientific advisors is Charles Brenner, who first discovered NR, and showed it could extend the life of yeast cells.
Niagens recommended serving size is 300mg (1 capsule) which may be less efficient at raising NAD levels than 1g of NMN.
If we compare NR & NMN at a price per gram, theyre more similar than I expected. Niagen works out approximately $5.22/gram, and NMN is around $5-$6/gram depending on brand.
In Davids recent interview with Rhonda Patrick, he discussed details around storage, saying:
Since David explained this Ive come to learn that Nicotinamide Riboside, when it its chloride form; Nicotinamide Riboside Chloride (as sold by Niagen), is in a stabilized form. This means that it doesnt need to be kept cold to have an adequate shelf life. More on that below
Looking at the data online around stabilized NR, I found:
What I gather from that, is that NR in its chloride form is stabilized. But like most edible products, cooling it does slow down the degradation that occurs over time. However for most people, the product isnt intended to sit on the shelf for a long time, and thus it will be consumed before the degradation becomes a problem.
There has been some concern in the field that consuming NR or NMN could decrease the bodys methyl groups and lead to health problems. The dropdown section below looks in detail at that issue.
So methylation itself, which utilizes methyl groups (CH), is an essential process for a host of critical functions in the body, including regulation of gene expression and the removal of waste products.
Consuming Niacin derivatives (which includes NR and NMN) will require the body to use up methyl groups in order to later degrade and excrete them. There has been some discussion and concern that by increasing the amount of methylation the body needs to do (through supplementation of NR/NMN), we might deplete the body of methyl groups needed to carry out essential processes.
David discussed this in his podcast with Paul Saladino (see 44mins mark), acknowledging that Niacin derivates (including NR/NMN) require methylation for excretion, but asserting that at this stage the idea of methyl depletion is anecdotal, and not something that has been shown in any NR/NMN studies.
Initially (circa 2019) David mentioned taking a supplement called betaine, also known as trimethylglycine. Then he moved to taking a combination of methyl folate plus methyl B12. This was all in an abundance of caution, rather than due to any new research that backed up the risk of methyl depletion.
After taking the B12/Folate supplement for a few months, in February 2020 David got some blood tests done, and found his B12 levels were double the recommended maximum so he stopped taking it (source: Davids Facebook post). He hasnt mentioned replacing it with anything since.
As Dr Brenner points out below, monitoring homocysteine levels (via blood test) is a proxy for methylation issues.
Methyl groups are primarily derived from nutrients in the diet, including; methionine (amino acid), folate (vitamin B9), choline, betaine, riboflavin (vitamin B2), pyridoxine (vitamin B6) and cobalamin (vitamin B12). For foods rich in these, see table 1 in this research paper.
A further source to add to this discussion is the research done by Chromadex. They hold a patent on nicotinamide riboside production, and make Niagen. In a tweet thread by their chief scientific adviser Charles Brenner, he explains that Chromadex took the potential risk of NR depleting methyl groups seriously. To test this they performed a randomized double blind placebo controlled trial administering 100, 300, or 1,000mg of NR over 56 days (study link). They used homocysteine levels as a proxy for methylation disturbance, and found no change to homocysteine in any of the dosage groups, including up to 1,000mg (see this image). If there was a shortage of methyl groups, they would have expected to homocysteine levels rise. Its worth noting the study used NR, not NMN.
In summary, current evidence for this issue is lacking, and as far as I can tell, David Sinclair is no longer taking any supplements to tackle potential methyl group depletion. However, if you wanted to be super careful, Dr Charles Brenner (an NAD researcher) mentions elevated homocysteine in the blood can be a sign of lower methyl status so one could get a blood test to check that.
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. Its 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.
Its 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 is a prescription drug, and thus needs to be acquired through a doctors prescription, at least in most countries. It isnt (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).
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 metformins inhibition of mitochondrial function that leads to some of the health benefits. Specifically, they cause the cell to think its 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.
When not exercising, which is most days for David, he opts to take 0.5g of metformin in the morning and 0.5g in the evening (for source, see 1:16:45 of his Ivy Lecture, which supersedes what he said in his book). Then on exercise days, he opts not to take it at all. For similar reasons he also skips resveratrol on exercise days (source: see last paragraph of section 1 Get Moving on Davids blog post).
This is viable for David who exercises vigorously in the order of 1-2x per week, but for someone training often, this might be impractical. At which point it would come down to a decision whether the benefits of metformin/resveratrol outweigh the (potential) small impact on recovery.
In a Reddit AMA (link) David was asked whether he would take Berberine if he didnt have access to Metformin. He responds by saying he would likely take Berberine.
Berberine is interesting to many people because it has similar properties to metformin, but it doesnt require a doctors prescription. In common with metformin, it has the ability to:
Berberine dosage in treating diabetes is not entirely dissimilar to Metformin. For example in this study, the patients took 500mg of Berberine 3x per day. Then in this study they took 850mg of Metformin 3x per day. We know with David he takes 500mg of Metformin 2x per day.
Both compounds can induce gastrointestinal distress, so its common to start off on lower dosages, and gradually increase to the desired amount. This gives the gut a chance to adapt, and allows the user to back off the dosage if gastrointestinal distress is reached.
Go here to read the rest:
David Sinclair Supplements List Deep Dive - Updated 2021
