Life-extension biohacks are on the rise. There have been many stories recently about radical techniques to stop aging such as blood transfusions from young to old animals, genetic tinkering, severe dietary restriction and other extreme methods that show some promise. But most are a long way from being useful for most people.
The exception is this new research, published March 22 in Cell, which identifies the key cellular mechanisms behind vascular aging and the key role it plays on muscle health.
Scientists at Harvard Medical School, Massachusetts Institute of Technology (MIT) and the University of New South Wales used Nicotinamide Mononucleotide (NMN), a substance found in foods and naturally occurs in the body.
These researchers fed 400 mg/kg of NMN per day to 20-month-old mice, an age comparable to 70 years in people. After two months, the mice had increased muscular blood flow, enhanced physical performance and endurance and the old mice became as fit and strong as young mice.
We are as old as our arteries, the adage goes, so could reversing the aging of blood vessels hold the key to restoring youthful vitality?
In this study, the answer appears to be yes, at least in mice.
“We’ve discovered a way to reverse vascular aging by boosting the presence of naturally occurring molecules in the body that augment the physiological response to exercise,” said study senior investigator David Sinclair, Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School.
As we grow old, we become weak and frail. A constellation of physiological changes—some subtle, some dramatic — precipitate this inevitable decline.
As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromises oxygenation of organs and tissues. Vascular aging is responsible for a myriad of disorders, such as cardiac and neurological conditions, muscle loss, impaired wound healing and overall frailty.
Scientists have known that loss of blood flow to organs and tissues leads to the build-up of toxins and low oxygen levels. Endothelial cells — which line blood vessels — are essential for the growth of new blood vessels that supply oxygen-rich and nutrient-loaded blood to organs and tissues.
But as these endothelial cells age, blood vessels atrophy, new blood vessels fail to form and blood flow to most parts of the body gradually diminishes. This dynamic is particularly striking in skeletal muscle, which is highly vascularized and depends on a robust blood supply to function.
REDUCED BLOOD FLOW TO MUSCLES
Muscles begin to shrivel and grow weaker with age, a condition known as sarcopenia. The process can be slowed down with regular exercise, but even exercise becomes ineffective.
Sinclair and team wondered: What precisely curtails blood flow and precipitates this unavoidable decline? Why does even exercise lose its protective power to sustain muscle vitality? Is this process reversible?
In a series of experiments, the team found that reduced blood flow develops as endothelial cells start to lose a critical protein known as sirtuin1, or SIRT1. Supplementation with NMN boosts NAD+, stimulates SIRT1 and restores growth of endothelial cells.
After two months of receiving NMN, new blood vessels sprouted within the skeletal muscles of old mice. Capillary density increased and matched the capillary growth of young mice.
Remarkably, blood flow increased and the animals’ endurance (measured by how long they could run on a treadmill before before exhausting) was 56%-80% greater than that of untreated old mice: 1,400 feet compared to 780 feet.
Treated mice received the benefits of exercise just as mice half their age. In young animals, exercise spurs the creation of new blood vessels (neovascularization) and boosts muscle mass, which declines with age in both people and mice.
- NMN restored the vascular system of old mice to that of young mice
- Mice treated with NMN had a 1.6-fold increase in time and distance runs compared to untreated mice
- In young, sedentary animals, NMN did not alter the capillarity or exercise capacity
- In young animals, NMN + exercise resulted in 70% more capillaries than untreated, sedentary mice
NMN restored the blood-vessel- and muscle-boosting effects of a good treadmill run, basically “reversing vascular aging in the mice,” said study co-leader, David Sinclair of Harvard Medical School.
With exercise, the effect is even more dramatic: 32-month-old mice (equivalent to a 90-year-old human) were able to run on average TWICE as far as untreated mice.
The benefits of exercise diminish with time as decreased blood flow and muscle deterioration prevents adequate recovery. It is truly amazing that elderly animals were able to make such dramatic physiological improvements.
NMN BOOSTS NAD+
In previous studies, scientists confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects and are learning that NAD+ precursors — NMN and NR — can restore NAD+ levels to prevent and even reverse aspects of aging.
NOT THE FIRST BIG NEWS FOR NMN OR DR SINCLAIR
This is not the first time NMN made headlines in anti-aging circles. The lead author for this study, Dr. David Sinclair, published research in 2013 that demonstrating:
Raising NAD+ levels in old mice restores mitochondrial function and homeostasis to that of young mice
Key biochemical markers of muscle health in 22-month-old mice returned to levels similar to 6-month-old mice
The 2013 study prompted more research on the benefits and safety of NMN, including this 2016 study, in which mice were treated with NMN for 12 months. The results showed:
NMN was able to mitigate most age-associated physiological decline in mice
Treatment of old mice with NMN reversed all of the biochemical aspects of aging
In a paper published in Science in 2017, Dr. Sinclair identified that the metabolite NAD+, which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. Treating old mice with NMN improved their cells’ ability to repair DNA.
WHY THIS STUDY STANDS OUT
The potential of NMN has been known for over 5 years now, but this most recent study stands out because it:
- Shows NEW growth (Angiogenesis) of blood vessels in OLD animals, which is very different than improvement in some metabolic markers that may be temporary.
- Is the first time we have seen such a significant improvement in physical performance that actually allowed very old animals to perform as they did when young.
- Renewed capillary growth and increased blood flow “reversed vascular aging” and may help reverse heart and neurological problems in addition to sarcopenia.
Remember, as we age, our arteries harden and atrophy resulting in decreased endurance and muscle loss.
Here, the process was not just halted, but REVERSED, with new growth. The number and density of capillaries was the same as in young animals. This is not a temporary phenomenon that might disappear as the body adjusts and homeostasis kicks in.
According to Dr. Sinclair, the same mechanism could also spur the creation of blood vessels in the brain, where “the lack of oxygen and buildup of waste products” (resulting from capillary loss) “sets off a downward spiral of disease and disability,” such as Parkinson’s and Alzheimer’s. This may be why studies with NMN and NR have proven effective in early studies of such neurological diseases.
Sinclair and his team are now studying whether increasing NAD+ levels will also spur the creation of blood vessels in the brain.
“Anything that contributes to muscle health through vascular health is likely to be quite important,” said the Buck Institute’s Verdin, who takes a daily NAD+ precursor.
There is great interest in anything that can improve angiogenesis and treat heart disease. Pharmaceutical companies have spent BILLIONS over the last 10 years testing various products. So far, all have failed. It’s interesting that the FDA insists any such medication must improve exercise performance in patients. It’s easy to see why Dr. Sinclair has plans for gaining approval for NMN as a pharmaceutical drug.
WHY WE THINK THESE RESULTS WILL BE REPLICATED IN HUMAN TESTING
Both NMN and NR boost NAD+ and have overlapping effects in studies. At least four clinical studies with humans given NMN supplements are ongoing or completed but not yet published. There have been three human studies published with NR that show results in humans that are similar to experiments in mice (r,r,r).
A study conducted by Elysium Health in 2017 using their product, Basis (NR + Pterostilbene), found improvements in mobility. 120 individuals aged 60-80 were given 250 mg or 500 mg of Basis daily for eight weeks. Those receiving the larger dose experienced: “7.8% improvement in chair stand and 7.5% improvement in distance walked.”
I wrote at the time that it is nice, but not overwhelming, especially since we don’t know if this increased mobility is at a plateau or may improve. Now, with these results from Dr. Sinclair’s latest research in mice over two months old, we see increased endurance on a much larger scale.
However, the improved capillary growth and blood flow behind the increased endurance would not occur quickly. Two months is a long time to a mouse that live around three years.
As humans live 30-40 times longer than mice, two months in mice time is like six years or so in humans.
If the improved endurance already found in human studies is due to the same increase in NAD+, Sirt1 and capillary growth, it would seem likely to continue and over six years might be similar to that of the 2-month experiment with mice.
We are awaiting results that show NMN works the same in humans, but we do have research that makes it plausible NMN could restore blood flow and physical performance as it does with mice.
Completed or in process human studies with NMN:
- Japanese study with 100 mg and 200 mg per day
- Dr. Sinclair company Metrobio study completed late 2017, with Phase 2 trials late 2018
- University of Washington
- Keio University
Neovascularization—the formation of new blood vessels—should be treated with caution, the researchers say, because increased blood supply could inadvertently fuel tumor growth.
“The last thing you want to do is provide extra blood and nourishment to a tumor if you already have one,” said study co-author Lindsay Wu, at the University of New South Wales School of Medical Sciences.
Sinclair and Wu point out that experiments done provide no evidence treatment with NMN stimulated tumor development in animals treated with the compound.
MAXIMIZE BIOAVAILABILITY OF NMN
We do not believe the best answer is large dosages of oral supplements (capsules), but rather taking Sublingual NMN, as it is a more direct route to the blood and avoids the “first pass” metabolism (stomach, intestines, liver) that degrade a very large percentage of NMN and NR supplements.
From studies on sublingual absorption rates on other molecules, we are convinced sublingual NMN is much more effective, but it is difficult to assign a percentage to how much more.
There is no data on how much more effective NMN is in sublingual form. It’s also difficult to study sublingual absorption with mice as they don’t cooperate when trying to put substances under their tongue. 🙂
THE PROBLEM with CAPSULES – DIGESTED IN STOMACH
More recently, this research published in 2018 confirms that most oral supplements of NMN and NR are digested to NAM in the GI tract or the liver.
Future pharmacological and nutraceutical efforts to boost NAD will need to take into account the minimal oral bioavailability of NR and NMN (R)
We also showed that intravenous, but not oral administration of NR or NMN delivered intact molecules to multiple tissues (R)
Unlike in cell culture where NR and NMN are readily incorporated into NAD, oral administration fails to deliver NR or NMN to tissues (R)
Interestingly, we found that neither compound was able to enter the circulation intact in substantial quantities when delivered orally (R)
The most recent studies showing tremendous health benefits with NMN were accomplished by feeding mice very large dosages of NMN in water (r). However the dosage of 300-400 mg per kg of bodyweight used in many of these studies would equate to approximately 2,000 Mg per day for a 70 kg human. A more effective delivery method is needed !
SUBLINGUAL VS CAPSULES
The absorption of the different molecules delivered through the sublingual route can be 3 to 10 times greater than oral route and is only surpassed by direct IV injection (r).
SUBLINGUAL CAN BE MORE BIOAVAILABLE THAN INJECTION !
With intraperitoneal injection, the primary route of absorption is via the mesenteric vessels, which drain into the portal vein and pass through the liver before reaching the bloodstream.
This means, IP avoids the GI tract, but is still sent directly to the Liver, where much of it is converted to NAD+. Elevated NAD+ in the liver is good, but its far better to reach the bloodstream with intact NMN.
Sublingual delivery is not filtered by the Liver and can reach systemic circulation intact, so can actually result in greater bioavailability that direct injection! Some examples are:
- A sublingual formulation of zol… exhibited a faster rate of absorption and higher drug exposure as compared to subcutaneous injection (r)
- sublingually administered epin… results in more rapid absorption and a higher peak plasma concentration compared to injected epin… .(r)
- 40mg of sublingually administered pir.. was found to be as effective as a 75 mg intramuscular injection of dicl… (r)
NMN PERFECT FOR SUBLINGUAL
Depending on the molecule, Sublingual delivery can substantially improve the speed and bioavailability. Smaller molecules that are hydrophilic such as NMN are well-suited.
a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 (r)
SHORT WINDOW FOR MAXIMUM AVAILABILITY
The chart at right is from the 2016 Mills study with mice given 300 mg/kg of bodyweight by oral gavage.
It clearly shows NMN is found in blood plasma within minutes, peaking at around 15 minutes. After that, NMN drops rapidly in blood, and appears as increased NAD+ in the liver.
Of course this is in Mice, and humans have a slower response, but we believe it is during the short time period when NMN is available in the bloodstream and can reach tissues throughout the body that the real benefits occur.
FREQUENCY – HOW OFTEN TO TAKE
Nearly all research on mice and humans using NR and NMN is focused on measuring NAD+ and the various metabolites in the Liver as it is the primary supplier of NAD+ throughout the body (r).
If elevating NAD+ in the liver is the goal, 1-2 larger dosages per day seem to be sufficient to achieve the maximum increase in liver NAD+ (r).
OUTSIDE THE LIVER
However, we believe supplying NMN directly to the bloodstream is more effective at increasing NAD+ not just in the Liver, but throughout the body.
Smaller, More Frequent dosages
Based on the short window that exogenous NMN is available in the bloodstream before being filtered out by the Liver, we believe smaller, more frequent dosages are likely more effective than 1-2 larger dosages.
Using this philosophy, many of our customers have been reporting more perceived benefit from more frequent intake, with many taking 6-12 times per day. We recommend taking 4-8 times per day, with at least 1 hour between dosages.
NOT EVERY DAY
We recommend taking 2-3 days off per week, ideally on days when you will be getting the least exercise. If you relax more on the weekend that is a good time to not take NMN.
CONCLUSION – WHAT WE RECOMMEND
Dr Sinclair takes 500 Mg of NMN CAPSULES per day and prescribes the same for his father, which is in line with dosages used in current and recently completed research on humans.
There is likely an upper limit on the effective dosage of NMN and NR capsules, which seems to be between 500 and 1,000 Mg per day.
We believe that sublingual delivery allows a much greater percentage of NMN to bypass the liver and reach other tissues.
When split between multiple smaller dosages, we believe 1,000-1,500 Mg a day can be taken before reaching the limit on maximum effectiveness.
We recommend taking 1 tablet, 4 to 8 times per day. Ideally, 1 upon waking, 1 immediately before and after exercise, and 1 before bed, with any others spread throughout the day.
According to Dr Wu:
“If these findings translate from mouse to human, we could have a revolutionary impact on the quality of life of older people, and not to mention the benefits of avoiding diseases of aging.”
“This new study adds to the body of work showing that the restoration of NAD+ in mammals can delay and reverse many of the effects of aging.”
Even Dr. Sinclair takes NMN to boost NAD+ levels. “In someone my age , it’s probably harder to see immediate benefits,” he said, though he said he feels sharper and younger from it. After his 78-year-old father began taking NMN, “he started climbing mountains and going whitewater rafting and looking forward to the next five years.”
There have been numerous studies documenting improvements from NMN and NR for a wide range of age-related issues, but this is the FIRST evidence that shows actual NEW GROWTH in OLD ANIMALS. NMN enabled them to perform as they did when young.
We are excited about the massive benefits this could bring to hundreds of millions of people. NMN is available now in sublingual tablets, and in powder form, which is perfect for what we believe is the more effective sublingual delivery method.