NAD+: The Molecule of Youth? + Factors That Increase It

Rewinding the Clock | Harvard Medical School

NAD+: The Molecule of Youth? + Factors That Increase It

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? The answer appears to be yes, at least in mice, according to a new study led by investigators at Harvard Medical School.

The research, published March 22 in Cell, identifies the key cellular mechanisms behind vascular aging and its effects on muscle health and has successfully reversed the process in animals.

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The findings pinpoint a glitch in the normal crosstalk that occurs between muscles and blood vessels and keeps both tissues healthy.

Using the synthetic precursors of two molecules naturally present in the body, the scientists also managed to reverse blood vessel demise and muscle atrophy in aging mice, boosting their exercise endurance in the process. The achievement, the team said, paves the way to identifying related therapies for humans.

“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 at Harvard Medical School and co-director of the Paul F.

Glenn Center for the Biology of Aging at Harvard Medical School.

“The approach stimulates blood vessel growth and boosts stamina and endurance in mice and sets the stage for therapies in humans to address the spectrum of diseases that arise from vascular aging,” added Sinclair, who is also a professor at the University of New South Wales School of Medical Sciences in Sydney, Australia.

The researchers caution that many promising treatments in mice don’t have the same effect in humans due to critical differences in biology. However, the results of the experiments were dramatic enough to prompt the research team to pursue experiments in humans. Clinical trials for safety are already under way, Sinclair said. 

As old as our blood vessels

Sinclair and team set out to unravel the mechanisms behind one of biology’s inevitabilities: aging. As we grow old, we become weak and frail. A constellation of physiological changes—some subtle, some dramatic—precipitate this inevitable decline.

What exactly happens inside our cells to cause the biological shifts that lead to aging? It’s a question that has vexed Sinclair and team for years.As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromised oxygenation of organs and tissues.

Vascular aging is responsible for a constellation of disorders, such as cardiac and neurologic conditions, muscle loss, impaired wound healing and overall frailty, among others. Scientists have known that loss of blood flow to organs and tissues leads to the build-up of toxins and low oxygen levels.

The so-called endothelial cells, which line blood vessels, are essential for the health and growth of 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 muscles, which are heavily vascularized and rely on robust blood supply to function.Muscles begin to shrivel and grow weaker with age, a condition known as sarcopenia. The process can be slowed down with regular exercise, but gradually even exercise becomes less effective at holding off this weakening.

Sinclair and team wondered: What precisely curtails the 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.

Previous studies have shown that SIRT1 delays aging and extends life in yeast and mice. 

SIRT1 loss is, in turn, precipitated by the loss of NAD+, a key regulator of protein interactions and DNA repair that was identified more than a century ago. Previous research by Sinclair and others has shown that NAD+, which also declines with age, boosts the activity of SIRT1.

A stimulating conversation 

The study reveals that NAD+ and SIRT1 provide a critical interface that enables the conversation between endothelial cells in the walls of blood vessels and muscle cells.

Specifically, the experiments reveal that in young mouse muscle, SIRT1 signaling is activated and generates new capillaries, the tiniest blood vessels in the body that supply oxygen and nutrients to tissues and organs.

However, as NAD+/SIRT1 activity diminishes over time, the study found, so does the blood flow, leaving muscle tissue nutrient-deprived and oxygen-starved. 

Indeed, when researchers deleted SIRT1 in the endothelial cells of young mice, they observed markedly diminished capillary density and decreased number of capillaries, compared with mice that had intact SIRT1.

Mice whose endothelial cells lacked SIRT1 had poor exercise tolerance, managing to run only half the distance covered by their SIRT1-intact peers.  

To determine SIRT1’s role in exercise-induced blood vessel growth, the researchers observed how SIRT1-deficient mice responded to exercise.

After a month-long training regimen, the hind-leg muscles of SIRT1-deficient mice showed markedly diminished ability to form new blood vessels in response to exercise compared with same-age mice that had intact SIRT1 in their endothelial cells.

Exercise-induced blood vessel formation is known to occur in response to growth-stimulating proteins released by muscles under strain. SIRT1, however, appears to be the key messenger relaying growth-factor signaling from muscles to blood vessels, the study found.

  Experiments showed that endothelial cells lacking SIRT1 were desensitized to the growth-stimulating proteins released by exercised muscles.“It’s as if these cells had grown deaf to the signals that muscles sent their way,” Sinclair said.

The observation, he added, explains why age-related loss of SIRT1 leads to muscle atrophy and blood vessel demise.

Since the experiments revealed the critical role of SIRT1 in exercise-induced blood vessel formation, the researchers wondered whether boosting SIRT1 levels would stimulate blood vessel growth and stave off muscle wasting.

Exercise in a pill?

The scientists set their sights on NAD+, a molecule conserved across many life forms, known to decline with age and previously shown to stimulate SIRT1 activity.

“We reasoned that declining NAD+ levels reduce SIRT1 activity and thus interfere with aging mice’s ability to grow new blood vessels,” said study first author Abhirup Das, who conducted the work as a post-doctoral fellow in Sinclair’s lab, currently a visiting scholar in genetics at Harvard Medical School and a post-doctoral research fellow at the University of South New Wales School of Medical Sciences. 

To test this premise, scientists used a chemical compound called NMN, a NAD+ precursor, previously shown to play a role in repairing cellular DNA and maintaining cell vitality.In lab dish experiments, endothelial cells from humans and mice treated with NMN showed enhanced growth capacity and reduced cell death.

Next, the team gave NMN over two months to a group of mice that were 20 months old—the rough equivalent of 70 in human years. NMN treatment restored the number of blood capillaries and capillary density to those seen in younger mice.

Blood flow to the muscles also increased and was significantly higher than blood supply to the muscles seen in same-age mice that didn’t receive NMN.

The most striking effect, however, emerged in the aging mice’s ability to exercise. These animals showed between 56 and 80 percent greater exercise capacity, compared with untreated mice the study showed.

The NMN-treated animals managed to run 430 meters, or about 1,400 feet, on average, compared with 240 meters, or 780 feet, on average, for their untreated peers. 

To see whether the effects of NMN could be further augmented, the researchers added a second compound to the treatment regimen.

The compound, sodium hydrosulfide (NaHS), is a precursor to hydrogen sulfide, which also boosts the activity of SIRT1. 

A group of 32-month-old mice—the rough equivalent to 90 in human years—receiving the combo treatment for four weeks were able to run, on average, twice as long as untreated mice. In comparison, mice treated with NMN alone ran 1.6 times farther, on average, than untreated animals.

“These are really old mice so our finding that the combo treatment doubles their running capacity is nothing short of intriguing,” said study co-author James Mitchell, associate professor of genetics and complex diseases at the Harvard T. H. Chan School of Public Health.

  Research led by Mitchell and published in the same issue of Cell also found sodium hydrosulfide to augment blood vessel formation in the muscles of mice.Interestingly, the NMN treatment did not improve blood vessel density and exercise capacity in young sedentary mice.

However, it did boost blood vessel formation and exercise capacity in young mice that had been exercising regularly for a month.

“This observation underscores the notion that age plays a critical role in the crosstalk between blood vessels and muscles and points to a loss of NAD+ and SIRT1 as the reason behind loss of exercise effectiveness after middle age,” Das said.

The researchers say their findings may pave the way to therapeutic advances that hold promise for the millions of older people for whom regular physical activity is not an option.

“Even if you’re an athlete, you eventually decline,” Sinclair said. “But there is another category of people—what about those who are in a wheelchair or those with otherwise reduced mobility?”

The team’s ultimate goal is to replicate the findings and, eventually, move toward developing small-molecule, NMN-based drugs that mimic the effects of exercise—enhanced blood flow and oxygenation of muscles and other tissues.

Such therapies may even help with new vessel growth of organs that suffer tissue-damaging loss of blood supply and oxygen, a common scenario in heart attacks and ischemic strokes, the team said.

Neo-vascularization—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 as part of the current study provide no evidence that treatment with NMN stimulated tumor development in animals treated with the compound.

Co-investigators included George Huang, Michael Bonkowski, Alban Longchamp, Catherine Li, Michael Schultz, Lynn-Jee Kim, Brenna Osborne, Sanket Joshi, Yuancheng Lu, Jose Humberto, Trevine-Villareal, Myung-Jin Kang, Tzong-tyng Hung, Brendan Lee, Eric Williams, Masaki Igarashi, James Mitchell, Nigel Turner, Zolt Arany and Leonard Guarente.

The work was supported by the Glenn Foundation for Medical Research (grants RO1 AG028730 and RO1 DK100263), and by the National Institutes of Health/National Heart, Lung and Blood Institute (grant RO1 HL094499).

Relevant disclosures:

Sinclair and Wu are consultants and inventors on patents licensed to Metro International Biotech, JumpStart Fertility, Vium, Life Biosciences and Liberty Biosecurity. Sinclair is consultant to EdenRoc Sciences, Arc Bio, Segterra, Animal Biosciences, Senolytic Therapeutics, Spotlight Biosciences and Continuum Biosciences.

Wu is consultant to Intravital and JumpStart Fertility. Bonkowski is a consultant to Metro International Biotech.

 Sinclair sits on the fiduciary board and has an equity interest in EdenRoc Sciences, Arc Bio, Segterra, Metro International Biotech, Liberty Biosecurity, Animal Biosciences, Life Biosciences, Senolytic Therapeutics, Spotlight Biosciences and Continuum Biosciences.

 He is a cofounder of EdenRoc Sciences, Arc Bio, Metro International Biotech, Liberty Biosecurity, Life Biosciences, and Spotlight Biosciences. Guarente is advisor to Segterra, Sebelius and Elysium Health. A provisional patent application has been submitted with Das, Wu and Sinclair as inventors.


7 Foods That Will Naturally Increase NAD+ and Restore Your Youth

NAD+: The Molecule of Youth? + Factors That Increase It

In the 16th century, Juan Ponce de Leon was in search of a mythical water source that could change the destiny of humanity. He was in search of the fountain of youth.

Having heard whispers that there was a fountain whose water could cure all disease and restore youth, he made it his life's mission to find it. Nobody knows if he really found it.

However, we do know that modern scientists have made a discovery that could very well be our fountain of youth. This discovery is NAD+. Nicotinamide Adenine Dinucleotide (NAD) is a compound of chemical nature which is found in every single cell in our bodies.

It is derived from Nicotinamide Riboside. Its levels in the body determine the speed of the aging process. More NAD+ results in younger cells, tissue and body overall. Here is how to naturally boost NAD+ and its contribution to the anti-aging process.

The contribution of NAD+ to the anti-aging process

Every living mammal today has NAD+ in its cells. The levels of this chemical in the body are directly related to the process of aging. As we increase in age, the levels of NAD+ in our bodies reduce. This means that this chemical is inversely proportional to advancing age. Scientists and nutritionists have found that we can actually raise the level of NAD+ in the body artificially.

This can be done using supplements containing this chemical. An example of such a supplement is Niagen. This can trick the body into thinking that it is younger. Thus, the characteristics of youth can resume in us. Examples of these are mental acuity, enthusiasm, physical strength, high energy, positive motivation and passion. This chemical could restore and maintain our youth when consumed.

How does it work to restore youth?

NAD+ facilitates the transfer of energy to our cells from the food we consume. This is done in a process known as oxidation. Under normal conditions, whenever our cells need to conduct some specific functions, they demand energy from the blood stream. This energy is found in the form of fatty acids and glucose.

NAD+ performs the task of getting these energy sources from the blood to the cells which require it. This results in high levels of mental and physical energy. NAD+ is responsible for performing very important biological processes which are related to aging.

These ones reverse the process of growing old by making body cells look and behave younger.

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The various activities performed by NAD+ to keep us young

One of the processes that NAD+ performs to make us look younger is to activate Sirtuin Genes in the body. It also enhances the growth of mitochondria and boosts their efficiency. This increases the mental and physical energy of body cells. Also, NAD+ increases metabolism as well as cognitive health.

This actually reverses the effect of advancing age on the brain. To make the body younger, NAD+ increases the sensitivity to insulin. This results in healthier levels of sugar in the blood. Last but not least, NAD+ repairs DNA. By performing all these tasks, NAD+ ensures that the body remains young.

Unfortunately, advancing age reduces the amount of this amazing chemical in the body. This brings about old age. By replacing NAD+ in the body through supplementation, you can replenish its levels and experience youth again, no matter how many years you have walked upon the earth.

Apart from taking supplements, there are some natural sources of this chemical. Here they are.

Dairy milk

Cow milk is a great source of Nicotinamide Riboside (NR). This is the precursor of NAD+. Thus, taking it gives you a good dose of some age-defying goodness.

According to a study performed by the University of Iowa, there is 3.9 μmol of NAD+ per liter of cow's milk.

By taking cow's milk every day, you can boost the levels of this chemical compound in your body and get younger day by day.


Known for its strong aroma and soft white meat, fish is consumed all over the world. Some varieties of fish have pretty high amounts of NAD+ in them. Examples of these are tuna, sardines and salmon. According to a nutritional study, tuna contains 20.5mg (milligrams) of NAD+ while salmon contains 10.1mg per cup of the chemical compound.

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Beer is one of the most popular beverages in the world. Many people take it to celebrate or simply to relax after a long day at work. Studies have found that this beverage contains yeast. Hence, it is a source of NAD+. As such, responsible drinking can grant you the benefit of youth over time.

The Crimini Mushroom

Mushrooms are a popular type of food among various societies around the globe. They are cooked into a stew or made into a soup. They are some of the foods which contain NAD+. In every cup of Crimini Mushroom, you can get 3.3mg of NAD+.


This well-known bird has some of the tastiest meat available today. You can get it grilled, roasted or stewed. Chicken meat is a good source of NAD+. It contains 9.1mg (milligrams) of this chemical compound. Therefore, never pass up a chance to eat some chicken. You can get younger with every tasty bite.


This is one of the most essential components in making bread and cakes. Yeast makes the dough rise. Interestingly, it contains Nicotinamide Riboside (NR). This is the precursor to NAD+. Hence, consuming pastries which have some yeast in it can contribute to growing younger. As a matter of fact, yeast actually contains more NAD+ per part than milk.

Green vegetables

Green vegetables are well known to contain all sorts of good nutrients. Now, they have been proven to contain the youth promoting NAD+ chemical compound. Peas and asparagus are some of the vegetables which have some amount of this chemical. They contain 3.2mg and 2mg of NAD+ per cup respectively.

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The Important Take Away

Modern research and technology have completed the quest of Juan Ponce de Leon. We have found the fountain of youth.

Instead of some remote island, it is everywhere around us in the food that we eat and the beverages we drink. A variety of edibles have been indicated above.

They all contain the youth restoring chemical known as NAD+. Including them in your diet is one of the best health decisions you can make today.