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.

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.

As old as our blood vessels

Sinclair and team set out to unravel the mechanisms behind one of biology’s inevitabilities: aging.

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.

In a series of experiments, Sinclair and 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.

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.

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.

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.

Read Full Article/ published By Harvard Medical School/ MARCH 22, 2018

Coronavirus is the biggest public health and economic challenge of our time. The pandemic has been especially difficult for older people. People over 60 are at higher risk for infection, and once infected have substantially higher severity and lethality. When infected with COVID-19, people over 60 are more likely to have life-threatening diseases even if they are in good health. Although there are many treatments and vaccines currently in development to fight the virus, they are expected to be less effective in older people. This leaves 1 billion people over 60 in a vulnerable position especially if the virus returns. „Now is the time to develop innovative strategies for prevention and treatment of the virus in older people“, said Dr. Alex Zhavoronkov.

Dr. Zhavoronkov is chief scientist of the Biogerontology Research Foundation, the UK’s leading non-profit focused on Longevity and ageing research. The Foundation has supported multiple initiatives relating to advancing Healthy Longevity. The Foundation was also actively involved in the successful initiative to add a new extension code for “ageing-related diseases” accepted in 2018 by the World Health Organization during the last revisions of its International Classification of Diseases framework.

Dr. Zhavoronkov suggests calling COVID-19 and other infections that are more harmful to the elderly gerolavic infections. Gerolavic comes from the Greek words geros (old man) and epilavís (harmful). He proposes a strategy for repurposing known geroprotectors such as rapamycin, nicotinamide riboside, nicotinamide mononucleotide, metformin, and other drugs with a known safety profile for prevention of SARS-CoV-2 infection. He has analyzed the prior clinical studies of everolimus (RAD001) in healthy elderly people, and previous evidence showing paradoxical immunopotentiation effects of rapamycin and proposed additional clinical trials for these molecules in the healthy elderly population. Zhavoronkov also proposes the use of inexpensive and minimally-invasive deep aging clocks to track the efficacy of these preventative geroprotective interventions and to stratify the patients by predicted severity of COVID-19.

While vaccination reduces infection rates, and therapeutic interventions reduce the severity and lethality of infections, these interventions have limitations in the elderly population.

COVID-19 infection rates in China

Dr. Zhavoronkov is pursuing several strategies for drug discovery and repurposing using the latest advances in AI integrated into their battle-tested discovery platform. He hopes that this research will yield insights that will help with COVID-19 and also help prevent age-associated diseases. Furthermore, he believes that keeping older people healthy will re-ignite the economy and could potentially lead to unprecedented economic growth.

Previously, Dr. Zhavoronkov proposed that increases in productive longevity will substantially boost economic growth in developed countries. Testing low-dose rapamycin individually or in combination with metformin, and NAD+ boosters such as nicotinamide riboside (NR), or nicotinamide mononucleotide (NMN) may help protect the elderly from gerolavic infection today and may also enhance economic recovery when the global pandemic is over. Now is the time to develop innovative strategies for prevention and treatment of COVID-19 in older people.

Read Full Article/ published By Forbes/ MARCH 31, 2020

Mice are by no means men — but the results of a new mouse study are still encouraging for man’s search for longer life.

In a study published in the journal Cell, researchers report that they found a molecule that essentially reactivates faltering blood flow in aging mice. Compromised blood flow is a major component of aging, since it deprives tissues and organs, including the brain, of the essential nutrients and oxygen they need to function.

“Loss of blood flow seems to be one of the early things that leads to diseases of aging,” says David Sinclair, the study’s senior author and co-director of the Paul F. Glenn center for the biology of aging at Harvard Medical School. “As organs like the brain and muscles lose their [blood] perfusion, they no longer function effectively.”

In the study, Sinclair and his colleagues found a way to restore that blood flow in aging mice. They provided elderly mice with a molecule called nicotinamide mononucleotide (NMN), which is then made into another compound that promotes the formation of tiny blood vessels in cells that line the muscle, as well as other organs. The mice given NMN increased their treadmill run time by 60% compared to animals that didn’t get the molecule, and they doubled their exercise endurance — to levels that matched or even exceeded that of younger mice.

What NMN does, Sinclair says, is provide the same benefits in improving blood flow that exercise does by promoting a family of molecules called sirtuins. “Here we have the potential of having a pill give the benefits of basically running for 10 miles a day without having to do that,” he says. That can be especially important for older people who are physically unable to exercise as much as they should. “It’s not just about trying to replace exercise when you are middle-aged, but giving you the benefits of exercise when you are too old to be able to do it.”

Sinclair anticipates that improved blood flow could be important in helping not just aging tissues and organs, but speeding healing of wounds, particularly for people with diabetes who often lose fingers and toes as their circulation falters.

There is also the possibility that the finding could be used not just to improve circulation in older people or those with blood flow problems, but to enhance blood flow for elite athletes. Improving the pumping of blood to muscles could give athletes an advantage in being able to train longer and outperform their rivals.

In a small early trial at Brigham and Women’s Hospital, Sinclair is already testing how the molecule works in people. Although it is currently available to purchase as a supplement, he wants to scientifically test NMN’s effect on aging. Previous so-called “anti-aging” compounds have not proved as effective in people as they have in animals.

But Sinclair is confident enough in its benefits for aging that he is taking NMN himself. So far, it appears to be relatively safe and does not lead to out-of-control growth of blood vessels that other agents have, but further studies are necessary to confirm its safety and efficacy. Sinclair plans to test NMN’s effects first in otherwise healthy elderly people, to see if it causes the same improvements in blood flow that he and his colleagues saw in animals.

Article published By TIME Magazine/ MARCH 22, 2018