There was something of a blizzard of publicity materials today for work on calorie restriction mimetics and a mechanism of action by which they improve endurance in old mice, acting to increase the generation of capillaries in muscle tissue via stress response systems related to sirtuins and NAD+. Given the present commercial efforts relating to supplements that enhance NAD+ levels, and given that the people involved are the same as those who popularized sirtuin research and development some years ago, we're probably in for at least a few years of hype related to these compounds and research into NAD+ in general.
It is worth remembering that nothing other than scientific knowledge emerged from all of the excitement surrounding sirtuins - well, that, and some people became wealthier by selling a company to GSK, but that research was later written off as not being a viable path to therapies. I'm not yet convinced that any excitement is justified in the present case either: ways to enhance NAD+ look little better than the past decade of ways to adjust sirtuin levels, and neither captures the full effect of calorie restriction. Marginal adjustments to the trajectory of aging are worth having when they are free, but as a major focus of aging research and development, I think this a poor investment. There are other roads to intervention in the aging process, such as SENS, that have a far better expectation value when it comes to the size of future benefits to human health and longevity. If we're going to put billions in funding and scores of scientists to work for decades, why not on the path that leads to comprehensive rejuvenation, rather than the path that leads to only modest effects on aging?
Anyway, that said, at the level of mechanisms and biochemistry this research is most interesting. It should adjust some of the present thinking regarding the relative contributions of various mechanisms to sarcopenia, for example, a condition with many possible causes. Loss of blood supply to muscles is on that list, and it is worth noting that other possible detrimental effects of a loss of capillaries with aging have also been investigated by researchers in recent years. Since calorie restriction is known to slow the progression of sarcopenia, that might increase the expectation for capillary loss to be significant in a variety of tissues - and thus worthy of a greater focus and further investigation. What are the underlying causes, however? This doesn't just randomly happen. Which of the known root causes of aging underlie this loss? It is far from clear as to why exactly this happens, unfortunately, but given greater interest in the topic, answers will arrive in time.
Some of the research here uses methionine restriction as a way to trigger many of the same stress response mechanisms as calorie restriction. While the two approaches don't produce exactly the same outcome in rodents, they clearly work through overlapping mechanisms. It is thought that much of the calorie restriction response is controlled through methionine sensing rather than mechanisms relating to the many other constituents of diet. It is, however, a very complex phenomenon, in which near everything in metabolism changes. That makes it a challenge to reverse engineer exactly what is taking place under the hood, and why progress towards effective calorie restriction mimetic therapies has been so slow and expensive. It is less an exercise of discovery and more an exercise of mapping large areas of cellular biochemistry so that discovery can take place at all.
"The benefits of methionine restriction in rodents are fascinating because they resemble those of calorie restriction, but without enforced restriction of food intake." Previous work has shown that a methionine-restricted diet increases production of the gas, hydrogen sulfide, made in our cells where it functions in myriad beneficial ways. One of these is to promote the growth of new blood vessels from endothelial cells - a process known as angiogenesis. So the researchers decided to test whether there was a direct connection between a methionine-restricted diet and angiogenesis.
They fed mice a synthetic diet containing limited methionine and lacking the only other sulfur-containing amino acid, cysteine. These two amino acids are found in high amounts in protein-rich foods. After two months, the diet-restricted mice had increased the number of small blood vessels, or capillaries, in skeletal muscles compared to mice fed a control diet. The authors identified a requirement for the amino acid-sensing kinase GCN2 and the transcription factor ATF4 in angiogenesis triggered by methionine restriction.
Researchers found that a decline in the blood flow to tissues and organs with age can be reversed by restoring molecules that improved exercise capacity and physical endurance in mice. The researchers found that the two molecules could replicate the benefits of exercise, a finding that could lead to better athletic performance, improved mobility in the elderly and the prevention of aging-associated diseases like cardiac arrest, stroke, liver failure, and dementia.
For the first time, the study showed that as levels of the metabolite NAD+ decline with age, the body's capacity to exercise decreases because of fewer blood vessels and reduced blood flow. By treating mice with the NAD+ booster NMN and increasing levels of hydrogen sulphide, physical endurance was extended in mice by over 60%. This was the case in both young and old mice. "With exercise, the effect is even more dramatic. We saw 32-month-old mice, roughly equivalent to a 90-year-old human - receiving the combination of molecules for four weeks ran, on average, twice as far as untreated mice. Mice treated only with NMN alone ran 1.6 times further than untreated mice." The scientists identified that this mechanism is due to a restoration of capillary formation in muscle by stimulating the activity of the protein SIRT1, a key regulator of blood vessel formation.
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 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. Researchers 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 has shown that NAD+, which also declines with age, boosts the activity of SIRT1.
Researchers decided to explore the role of sirtuins in endothelial cells, which line the inside of blood vessels. To do that, they deleted the gene for SIRT1, which encodes the major mammalian sirtuin, in endothelial cells of mice. They found that at 6 months of age, these mice had reduced capillary density and could run only half as far as normal 6-month-old mice.
The researchers then decided to see what would happen if they boosted sirtuin levels in normal mice as they aged. They treated the mice with a compound called NMN, which is a precursor to NAD, a coenzyme that activates SIRT1. NAD levels normally drop as animals age, which is believed to be caused by a combination of reduced NAD production and faster NAD degradation. After 18-month-old mice were treated with NMN for two months, their capillary density was restored to levels typically seen in young mice, and they experienced a 56 to 80 percent improvement in endurance. Beneficial effects were also seen in mice up to 32 months of age (comparable to humans in their 80s).
The researchers also found that SIRT1 activity in endothelial cells is critical for the beneficial effects of exercise in young mice. In mice, exercise generally stimulates growth of new blood vessels and boosts muscle mass. However, when the researchers knocked out SIRT1 in endothelial cells of 10-month-old mice, then put them on a four-week treadmill running program, they found that the exercise did not produce the same gains seen in normal 10-month-old mice on the same training plan. If validated in humans, the findings would suggest that boosting sirtuin levels may help older people retain their muscle mass with exercise. Studies in humans have shown that age-related muscle loss can be partially staved off with exercise, especially weight training.