Methionine Restriction (and Calorie Restriction and Mimetics) Improve Endurance in Old Individuals by Boosting Capillary Formation

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.

Sulfur amino acid restriction diet triggers new blood vessel formation in mice

"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.

Discovery offers hope for improving physical performance as we age

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.

Treatment restores blood vessel growth, muscle vitality, boosts exercise endurance in aging animals

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.

Study suggests method for boosting growth of blood vessels and muscle

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.

Comments

It is quite amazing to me that even 10 years later people are still taking swipes at Sinclair & Co over the Sirtris deal. If GSK shows up at your doorstep with $720 M offering to pay a kings ransom for what is a pile of beans, what would you do? The fact that Sirtris didn't pan out, but the science has evolved quite spendidly, and yet people still whine about how someone got rich over it, is just downright pathetic. Pharmaceutical companies spend hundreds of millions of dollars in Alzheimer's research & development, but not through splashy acquisitions per se, and all that money still goes into various pockets of people and companies. And when those drugs don't work out, are you railing against the promotional scientists for their failed work?

Bottom line: Your first two paragraphs are a bunch of asinine "purist" drivel.

Posted by: Alan Donahue at March 22nd, 2018 7:05 PM

@Alan Donahue: If the same sequence of events had played out absent the relentless promotional exaggeration of potential outcomes, I'd have no complaints.

Posted by: Reason at March 22nd, 2018 7:34 PM

@Alan Donahue, I guess problem is not that Sinclair has sold uselles junk for $720 M 10 years ago. In fact in the fist time he really could not know what will or will not work. The problem is the following:

a) Sinclair publicly support rejuvenation biotechnology, SENS and life extention,
b) given his wealth he could alone finance all SENS programme, which costs no more than $500 M now, hovever, he doesn't,
c) now he does exactly the same with NMN what he did with the sirtuins 10 years ago, even though now we knows much more on biology and much more confident that any results will be marginal.

Conclusion: he either fool or cynic and liar. And he really do not look like a fool! ;-)

Posted by: Ariel at March 22nd, 2018 8:45 PM

@Reason Oh please. You act like you are completely unaware of what goes on Silicon Valley or other burgeoning industries, where the marketing hype can often exceed technical reality. It happens everywhere, all the time. When Larry Ellison sold Oracle 5.0 to dozens of clients, the software didn't even work.

@Ariel The idea that you think you know better about where Sinclair should spend his own personal wealth is astonishing and presumptuous. And Sinclair doesn't have $500 M, because there were many other owners of Sirtris. Maybe post your calendar for the next year online and your bank account balance. Then let everyone (crowd source) tell you how you can better spend your time and money.

I'm not saying Sinclair is the greatest thing to happen to longevity science. I just find it so pathetic that people are still taking shots at him 10 years later. Bad deals happen all the time, particularly in pharma. Promising drugs die in clinical development all the time. Pinning it on Sinclair and him 'getting rich' is so lame. These persistent false equivalences between the 'purity of SENS and Aubrey' and 'the evil scoundrels from Sirtris like David Sinclair' is just that. False.

Posted by: Alan Donahue at March 22nd, 2018 8:57 PM

I'm pretty sure that I heard David Sinclair say that he takes nicotinamide mononucleotide (NMN) himself. I am disappointed that it is not doing anything for his nasolabial folds.

Posted by: NY2La at March 22nd, 2018 10:43 PM

Older individuals? All studies mentioned there are animal studies.

Posted by: Dv at March 23rd, 2018 2:04 AM

Reason, please, don't write about pseudoantiaging (healthspan, cr, mtor, igf, nad). Write about reversive geroscience

Posted by: Qq at March 23rd, 2018 2:06 AM

@Dv: "Older individuals" is a bucket that includes "older animals."

Posted by: Reason at March 23rd, 2018 4:30 AM

Most of the discussion and quotes above relate to the decline of blood vessels with aging. A Finnish Study found that 3 SNP's of the IL-!0 gene is the early and main cause of atherosclerosis as we age. The reference is: Heiskanen, 2009, Atherosclerosis, Polymorphisms in the IL-10 promoter region and early markers of atherosclerosis. The 3 IL-10 SNP's implicated are rs1800896, rs1800871 and rs1800872, the G,C, and C alleles, respectively. I checked my own alleles and found I am homozygous for the good alleles for these SNP's, T, A, and T, respectively.

Posted by: Biotechy at March 23rd, 2018 5:53 AM

PS: Another problem discussed with aging in the above article and quotes is the general frailty that often develops in the elderly. There is a SNP (rs2811712) of the CDKN2B gene that is associated with physical impairment in the elderly, which I refer to as the frailty SNP if you have the A allele, which I have. About 88% of Caucasians are homozygous for this frailty allele. A 2012 Chinese Han study found that this SNP allele is associated with cerebral small blood vessel disease. Probably this SNP allele of the CDKN2B gene results in more senescent endothelial cells that give rise to the frailty conditions in the elderly.

Posted by: Biotechy at March 23rd, 2018 6:25 AM

To Biotechy
Have you considered to measure bone density and do a once year bisphosphonate treatment? I believe a lot of frailty cases could be attributed to this issue.
As an additional benefit bisphosphonate treatment shown to decrease DNA damage and decrease an all-cause mortality level by a decade or so. Some folks do this treatment midlife even without density issues, seeking for this benefits.

Posted by: Andey at March 23rd, 2018 8:59 AM

The blizzard of publicity materials is no coincidence. Looks like we have entered the next phase of building the longevity industry.

Whew.

The biggest barrier we have to acceptance and funding is putting a crack in the wall that its even POSSIBLE to affect aging. Since we could talk and write, there have been nothing but stories of the inevitability of aging and its horrific effects. Nobody has survived being alive. Our entire society, its infrastructure, its institutions, everything about us has been about the life cycle out of its inescapable conclusion.

People won't believe its possible. We're going to have to drill it into their skulls. Its a herculean effort to change something as the defining, fundamental core of our identity. We as a species have always met our end. If it wasn't an infectious disease or unfortunate mishap, age would come to claim us later on. This nihilistic outlook isn't going to go away easily.

THAT BEING SAID...

David's prior work, intentional or not only adds to the mental pile of inevitability we have to overcome. It didn't help our cause. Now does that mean that his work is suspect or worthless? Not at all. David has all his work peer reviewed. That's the gold standard. Just because he swung and missed last time does not mean he's not going to knock one out of the park. He's one of the good guys.

I have no doubt of his motivation. David doesn't want to die. He's a damn good geneticist. He WANTS his stuff to work not only for him, but for everyone. This stuff CAN benefit. Hear me out.

NAD+ will not be the rejuvenation we want, but its VERY close to commercialization. Lets say between 2-4 years out. And lets say that it DOES work as advertised. Increased health span, increased energy, puts a dent in sarcopenia, etc etc etc. We have now something to point at that PROVES we have a crack in the wall of aging.

That certainly can't hurt.

Certainly putting these scientists to work on damage repair, regeneration and stem cell tech would be a better use. But our efforts to jump that hurdle mentally is moving really slowly, and getting funding is like pulling teeth because nobody thinks its possible.

Same goes for metformin, or GDF11.

So here we are. Stuck in the slow lane, waiting for someone to clear the blockage up ahead.

I look at it from a different point of view. Its a roulette game. Each of these therapies has a chance of coming up with a win. Right now there is no winning move. All roads lead to the grave. The mental block of our entire species existence is in the way. Putting all our money on one square is a bad idea. If we get a win, its only going to spark others greed and desire to live. They will be willing to put their money on the table and take a spin. The credibility of people like Aubrey, Jim and others will jump... and it will jump HIGH.

People just don't believe its even possible.

Give a spark of hope in a VERY dark world right now and people will flock to it.

One win. All we need is one. The game changes overnight.

Trust in greed.

Posted by: Mark Borbely at March 23rd, 2018 11:07 AM

@Mark Borbely, there is plenty of evidence not only theoretical but also practical that SENS will work! They have proved WILT to work, hovewer, stopped the research because of lacks of funds. While Big Pharma invests billions in various CR supplements or not working small molecules. https://www.quora.com/Whats-been-the-progress-if-any-on-the-WILT-Whole-body-interdiction-of-the-lengthening-of-telomeres-strategy

We live in a broken world where failing sirtuins research with no evidence was sold for $720 M while Oisin -- the most innovative company in senescent cell clearance whose approach was also proved to work and can be expanded to cancer and immunotherapy -- struggles to rise a few tens of millions. What else evidence people need?

Posted by: Ariel at March 23rd, 2018 9:09 PM

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