NMN Goes With the Flow to Restore Blood Circulation and Reverse Vascular Muscle Aging in Older Mice

With age, our vascular systems — the network of vessels that circulate blood throughout the body — decline in function, leading to poor blood flow. This impaired blood flow can then increase the risk of cardiovascular issues, neurovascular disorders, and muscle-related conditions, including age-related loss of muscle mass. Losing muscle mass and strength causes a significant decline in quality of life in older adults and an increased risk of falls, fractures, and mortality.

While some people think that becoming increasingly frail is an inevitable part of aging that can’t be prevented or reversed, many researchers may disagree. In a 2018 study published in Cell and authored by Das and colleagues, this Australian- and Boston-based group aimed to uncover which biological mechanisms become dysfunctional with age and cause the decline in muscle mass, strength, and endurance that is characteristic of most older adults. As previous research has found that older adults with higher frailty scores have a two-fold increased risk of death, uncovering how to stop this muscle deterioration may bring a significant boost to longevity.

In this study, researchers tested the effects of the compound nicotinamide mononucleotide (NMN), a precursor to the vital coenzyme nicotinamide adenine dinucleotide (NAD+). Although NAD+ is essential for healthy cellular functioning, its levels typically decline with age and lead to tissue and organ dysfunction and many chronic diseases. So, this team supplemented older mice with NMN to determine if increasing NAD+ levels would have any effect on the vascular function, blood flow, and exercise capacity that typically diminish with age — and, it did.

How vascular aging ages us

Within our vascular system, a single layer of cells called the endothelium lines the inside of our arteries, veins, and capillaries — the smallest and most abundant blood vessels we have, responsible for exchanging oxygen and nutrients between the blood and tissue. As our vascular system deteriorates with age, so does the quantity and quality of these endothelial cells. Also known as the Vascular Theory of Aging, many researchers now speculate that this physiological decline in vascular health is a leading cause of aging and age-related diseases, as organs and tissues are dependent on the proper functionality of their capillary networks. 

One of the tissues in the body that is highly affected by vascular aging is skeletal muscle. With age, our muscles’ endothelial cells have reduced neovascularization — the formation of new blood vessels — along with increased blood vessel loss and apoptosis, or programmed cell death. These age-related changes cause the sarcopenic loss of muscle mass, strength, and endurance in older adults that leads to frailty and premature mortality.

It’s known that exercise promotes neovascularization and delays vascular aging in young- and middle-aged adults, but we don’t know yet why older age causes the skeletal muscle to become desensitized to these effects of exercise. This led Das and colleagues to speculate that this vascular and muscular dysfunction involves declining levels of NAD+ and a protein called SIRT1 that is dependent on it to function  — as NAD+ levels decline with age, so does SIRT1 activity. In addition to supporting cellular metabolism and promoting longevity, SIRT1 activity is vital to the neovascularization process in young muscles. However, it’s unknown if the protein can also repair and remodel the vasculature of skeletal muscle in older animals. 

The decline and dysfunction of matured muscles

To answer these questions, the research team looked at whether low SIRT1 and NAD+ activity in skeletal muscle endothelial cells caused insufficient blood flow and endurance with age, and whether restoring these low levels could reverse the damage. First, as expected, they found that 20-month-old mice (approximately 60 in human years) had significantly lower quantity and quality of endothelial cells and capillaries in their skeletal muscle and reduced exercise endurance, compared to 6-month-old mice that represent 30-year-old humans. Additionally, the older mice had significantly lower NAD+ levels in their endothelial cells than the young mice.

Next, they deleted SIRT1 activity from some of the younger mice. Although they were young, without active SIRT1, these mice had much lower capillary density and quantity and only ran half as far and long as their SIRT1-active littermates. Essentially, deleting SIRT1 in the endothelium mimicked the vascular effects of aging. After increasing SIRT1 activity, middle-aged mice benefitted from the exercise-induced muscular neovascularization that younger groups experience. 

NMN teaches old mice new tricks

After uncovering the differences between young and old mice in terms of capillary health and exercise endurance, the next step was to see if replenishing NAD+ levels — and subsequently boosting SIRT1 activity — could reverse these age-related vascular changes. In this experiment, aging mice received supplemental NMN in their drinking water for two months. At 400 milligrams of NMN per kilogram of body weight per day, this dosage roughly translates to 2,600 mg of NMN in an average-sized American of 176 pounds. After NMN treatment, these mice had their capillary quantity and density restored to that of the young mice, and their endurance capacity boosted by up to 80%. They also tested whether or not SIRT1 was vital to this reversal — and it was, as mice without SIRT1 did not experience the same capillary-improving results.

Lastly, another compound called hydrogen sulfide was found to be beneficial to this vascular-reviving process. Although primarily a signaling molecule (and the compound that causes the offensive rotten egg smell), hydrogen sulfide also regulates many cellular processes and plays a role in preventing chronic diseases. As hydrogen sulfide shares many commonalities with NAD+, like protecting cells from inflammatory oxidative stress and increasing SIRT1 activity, Das and colleagues wondered if supplementing with this compound could amplify the effects of NMN on the endothelial cells. 

In aged mice (mid-80s in human years), the cumulative effects of supplementing both NMN and a form of hydrogen sulfide (NaHS) were indeed enhanced. The combination package markedly increased capillary density and reduced endothelial cell apoptosis by 31%, compared to 25% when supplemented with NMN alone. Exercise endurance was also augmented by the duo — while the NMN-treated mice had improved running times and distances by 1.6-fold, the NMN-NaHS combination mice doubled their endurance.

Mitigating muscle loss, one endothelial cell at a time

As even mice who were well into their 80s (in human years, at least) saw significant reversals of the typical age-related decline in muscle and vascular health, these results could have wide-reaching effects for older adults who are at increased likelihood of frailty and its subsequent elevated risk of mortality. In reference to NMN, the authors summarize, “As far as we are aware, this is the first time a small molecule has induced neovascularization at an advanced age.”

Although we don’t know if these results will translate to humans, it’s highly possible that NMN and hydrogen sulfide may be effective for not only promoting new capillary growth but also for treating age-related diseases that occur from reduced blood flow and impaired vascular function. Additionally, other organs that require healthy blood flow but decline in function with age, like the brain, heart, liver, and bones, may benefit from similar NAD+-boosting treatments. But for now, we’ll just have to go with the flow until more research is completed. 

References:

Das A, Huang GX, Bonkowski MS, et al. Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging [published correction appears in Cell. 2019 Feb 7;176(4):944-945]. Cell. 2018;173(1):74-89.e20. doi:10.1016/j.cell.2018.02.008

Hao Q, Zhou L, Dong B, Yang M, Dong B, Weil Y. The role of frailty in predicting mortality and readmission in older adults in acute care wards: a prospective study. Sci Rep. 2019;9(1):1207. Published 2019 Feb 4. doi:10.1038/s41598-018-38072-7