The Cost of Conflict


Time’s toll reversed by bolstering blood vessels

As we age, our tiniest blood vessels wither and die, depriving muscles of oxygen and allowing wastes to build up and affect muscle health. Scientists have long wondered whether reversing the aging of blood vessels could help us maintain our youthful vigor. In work by researchers in the Department of Genetics at HMS, the answer appears to be yes, at least in mice. The achievement, the research team said, paves the way to identifying related therapies for humans.

The study focused on endothelial cells, which line blood vessels and are essential for the health and growth of blood vessels that supply oxygen-rich and nutrient-loaded blood to tissues. As endothelial cells age, blood vessels atrophy, new blood vessels fail to form, blood flow to muscles lessens and muscles weaken. Although this weakening process can be slowed with regular exercise, over time, the effects of such beneficial efforts become less effective.

In a series of experiments, the scientists found that reduced blood flow develops as endothelial cells start to lose a critical protein known as sirtuin1, or SIRT1. They also found that SIRT1 loss is precipitated by the loss of NAD+, a key regulator of protein interactions and DNA repair. Previous studies have shown that SIRT1 delays aging and extends life in yeast and mice and that NAD+, which also declines with age, boosts the activity of SIRT1.

The experiments showed that in young mouse muscle, SIRT1 signaling is activated and generates the tiny new blood vessels that supply oxygen and nutrients to tissues. As NAD+/SIRT1 activity decreases over time, however, so does blood flow, leaving muscle tissue nutrient deprived and oxygen starved.

The study also showed that SIRT1 may be the molecule that relays growth-factor signaling from muscles to blood vessels, a signaling chain that induces blood vessel formation. It further showed that endothelial cells lacking SIRT1 fail to recognize signals from growth factors released by exercised muscles, explaining why age-related loss of SIRT1 leads to muscle atrophy and blood vessel death.

To test whether boosting SIRT1 levels would affect these declines, the scientists used NMN, a NAD+ precursor known to play a role in repairing cellular DNA and maintaining cell vitality. When NMN was given over two months to a group of 20-month-old mice, an age equivalent to about 70 years in humans, NMN restored the number and density of blood capillaries to that seen in younger mice. Blood flow to the muscles also increased and was significantly greater than blood supply to the muscles seen in same-age mice that didn’t receive NMN.

Das A, et al., Cell, March 2018