The pressing need to develop treatments for heart diseases, also termed cardiovascular diseases, comes from the aging global population. Cardiovascular diseases constitute the leading cause of mortality in developed countries. Advancing age is the primary risk factor for cardiovascular disease, and the number of older adults will likely at least double by 2050.

Scientists from the University of Colorado published a study in Aging Cell demonstrating nicotinamide mononucleotide (NMN) reverses vascular dysfunction in mice. Vascular dysfunction entails blood vessel stiffening, which occurs with age as collagen, a protein which provides structural integrity of tissues, builds up. The reduced level of elastin, a protein conferring tissue elasticity, in the blood vessels as we grow old also results in the stiffening of blood vessels that often leads to cardiovascular diseases. Finding a therapeutic agent, such as NMN, with potential to reverse vascular dysfunction could help reduce the risk of cardiovascular diseases.

NMN boosts levels of nicotinamide adenine dinucleotide (NAD+) in cells. NAD+ levels decrease with age, which scientists have associated with the onset of multiple age-related diseases such as cardiovascular disease. Past studies showed that boosting NAD+ levels in aged animals could activate a protein called SIRT1 to improve metabolic and stress responses. 

SIRT1 is a member of the sirtuins family of proteins that plays a pivotal role in maintaining metabolic health and chromosome integrity. The protein depends upon the bioavailability of NAD+ to function. SIRT1 is an essential protein for overall cellular health, and lower levels of NAD+ available in cells can reduce the ability of SIRT1 to perform these functions. The team of researchers wanted to find out if boosting NAD+ levels with NMN increases SIRT1 activity in the aorta, a large vessel in the heart, and if it could reverse vascular dysfunction in older mice.

Older mice given small amounts of NMN in their drinking water throughout the day had normalized stiffness of the aorta, a blood vessel of the heart muscle, which indicated improved heart health. Following NMN treatment, older mice showed reduced collagen and increased elastin levels not significantly different than those in young mice. These results indicate improved elasticity of the aorta and normalized aortic stiffness.

(de Picciotto et al., 2016 | Aging Cell) NMN reduces collagen in the aorta in older mice and increases elastin. The graph on the left shows significantly higher levels of collagen in older mice, which NMN lowers and reverses. The graph on the right shows significantly lower levels of elastin in older mice, which NMN administration raises and reverses.

NMN supplementation activated SIRT1 in the arteries as well. SIRT1 levels in the artery were ~50% lower in older animals. NMN raised levels and activity of the SIRT1 protein in older animals. SIRT1 removes molecular tags, acetyl groups, from specific proteins. Following NMN treatment, the team of researchers measured reductions in these molecular tags on the specific proteins. In other words, they found less acetylation or molecular tags on these proteins.

(de Picciotto et al., 2016 | Aging Cell) NMN supplementation increases SIRT1 expression. The far left bar shows SIRT1 expression for young mice, the middle left bar for old mice, the middle right bar for young mice given NMN, and the far right bar showing SIRT1 expression for old mice given NMN.

“Overall, our findings provide the first evidence supporting the promising translational potential of NMN supplementation for the treatment of arterial aging,” stated the scientists in their study.

The researchers say that the mechanism with which NMN supplementation can ameliorate vascular dysfunction might come from the activation of SIRT1 through NAD+. NMN administration increases NAD+ bioavailability in aging animals, and since SIRT1 depends on NAD+ to function, improving NAD+ levels with NMN supplements could improve SIRT1 function.