NMN Rejuvenates Blood Vessels By Boosting NAD+ Availability

We know that the age-related impairment of angiogenesis — the generation of new blood vessels — in the brain likely has a critical role in the development of vascular cognitive impairment and decline in the elderly. We also know that levels of the vital molecule nicotinamide adenine dinucleotide (NAD+) decline with age in tissues and cells all over the body, including the brain’s blood vessels. So, it’s been an open question as to whether administering precursors that elevate NAD+ levels can exert potent anti-aging vascular effects, improving cerebral blood supply and circulation.

A group of researchers from the University of Oklahoma took a look at how treatment with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, impacts age-related impairment of blood vessel development processes. They found that NMN treatment in isolated brain blood vessels significantly improved blood vessel generation-related processes. “We recommend that pro-angiogenic effects of NAD+ boosters should be considered in both preclinical and clinical studies,” concluded Kiss and colleagues in their article.

What’s at the Root of Vascular Aging?

Maintaining a healthy cardiovascular system is important for longevity because diseases that affect this system are a significant cause of disease and mortality in older age (1-3). Several conditions that occur as we age — such as stiffening of arteries, inflammation, and oxidative stress — are associated with cardiovascular disease. Deterioration of blood vessels not only increases the risk of heart attacks and strokes but also plays a role in age-related cognitive decline.

To design prevention strategies that can preserve cardiovascular health, researchers are working to understand how our cardiovascular system ages. Developments in our understanding of epigenetics — heritable changes in gene activity that do not involve changes to the underlying DNA sequence — show that certain conditions in cells influence the way genes get activated, which in turn may affect longevity (4). Recent studies show that cellular dysfunction leads to the development of age-related changes in the vasculature that can be traced to changes in gene activation.

One important target of epigenetic research is a family of genes called microRNAs, or miRNAs. These are naturally occurring genetic fragments that repress the activation of certain genes. MiRNAs regulate important functions in the endothelium — cells forming the inner lining of blood vessels. Endothelial function is dependent on miRNA-controlled gene activation. These small genetic bundles play an important role in regulating the endothelial cells of blood vessels, which are critical to preserving homeostasis, or balance, in the circulatory system.

Recent studies show that miRNAs have an impact on vascular health and lifespan regulation (5,6). More importantly, disruptions to the proper functioning of miRNAs have been shown to affect observable signs of aging (7). Other studies show that defective miRNA function promotes the development of atherosclerotic disease through inflammation and plaque formation and destabilization in blood vessels (8, 9). These changes may lead to complications like blood clots, strokes, and myocardial infarctions (heart attacks).

Some experimental procedures that have focused on cellular metabolism have shown that it is possible to reverse aging-induced alterations in vascular miRNA. For these reasons, researchers hypothesize that preserving cellular function may prevent the miRNA dysfunction that leads to premature aging.

Nicotinamide Mononucleotide (NMN) May Have an Effect on Epigenetic Processes

Recent studies show that vascular aging is linked to NAD+ depletion, an important cofactor for metabolic processes and cell vitality (10, 11). That’s why researchers have been exploring different ways to preserve NAD+ levels in old age. One strategy that has produced successful results in animal models is the restoration of cellular NAD+ by supplementation with the NAD+ precursor NMN (12). This strategy has previously shown some potent anti-aging effects, such as reversal of age-related vascular damage, improving cellular metabolism, and reducing oxidative stress.

In light of these findings, a group of researchers from the University of Oklahoma, have recently published a paper in the journal GeroScience examining the effects of age-related NAD+ depletion on vascular miRNA activation. These researchers previously studied the use of NMN supplementation and its role in preserving cellular NAD+ availability. In a previous study using this approach, they were able to reverse some of the age-related changes to blood vessels (13). For this study, Kiss and colleagues used an animal model to study the effects of NMN supplementation on miRNA activation in blood vessels.

The research team found that after two weeks of NMN supplementation, they could see significant results. What they saw was that the activation of miRNA in young mice and NMN treated mice was similar, in stark contrast to the results seen in the untreated aged mice. More significantly, miRNA activation was restored to youthful levels in the aortas of NMN-treated aged mice. These results add to evidence that shows that NAD+ depletion has an important role in age-related dysregulation of vascular miRNA activation and that treatment with NMN has measurable anti-aging effects.

Boosting NAD+ Availability with NMN Rejuvenates Cells

Cellular changes related to NAD+ availability that occur as part of the natural aging process affect miRNA activation. Consequently, the decline in miRNA activation affects epigenetic pathways that regulate inflammatory processes and cellular mechanisms that can impair the structural and functional integrity of blood vessels. In addition to the observed epigenetic rejuvenation, NMN supplementation confers anti-atherogenic effects. These findings can help researchers further understand vascular alterations present in humans that increase the risk for cardiovascular and cerebrovascular diseases.

It’s clear that NMN acts as an NAD+ booster at the cellular level, but researchers do not have a clear understanding of exactly how these effects lead to changes in miRNA activation. One proposal is that these effects are achieved by reducing levels of oxidative stress, a known result of NMN supplementation. Understanding the biological pathways that lead to these anti-aging effects produced by the miRNA gene activation is key to the development of new pharmacological strategies for the prevention and treatment of cardiovascular diseases. 

References:

1. Abdellatif M, Sedej S, Carmona-Gutierrez D, Madeo F, Kroemer G. Autophagy in Cardiovascular Aging. Circ Res. 2018;123(7):803-824. doi:10.1161/CIRCRESAHA.118.312208
2. Alfaras I, Di Germanio C, Bernier M, et al. Pharmacological Strategies to Retard Cardiovascular Aging. Circ Res. 2016;118(10):1626-1642. doi:10.1161/CIRCRESAHA.116.307475
3. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A. Mechanisms of Vascular Aging. Circ Res. 2018;123(7):849-867. doi:10.1161/CIRCRESAHA.118.311378
4. Ibáñez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M. Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell. 2006;5(3):235-246. doi:10.1111/j.1474-9726.2006.00210.x
5. Ito T, Yagi S, Yamakuchi M. MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun. 2010;398(4):735-740. doi:10.1016/j.bbrc.2010.07.012
6. Boehm M, Slack F. A developmental timing microRNA and its target regulate life span in C. elegans. Science. 2005;310(5756):1954-1957. doi:10.1126/science.1115596
7. Badi I, Mancinelli L, Polizzotto A, et al. miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase). Arterioscler Thromb Vasc Biol. 2018;38(9):2079-2090. doi:10.1161/ATVBAHA.118.311298
8. Lu Y, Thavarajah T, Gu W, Cai J, Xu Q. Impact of miRNA in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2018;38(9):e159-e170. doi:10.1161/ATVBAHA.118.310227
9. Zhang F, Zhang R, Zhang X, et al. Comprehensive analysis of circRNA expression pattern and circRNA-miRNA-mRNA network in the pathogenesis of atherosclerosis in rabbits. Aging (Albany NY). 2018;10(9):2266-2283. doi:10.18632/aging.101541
10.   Tarantini S, Valcarcel-Ares MN, Toth P, et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019;24:101192.
11.   Kiss T, Balasubramanian P, Valcarcel-Ares MN, et al. Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment. Geroscience. 2019;41(5):619-630. doi:10.1007/s11357-019-00074-2
12.   Yoshino J, Baur JA, Imai SI. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018;27(3):513-528. doi:10.1016/j.cmet.2017.11.002
13.   Kiss T, Balasubramanian P, Valcarcel-Ares MN, et al. Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment. Geroscience. 2019;41(5):619-630. doi:10.1007/s11357-019-00074-2