NMN Staves Off Blood Vessel Cell Aging and Supports Cardiovascular Health In Mice, Study Shows

Our cells and organs are quite chatty, as they talk to each other by sending messages to keep one another informed of their health and ability to replicate (or the lack thereof, which is called senescence). One means of communication between cells and organs is through extracellular vesicles — secreted vehicles carrying molecular payloads. But this messaging does more than just inform cells of one another’s state; it can influence the state of the receiving cell. For example, as we age and cells become senescent, they send signals to neighboring cells that induce their senescence, starting a cascade of cellular arrest throughout the body that is associated with aging and age-related disease.

Now, new research shows that blocking extracellular vesicles carrying signals of senescence between blood vessels helps mitigate processes underlying aging and the development of age-related cardiovascular diseases (e.g., heart failure, atherosclerotic disorder, and hypertension [high blood pressure]).

Published in the journal Signal Transduction and Targeted Therapy, this work points to the importance of maintaining proper levels of nicotinamide adenine dinucleotide (NAD+) — a molecule involved in innumerable processes in all cells — to stave off the senescence of blood vessel cells, which the authors show can be modulated with supplementation of the NAD+ precursor, nicotinamide mononucleotide (NMN). “Our results provide strong evidence that … [NAD+] supplementation may serve as potential therapeutic strategies for age-related diseases,” concluded Gan and colleagues. 

Blood vessel “age” underlies cardiovascular health

Keeping blood vessels healthy as we age is important since many chronic conditions and age-related diseases have their root in the deterioration of the vascular system. With aging, cardiovascular diseases like high blood pressure, heart failure, and strokes become more common. Scientists think that increases in old or “senescent” cells that line our blood vessels may be at the root of this aging and disease development. These old cells become less functional, or defective, and will eventually die off. As more and more cells become senescent, the tissues and organs that they make up become compromised and less youthful. This is a major step in how many different health conditions develop.

Researchers are focused on finding ways to prevent this kind of aging, starting at the cellular level. Taking a closer look at the cells from the vascular system has allowed researchers to understand how issues at the cellular level may lead to the development of chronic diseases that affect the whole body. For example, one recent study showed that the accumulation of old, senescent cells in the lining of blood vessels can lead to hard-to-treat high blood pressure (1).  Understanding how these age-related changes work has allowed researchers to develop strategies that keep cells young and healthy.

NAD+, the molecule at the heart of aging

One important anti-aging strategy consists of maintaining adequate levels of NAD+ at the cellular level, as NAD+ is an important cofactor for metabolic processes and cell vitality (2). For this reason, researchers have explored different ways of preserving intracellular levels of NAD+ in old age. Essentially, NAD+ holds the key to keeping cells healthy and youthful.

Previous research shows how to reverse some of the age-related changes caused by reduced levels of NAD+ (3). One study examined the anti-aging effects of supplementing mice with the NAD+ precursor nicotinamide mononucleotide (NMN) (4). After just two weeks of supplementation, researchers were able to see more youthful characteristics in the aorta (the main blood vessel also present in humans) of the mice that were treated with NMN, compared to an untreated control group.

The Body’s Inter-Cell Postal Service

Cellular communications affect aging. Cells rely on neatly packaged protein messages for communication. These messages are packaged in bundles known as small extracellular vesicles (SEVs). Scientists believe that the proper functioning of this system affects the availability of NAD+ within cells. Defective messaging leads to cellular aging and the appearance of diseases.

Digging deeper into this messaging system has uncovered other ways that affect NAD+ within cells. The SEVs that carry messages also regulate the production of a protein known as CD38 that has a degrading effect on NAD+. These effects have been observed in various animals, and scientists believe that this protein is the main restrictive agent to the availability of NAD+ (5).

An NAD-consuming enzyme controls blood vessel cell age

A group of Chinese researchers recently published a study in the journal Signal Transduction and Targeted Therapy that focuses on the effects of CD38, an enzyme that consumes NAD+,  on cellular aging. This study provides some insight into how the CD38 protein may be important for limiting the effects of aging in blood vessels, but their results have implications for aging in all the cells of the body (6).

The researchers used an animal model to examine how controlling CD38 affects the lining of blood vessels in mice. Their first step was to induce high blood pressure with a chemical called angiotensin II — a naturally produced blood-constricting molecule — in mice to simulate the vascular aging seen in hypertension. After some time, senescent cells slowly replaced the young, healthy cells that normally line blood vessels.

Once these changes were established, they modulated NAD+ levels in several ways: with an inhibitor to CD38 and the NAD+ precursor NMN, which was administered orally. Both these treatments increased the availability of NAD+ and reversed some of the senescence-induced changes in the blood vessels. What’s more, Gan and colleagues found that both these NAD+ level modulating treatments reversed the chemically-induced high blood pressure.

These results provide a promising new strategy for keeping cells young. By limiting the amount of CD38, researchers were able to reduce the amount of old, senescent cells in the mice’s blood vessels. The study also found that this approach had the added benefit of activating sirtuin proteins. These proteins preserve the health and proper function of the mitochondria, the “powerhouse” of the cell, from senescent damage associated with aging (7). These combined effects protected the blood vessels of mice from the study and prevented cells from becoming senescent.

Can NMN fight off blood vessel aging and cardiovascular disease?

This research shines the light on how maintaining NAD+ levels in cells with supplements like NMN can help fight off age-related diseases. By preventing cells from becoming senescent, keeping NAD+ levels from dropping with age might be the key to staying healthy in old age. However, whether NMN can help prevent the aging of our blood vessels and the development of cardiovascular disease in people remains to be seen, as there have yet to be clinical trials testing the efficacy of this NAD+ precursor on these conditions.

References:

1. Chi C, Li DJ, Jiang YJ, et al. Vascular smooth muscle cell senescence and age-related diseases: State of the art. Biochim Biophys Acta Mol Basis Dis. 2019;1865(7):1810-1821. doi:10.1016/j.bbadis.2018.08.015
2. 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.
3. 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
4. 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
5. Hogan KA, Chini CCS, Chini EN. The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases. Front Immunol. 2019;10:1187. Published 2019 May 31. doi:10.3389/fimmu.2019.01187
6. Gan L, Liu D, Liu J, et al. CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice. Signal Transduct Target Ther. 2021;6(1):223. Published 2021 Jun 11. doi:10.1038/s41392-021-00625-0
7. Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell. 2016;61(5):654-666. doi:10.1016/j.molcel.2016.01.028