Longevity Articles

An NMN Receptor In the Brain Supports Healthy Skeletal Muscle Aging

An NMN Receptor In the Brain Supports Healthy Skeletal Muscle Aging

For NMN to exert its ability as a supplement to support healthy aging, there needs to be a way for the molecule to get into cells. There has been some evidence that there is a receptor called Slc12a8 that takes up NMN, notably in the intestine of mice.

New research shows that Slc12a8 also is found in the lateral hypothalamus (LH), where it regulates whole-body metabolism and skeletal muscle function.

The Importance of Supporting Healthy Muscle Aging

In rapidly aging societies, frailty, defined by the deterioration of physical and mental functions because of aging, is an urgent socio-economic problem. In particular, age-related muscle weakness with decreases in muscle weight and force can induce frailty. The development of interventions to support muscle health is critical for the extension of healthspan — the number of years lived in good health. At the heart of this problem is gaining a better understanding of how muscles age and cause frailty.

What Do We Know About NMN and Skeletal Muscle Aging?

Over the past several years, some studies have revealed that progressive, systemic decreases in nicotinamide adenine dinucleotide (NAD+) levels and the resultant dysfunctions of NAD+-consuming enzymes can drive aging. Supplementation of NAD+ intermediates, such as nicotinamide riboside or nicotinamide mononucleotide (NMN), has been extensively tested to boost NAD+ levels systemically. 

The effects of these NAD+ precursors to support healthy tissue aging have been demonstrated. NMN also works to enhance energy metabolism in mice, and it improves skeletal muscle insulin sensitivity and signaling in humans. However, knowledge of the precise mechanism for its action is still poor.

An NMN Receptor Regulates Healthy Skeletal Muscle Aging

An NMN Receptor Regulates Healthy Skeletal Muscle Aging

The present study, which was conducted by a team of Japanese researchers across several institutions, was originally initiated by our interesting finding that Slc12a8 is also found in a specific neuronal subpopulation in the LH. This finding led the researchers to suspect that Slc12a8 in the LH might be involved in the hypothalamus-skeletal muscle interaction and that dysfunction of this interaction could be involved in skeletal muscle aging and frailty.

To address this hypothesis, the researchers analyzed the functions of Slc12a8 in the LH and its effects on skeletal muscle functions. Specifically, they deleted Slc12a8 in the LH of young mice, which reduced activity-dependent energy expenditure and skeletal muscle functions, decreased skeletal muscle mass through impaired protein synthesis, and caused a decrease in glycolysis. Young mice lacking Slc12a8 aged faster, and older mice genetically altered to have more Slc12a8 in the LH displayed healthier aging and energy expenditure, and skeletal muscle functions. “Our present study … reveals the physiological relevance of the Slc12a8 NMN transporter in regulation of activity-dependent energy expenditure and skeletal muscle functions during the process of aging,” wrote the authors.

In trying to pin down how an NMN receptor in the brain translated to supporting healthy skeletal muscle aging, the researchers demonstrate that the connection between the LH and skeletal muscle is mediated by the sympathetic nerve-β2AR axis. The major role of sympathetic innervation in skeletal muscle has long been considered for vasoconstriction. Recently, direct innervation of sympathetic nerves to skeletal muscle neuromuscular junction (NMJs) — where nerves connect to muscle — has been reported. In the present study, the researchers showed that Slc12a8 deletion in the LH causes significant decreases in β2AR signaling at NMJs and induces poor skeletal muscle aging and frailty in mice.

What Does This Mean for NMN Supplementation?

These findings help tie the findings that NMN supports healthy skeletal muscle aging and insulin sensitivity in humans. This study suggests that NMN can induce the LH to regulate the sympathetic nervous system and skeletal muscle function, resulting in healthier aging and energy consumption.



Ito N, Takatsu A, Ito H, et al. Cell Rep. 2022;40(4):111131. 

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