NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies

Abstract

The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD precursor NMN binds to and activates the pro-degenerative enzyme SARM1, so a failure to convert sufficient NMN into NAD leads to toxic NMN accumulation and axon degeneration. This involvement of NMN brings the axon degeneration field to an unexpected overlap with research into ageing and extending healthy lifespan. A decline in NAD levels throughout life, at least in some tissues, is believed to contribute to age-related functional decay and boosting NAD production with supplementation of NMN or other NAD precursors has gained attention as a potential anti-ageing therapy. Recent years have witnessed an influx of NMN-based products and related molecules on the market, sold as food supplements, with many people taking these supplements daily. While several clinical trials are ongoing to check the safety profiles and efficacy of NAD precursors, sufficient data to back their therapeutic use are still lacking. Here, we discuss NMN supplementation, SARM1 and anti-ageing strategies, with an important question in mind: considering that NMN accumulation can lead to axon degeneration, how is this compatible with its beneficial effect in ageing and are there circumstances in which NMN supplementation could become harmful?

Keywords: Ageing; Axon degeneration; Lifespan; NAM, NAD, SARM1; NMN; NMNAT; NR; Programmed axon death.