How to Reconcile the Axonal Degeneration with the Anti-aging Effect of NMN

How to Reconcile the Axonal Degeneration Caused by NMN Accumulation with the Anti-ageing Effect of NMN



1. Introduction

The NAD precursor nicotinamide mononucleotide (NMN) shows a beneficial effect on ageing, yet excessive NMN accumulation may lead to axon degeneration. How to make the anti-ageing effect of NMN compatible with axonal degeneration caused by NMN accumulation is still a challenge. A preliminary discussion on this issue is conducted in this study.

2. The definition and pathological changes of axonal degeneration

Axonal degeneration refers to degenerative changes in the axon as a result of direct damage to the primary or as a result of diseases such as neuronal metabolic disorders, which is a common pathological change of the nervous system. The pathological changes after axonal injury include axonal swelling, fracture, retraction and atrophy.

3. The relationship between NMN and sterile alpha and TIR motif–containing 1 (SARM1)

SARM1 is a multi-functional enzyme with base exchange activity, which can cleave nicotinamide adenine dinucleotide (NAD) into adenosine diphosphate ribose (ADPR), cyclic adenosine diphosphate ribose (cADPR) and nicotinamide (NAM). A substantial body of evidence mirrors that the degenerative enzyme SARM1 will be bound to and be activated by NMN. Hence, failed conversion of sufficient NMN into NAD may give rise to toxic NMN accumulation and axon degeneration. 

4. The specific pathway of axon degeneration

NMN only induces axon degeneration in the presence of SARM1, placing the toxic accumulation on a common pathway of axon death. Notably, nicotinamide mononucleotideadenylyltransferases (NMNATs) has a broader, compartment-specific regulatory role in SARM1 activity. For instance, NMNAT2 depletion is associated with SARM1 activation in axons.

In a nutshell, NMNAT2 depletion can give rise to NMN accumulation. Next, NMN binds to and activates the pro-degenerative protein SARM1, leading to rapid NAD consumption and axon degeneration.

5. The impacts of NAD precursors upon axonal health

NAD precursors are likely to be safe for most people, but there is a risk for people with compromised NMNAT activity, as these supplements could cause SARM1 activation and neurodegeneration. 

In healthy individuals, rapid conversion from NMN into NAD can be accomplished by NMNAT2, which is conductive to the prevention of NMN toxic accumulation and maintenance of healthy neurons and axons. Yet, downregulation of NMNAT2 level or activity may result in the upregulation of NMN, thereby leading to SARM1 activation, increased axonal vulnerability and/or axon degeneration.

6. The factors for SARM1 activity

SARM1 activity is regulated by a ratio between NMN and NAD. When NMN rises, partial inhibition of SARM1 is only seen at high concentrations of NAD. Inefficient conversion of NMN into NAD because of compromised NMNAT activity is the most likely scenario in which NMN can become toxic.

The change in NMN level close to the physiological concentration has a much more significant impact on SARM1 activity than NAD level. A twofold increase in NAD level is not sufficient to delay axon degeneration after injury, and even higher NAD level only temporarily delays axon degeneration.

7. The interaction between SARM1 activation and ageing effect of NMN

Sub-lethal/chronic SARM1 activation could increase axonal vulnerability or have a significant impact upon NAD homeostasis and important intracellular signalling pathways in neurons.It is pivotal for life to preserve NAD homeostasis. Maintaining NAD homeostasis could be a viable anti-ageing strategy.

Similarly, NMNAT2 depletion increases axon vulnerability and the level of the NMNAT2 is declined with ageing. These findings signify that SARM1 and NMNAT2 may be the key factor to reconcile the axonal degeneration caused by the accumulation of the NAD precursor NMN and ageing effect of NMN.

8. Conclusion

 Efficient conversion of NMN into NAD is key to preventing SARM1 activation and neurotoxicity. SARM1 and NMNAT2 may be the intersection factors between axon degeneration and anti-ageing therapy.

Reference

Loreto, Andrea et al. “NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies.” Neuroscience research vol. 197 (2023): 18-24. doi:10.1016/j.neures.2023.01.004

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