The Axon's Self-Destruct Switch
Most enzymes here consume NAD+ as a by-product of doing something useful. This one appears to consume it on purpose, as the trigger for a programmed axonal breakdown — which is why it is a serious drug target in neuropathy and nerve injury. Its affinity for NAD+ is the highest of the four consumers. Two boundaries must travel with it, and the source states both plainly: its role in tissues other than nerve is uncertain, and its role in aging is still unknown. It is drawn here so the axonal route is visible on the map, not because it explains why NAD+ falls as you get older.
In depth
A NADase that lives in nerve axons and stays inert until the axon is injured. When it dimerises it destroys NAD+ locally, and the axon degenerates.
What drives it
Stress & cortisol increases it.
SARM1 is inert until injury. Its NADase activity is engaged by axonal injury and metabolic stress, and SARM1-mediated NAD+ degradation is observed during axonal degeneration both in vitro and in vivo. Drawn from the exposure layer because injury is an input rather than a state, and so the pathway is not an orphan. Limit repeated from the node itself: the source states the role of SARM1 in NAD+ depletion in tissues other than nerve "remains uncertain" and its role in aging "is still unknown" — this edge draws the injury route, not an aging claim. Cell Metab 2019 S1550413119305029 ; Chini 2024 Aging Cell. doi 10.1111/acel.13920
What it drives
It reduces Cellular fuel.
Drain three, and the most narrowly scoped. In neurons the dimerised SARM1 degrades NAD+ to nicotinamide, ADPR and small amounts of cADPR, much like CD38; its Km is 24 uM. SARM1-mediated degradation is observed during axonal degeneration in vitro and in vivo. Two limits the source states outright: "the role that SARM1 plays in NAD+ depletion in other tissues remains uncertain" and "the role of SARM1 in aging is still unknown." Drawn so the axonal route is visible, not as a claim about aging. Cell Metab 2019, S1550413119305029 — NAD+ in brain aging and neurodegenerative disorders ; Chini 2024, Aging Cell, doi 10.1111/acel.13920 / PMC10776128 — NAD metabolism: role in senescence regulation and aging. doi 10.1111/acel.13920 · PMC10776128
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.