Hypothalamic Menin expression in VMH SF-1 neurons drives circadian NAD+ biosynthesis by activating Nampt transcription, thereby linking SCN timing to systemic SIRT1 activity. When Menin declines with age, Nampt expression falls, reducing NAD+ and SIRT1 deacetylase activity, which leads to hyperacetylation of core clock proteins (BMAL1, PER2) and weakens SCN neuronal rhythms. This circadian dampening further suppresses Menin via diminished CREB‑mediated transcription in VMH, creating a vicious cycle that accelerates multiple hallmarks of aging including genomic instability, inflammation, and proteostatic loss. We'll predict that restoring NAD+ with timed nicotinamide riboside (NR) administration will rescue Menin expression, re‑synchronize central‑peripheral clocks, and ameliorate aging phenotypes in aged mice. It's known that Menin also regulates D-serine metabolism and neuroinflammatory pathways[1]. The hypothesis is falsifiable: if NAD+ repletion normalizes systemic NAD+ and SIRT1 activity but fails to increase Menin levels or restore clock gene rhythmicity in VMH, the proposed upstream controller model is invalid. To test, we'll measure Menin protein, Nampt mRNA, NAD+ concentrations, SIRT1 activity, and clock gene expression (Bmal1, Clock, Per2, Cry1) in VMH and liver of young, old, and old + NR mice under constant darkness, alongside behavioral rhythms and senescence markers (p16, γH2AX). A significant interaction where NR improves Menin and clock metrics only in old mice would support the hierarchical model; absence of such effects would refute it.1 2 3 4 5 Nampt-Menin link NAD+-SIRT1 circadian