Hypothesis

Chronic exposure to light at night uncouples the BMAL1‑mTOR oscillatory circuit in the suprachiasmatic nucleus, causing ectopic mTORC1 signaling in peripheral metabolic tissues that accelerates aging phenotypes.

Mechanistic basis

• Light‑induced ERK/MAPK activation in the SCN phosphorylates BMAL1, reducing its ability to repress mTORC1 during the subjective night [2].
• Loss of BMAL1‑mediated repression lengthens the period of mTORC1 activity and blunts its normal trough [4].
• The desynchronized SCN output alters sympathetic tone and vagal signaling to liver, adipose and pancreas, where nutrients are low but mTORC1 becomes persistently active [6].
• Ectopic mTORC1 drives S6K1‑mediated insulin resistance, suppresses autophagy, and promotes inflammasome activation, thereby mimicking the aging phenotype seen in global BMAL1 knockouts [3].

Novel insight

We propose that the SCN communicates its mTOR state via rhythmic release of vasoactive intestinal peptide (VIP). VIP normally gates peripheral mTORC1 through VPAC2 receptors; when SCN mTOR is mistimed, VIP secretion becomes arrhythmic, delivering a constant proliferative signal to peripheral cells independent of nutrient cues.

Testable predictions

1. Mice exposed to dim light at night will show higher phospho‑S6K1 levels in liver and white adipose tissue at zeitgeber times when mTORC1 should be low, despite unchanged food intake.
2. Genetic ablation of VIP in the SCN will prevent the peripheral mTORC1 rise and extend lifespan under light‑at‑night conditions.
3. Pharmacological inhibition of mTORC1 with rapamycin administered only during the dark phase will rescue autophagy flux and improve glucose tolerance in light‑exposed mice.

Experimental design

• House C57BL/6J mice in 12:12 light‑dark vs. 12:12 dim light‑at‑night (5 lux) for 6 months.
• Collect liver, epididymal fat, and plasma every 4 h over 24 h to measure p‑S6K1, p‑4EBP1, LC3‑II/I ratio, and circulating cytokines.
• Parallel cohorts: SCN‑specific Vip‑Cre;Rosa26‑DTA mice (VIP‑deficient SCN) and wild‑type controls under the same lighting.
• Treatment arm: rapamycin (4 mg/kg i.p.) injected at ZT16 only.
• Primary outcomes: median lifespan, frailty index, and tissue‑specific mTORC1 activity rhythm amplitude (cosinor analysis).
• Statistical test: two‑way ANOVA (lighting × genotype) with post‑hoc Tukey; survival compared by log‑rank test.

Potential outcomes

If the hypothesis is correct, light‑at‑night mice will exhibit loss of mTORC1 rhythmicity, elevated inflammatory markers, and shortened lifespan; VIP‑deficient SCN or timed rapamycin will restore rhythmicity and longevity. Failure to observe peripheral mTORC1 dysregulation or rescue would falsify the proposed SCN‑VIP‑mTOR axis.