Hypothesis Statement

Chronic artificial light at night (ALAN) maintains mTORC1 activity during the subjective night, suppressing the circadian‑driven trough that normally promotes autophagy and stress resistance. This persistent "civilization" signal forces cells to prioritize growth and specialization over survival mechanisms, leading to cumulative cellular damage and shortened lifespan.

Mechanistic Rationale

1. Light‑dependent mTOR activation – Photic input via the MAPK/ERK pathway rapidly stimulates mTORC1 during darkness, a process that is normally gated to the subjective night to synchronize transcription and translation in SCN neurons [3][4].
2. Circadian gating loss – Under constant or ALAN conditions, the usual BMAL1‑mediated inhibition of mTORC1 is blunted, resulting in elevated basal mTOR signaling even when nutrients are low [1][2].
3. Civilization‑versus‑survival trade‑off – Persistent mTORC1 drives protein synthesis, ribosome biogenesis, and anabolic pathways, while inhibiting ULK1‑dependent autophagy and FOXO‑mediated stress responses [1][5]. The net effect is a shift from the survival mode that occurs during the dark phase to a continual growth mode.

Testable Predictions

• Prediction 1: Mice housed under dim ALAN (≤5 lux) will show higher phospho-S6K and phospho-4EBP1 levels in liver and brain during the night compared with controls kept in true darkness, despite identical feeding schedules.
• Prediction 2: Night‑time mTORC1 activation under ALAN will correlate with reduced LC3-II conversion and diminished p62 degradation, indicating suppressed autophagy.
• Prediction 3: Genetic or pharmacological reduction of mTORC1 activity (e.g., heterozygous Tsc1 knockout or low‑dose rapamycin) administered only during the dark phase will rescue autophagy markers and extend median lifespan in ALAN‑exposed mice, whereas the same intervention given during the day will have no additional benefit.
• Prediction 4: Human shift workers reporting chronic night‑light exposure will exhibit elevated circulating markers of mTOR activity (e.g., phospho-S6K in peripheral blood mononuclear cells) and lower autophagy flux (e.g., reduced beclin-1‑associated vesicles) compared with day‑only workers, after controlling for age, BMI, and diet.

Experimental Approach

• Animal model: C57BL/6J mice assigned to three lighting regimens: (a) 12 h light/12 h dark (LD) with <0.1 lux night, (b) LD with 5 lux ALAN throughout the dark phase, (c) LD with 5 lux ALAN plus timed rapamycin (0.1 mg/kg i.p.) administered ZT14-ZT22.
• Readouts: Western blot for p‑S6K, p‑4EBP1, LC3‑I/II, p62; immunofluorescence for nuclear FOXO3a; metabolic cages for food intake and energy expenditure; survival monitoring.
• Human component: Cross‑sectional study of night‑shift vs day‑shift workers (n=150 per group). Collect peripheral blood mononuclear cells, quantify p‑S6K by flow cytometry, measure autophagy flux using monodansylcadaverine staining, and adjust for confounders via multivariate regression.

Falsifiability

If ALAN does not increase nocturnal mTORC1 signaling, or if reducing mTORC1 activity during the night fails to restore autophagy or improve longevity under ALAN, the hypothesis would be refuted. Conversely, confirming the predicted molecular and physiological changes would support the idea that artificial night light locks mTOR in a civilization mode, compromising the survival dial.