Hypothesis: The longevity benefits of rapamycin are not solely due to chronic suppression of anabolic growth but arise from its ability to trigger a reversible metabolic state that, when followed by periods of nutrient repletion, activates a coordinated lysosomal‑nuclear repair program. Continuous mTOR inhibition locks cells in a low‑energy, stress‑resistant mode that limits damage accumulation but does not engage the full autophagic‑lysosomal flux needed to remove persistent aggregates such as lipofuscin or cross‑linked proteins. In contrast, an intermittent regimen—rapamycin administered during fasting windows followed by refeeding—creates a hormonal oscillation: mTORC1 inhibition during famine activates TFEB‑driven lysosomal biogenesis and autophagy, while the subsequent refeeding spike raises intracellular NAD+ levels via increased mitochondrial respiration, activating SIRT1 and SIRT3. These sirtuins deacetylate TFEB and other autophagy regulators, enhancing lysosomal acidification and cathepsin activity, thereby converting autophagosome formation into effective cargo degradation. The metabolic switch also transiently elevates AMP‑activated protein kinase (AMPK) and inhibits acetyl‑CoA carboxylase, promoting fatty‑acid oxidation and reducing lipogenesis, which limits new lipid‑based damage formation. Together, this cycle couples damage sequestration (autophagy) with damage clearance (lysosomal degradation) and boosts NAD+-dependent DNA repair pathways (PARP1, SIRT6), addressing both prevention and removal of age‑related lesions.

Testable predictions: (1) Mice receiving rapamycin only during 20‑hour daily fasts (intermittent dosing) will show a greater reduction in hepatic lipofuscin and skeletal muscle carbonylated proteins after 12 months compared with mice receiving continuous rapamycin or ad libitum controls, despite comparable mTORC1 inhibition measured by p‑S6K levels. (2) The intermittent group will exhibit higher hepatic TFEB nuclear localization and increased lysosomal cathepsin activity during refeeding phases, alongside elevated NAD+/NADH ratio and SIRT1 activity. (3) Genetic knockdown of TFEB or SIRT1 in liver will abolish the additional clearance benefit of intermittent rapamycin, confirming the mechanistic dependency. (4) Providing a NAD+ precursor (e.g., nicotinamide riboside) during refeeding will further enhance clearance, whereas NAD+ depletion will negate it, confirming the nutrient‑sensing link.

Falsification: If intermittent rapamycin fails to produce superior damage clearance or if TFEB/SIRT1 manipulation does not alter the outcome, the hypothesis that pulsed mTOR inhibition synergizes with refeeding‑activated lysosomal‑sirtuin signaling to drive actual repair—not just damage retardation—would be rejected. This framework shifts the focus from mimicking famine to exploiting feast‑famine dynamics to engage evolutionarily conserved repair machinery that constant austerity cannot access.