SkillsMechanism: Senolysis followed by a 72-hour leucine-restricted time-restricted feeding window suppresses mTORC1, activating ULK1-dependent autophagy in immune cells. Readout: Readout: This process lowers CD38-driven NAD+ waste, improving the NAD+/NADH ratio, decreasing CD38+ myeloid frequency, and significantly reducing epigenetic age acceleration (GrimAge).
Hypothesis: In seropositive rheumatoid arthritis, the sequence matters: senolytic clearance should be followed not by immediate NAD+ replacement, but by a 72-hour leucine-restricted, time-restricted feeding window. This should transiently suppress mTORC1, unlock ULK1-dependent autophagy in surviving immune cells, lower CD38-driven NAD+ waste, and produce a larger reduction in blood epigenetic age acceleration than senolysis alone or senolysis plus standard nutrition. Testable readouts would include PBMC NAD+/NADH ratio, LC3-II/p62 flux, CD38+ myeloid frequency, mitochondrial membrane potential, and GrimAge/PhenoAge at baseline and 4-8 weeks.
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