Hypothesis

Administering senolytic drugs (dasatinib+quercetin) at the peak of fasting‑induced autophagy—typically 14‑16 h into a time‑restricted eating window—will produce a synergistic increase in senescent cell clearance compared with either intervention alone, driven by enhanced MerTK‑dependent efferocytosis and lysosomal acidification.

Mechanistic Rationale

• Fasting activates AMPK and inhibits mTORC1, upregulating autophagic flux and increasing expression of the phagocytic receptor MerTK on macrophages.
• Senolytics transiently disrupt pro‑survival SCAP networks in senescent cells, exposing phosphatidylserine and other “eat‑me” signals.
• When senolytic‑induced apoptotic senescent cells encounter macrophages primed by fasting, MerTK‑mediated efferocytosis is amplified, leading to faster lysosomal degradation and reduced SASP release.
• Concurrently, fasting‑driven NAD+ boost supports SIRT1 activity, which deacetylates MerTK and enhances its signaling, creating a feed‑forward loop that favors clearance over inflammation.

Testable Predictions

1. In a crossover pilot study with older adults, plasma SASP factors (IL‑6, IL‑8, MCP‑1) will drop ≥30 % more after senolytic dosing at the fasting peak versus dosing at a random fed state.
2. Peripheral blood mononuclear cells isolated 4 h post‑dose will show higher LC3‑II/I ratios and greater MerTK phosphorylation only in the fasting‑synced arm.
3. Senescent cell frequency in skin biopsies, measured by p16^INK4a immunostaining, will decline significantly more in the fasting‑synced condition after four weekly cycles.

Falsifiability

If SASP reduction, autophagic markers, or senescent cell burden do not differ between the fasting‑synced and control schedules beyond statistical noise, the hypothesis is falsified. Likewise, absent increase in MerTK activity or lysosomal acidification (measured by LysoSensor intensity) would refute the proposed mechanistic link.

Novel Insight

Beyond shared AMPK/mTOR signaling, the hypothesis posits that fasting creates a immunometabolic milieu that converts senolytic‑induced apoptosis into a highly efficient clearance event, turning a drug‑driven stress into a physiologic efferocytic surge—an angle not captured by current senolytic‑TRE discussions.

It won't be enough to rely on biomarker shifts alone; functional endpoints such as gait speed or grip strength must also improve to claim a true healthspan extension.