From hyperfunction to systemic amplification: reframing the logic of late-life rejuvenation

Aging is often modeled, and interventions prioritized, as the near-linear accumulation of cell-intrinsic lesions; yet the exponential acceleration of late-life mortality under the Gompertz law points to an active, program-like component shaping the trajectory. Furthermore, systemic interventions - including therapeutic plasma exchange and extracellular-vesicle-based therapies - together with the transient embryonic rejuvenation phase, can induce rapid, broadly coordinated organism-level rejuvenation on timescales difficult to attribute to gradual repair alone. Here, we propose an integrative-first load-gain framework in which primary lesions provide the damage load, while the systemic communication architecture sets the gain: a systemic hyperfunction of intercellular signaling that converts slow cellular inputs into self-amplifying late-life acceleration. This architecture provides a mechanistic basis for both the embryonic biological-age reset and Gompertzian late-life acceleration by positioning organism-level coupling as a central gain-setting layer governing aging trajectories. It further implies regime-dependent therapeutic leverage: cell-autonomous approaches are most effective as early-life prevention and may slow progression in midlife, but durable late-life reversal requires systemic signaling reset that suppresses amplification and restores buffering capacity. By treating rejuvenation as a shift in the organism's regulatory state rather than local lesion repair, the framework positions partial reprogramming and other cell-autonomous strategies as complementary to systemic recalibration and most effective within a rejuvenated systemic milieu.