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

Ageing is often modelled and prioritised as near-linear accumulation of cell-intrinsic lesions, yet late-life mortality risk accelerates exponentially following the Gompertz law. 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 hierarchical framework in which primary lesions provide the load, while organism-level signalling networks — especially senescence-associated intercellular communication — provide the gain, converting 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 control layer governing ageing trajectories. It further implies regime-dependent therapeutic leverage: cell-autonomous approaches are most effective as early-life prevention and may slow progression in midlife, whereas durable late-life reversal requires systemic signalling reset that suppresses amplification and restores buffering capacity. By framing rejuvenation as a global state change, the framework positions cell-autonomous strategies, including partial reprogramming, as complementary to systemic recalibration and most effective when deployed within a rejuvenated systemic milieu.