We hypothesize that complement C3/C5a–mediated synapse elimination functions as an evolved, programmable aging clock whose activity is set by species‑specific lifespan expectations rather than by the accumulation of molecular damage. If true, then (1) the rate of C3 deposition in the neuropil should scale with the donor’s chronological age divided by the species’ maximal lifespan, producing a constant "complement age" across mammals; (2) experimental reduction of C1q or C3 activity will extend health‑ and lifespan without lowering established damage markers such as 4‑HNE adducts or γ‑H2AX foci; and (3) heterochronic parabiosis between short‑lived (e.g., killifish) and long‑lived (e.g., naked mole‑rat) species will transfer complement activity proportional to the donor’s lifespan fraction, not to absolute age.

To test (1), we will quantify C3b/iC3b immunoreactivity in cortical synaptosomes from mice, rats, guinea pigs, rabbits, and humans, normalizing to synapse density. Plotting complement signal versus age/maximum lifespan predicts a linear relationship with slope near zero if complement tracks proportional age. Deviation would support a damage‑driven model. This builds on the programmed aging idea that senescence is an adaptive trait [1, 2] and contrasts with the disposable soma view [3].

For (2), we will generate inducible, forebrain‑specific C1q knock‑down mice and administer a C5aR antagonist starting at mid‑life. Longitudinal MRI, behavioral batteries, and synaptic density assays will determine lifespan and healthspan. Parallel immunoblotting for 4‑HNE and γ‑H2AX will assess whether damage accumulation is altered. A significant lifespan extension without change in these markers would indicate that complement actuation drives senescence independently of damage, consistent with a dedicated aging program.

For (3), we will create parabiosis pairs between 2‑month‑old killifish (median lifespan ~4 mo) and 6‑month‑old naked mole‑rats (median lifespan >20 yr). After 4 weeks, we will isolate brain tissue and measure C3 activation, C5a levels, and downstream microglial phagocytic markers. If complement activity reflects the donor’s proportional lifespan, the killifish partner exposed to mole‑rat circulation should show a reduction in C3 signaling relative to its age‑matched controls, whereas the mole‑rat partner exposed to killifish blood should exhibit a premature rise. Conversely, a damage‑centric view predicts changes only when absolute donor age exceeds a threshold, producing no effect in these extreme lifespan mismatches. The rejuvenating effects of young blood [4] provide a precedent for circulating signals that regulate aging rate.

This hypothesis is falsifiable: a failure to observe proportional complement scaling, or a lack of lifespan benefit from complement inhibition despite reduced synapse loss, would refute the programmed‑clock model and favor the view that complement activation is a downstream consequence of accumulated damage. Demonstrating, however, that complement activity behaves as a conserved, adjustable timer would reframe longevity medicine as the calibration of an evolved program rather than the repair of stochastic wear.