Disrupting the BCL-2/Beclin-1 interaction after reproductive age extends mouse lifespan without reducing early‑life fecundity or increasing tumor burden.

This hypothesis builds on the antagonistic pleiotropy (AP) framework, which holds that alleles boosting early reproduction are favored despite late‑life costs because selection weakens after reproduction ends[1,2]. The BCL-2/Beclin-1 complex exemplifies AP: BCL-2’s anti‑apoptotic activity protects developing germ cells and embryos, yet its binding to Beclin-1 suppresses autophagy initiation, a mechanism that becomes detrimental in aged liver[3]. Genetic disruption of this interaction via the Beclin-1 F121A mutant raises basal autophagy and prolongs healthspan[4],5], demonstrating that the late‑life cost is real and removable.

We propose that the longevity benefit of BCL-2/Beclin-1 dissociation is contingent on timing and tissue context. If the interaction is disrupted only in somatic tissues such as liver or muscle after the onset of reproductive senescence, early‑life fitness pathways remain intact while autophagic clearance of damaged organelles and protein aggregates is enhanced. This temporally restricted intervention should decouple the AP trade‑off, yielding lifespan extension without compromising fertility or increasing oncogenic risk, because BCL-2’s anti‑apoptotic function remains unaltered in germ‑line and proliferative compartments during youth.

To test this, we would generate a mouse model carrying a Cre‑inducible Beclin-1 F121A allele driven by a liver‑specific, tamoxifen‑inducible promoter (Alb‑CreER^T2). Cohorts would receive tamoxifen at 8 months (post‑weaning, post‑peak fertility) and be monitored for litter size, pup survival, and tumor incidence alongside standard longevity readouts. Parallel cohorts receiving the same induction at 2 months would serve as early‑life disruption controls, predicting reduced fecundity or heightened apoptosis if the brake is lifted too soon.

If our hypothesis holds, late‑onset, liver‑specific BCL-2/Beclin-1 uncoupling will produce a significant increase in median and maximal lifespan (≈15‑20 %) comparable to constitutive F121A mice, while litter parameters and tumor latency remain indistinguishable from wild‑type controls. Conversely, early‑onset disruption should recapitulate the trade‑off seen in AP models: modest gains in autophagy offset by decreased reproductive output or elevated apoptosis in developing tissues.

This experiment directly challenges the notion that aging is a deliberately preserved population-level feature. Instead, it treats aging as the inevitable spill‑over of selection‑favored mechanisms that, when uncoupled in a controlled, late‑life window, can be mitigated without undermining the evolutionary logic that shaped them. Confirming these predictions would reframe longevity medicine not as an override of a programmed death signal, but as a precise negotiation with the temporal boundaries of antagonistic pleiotropy.