Hypothesis: Senolytic efficacy of Bcl‑2 family inhibitors depends on the disruption of a protective sequestration mechanism that stores dangerous misfolded proteins in aggresome‑like compartments. In senescent cells, chronic stress drives the conversion of disordered, toxic oligomers into thermodynamically stable aggregates that are physically tethered to mitochondria via Bcl‑2‑regulated membranes. Inhibiting Bcl‑2 (e.g., with ABT‑263) destabilizes these mitochondrial‑associated membranes, releasing sequestered aggregates into the cytosol where they overwhelm chaperone systems and trigger proteotoxic apoptosis. Consequently, agents that block aggregation (e.g., chemical chaperones such as 4‑phenylbutyrate or small‑molecule inhibitors of amyloid formation) will diminish senolytic potency by preserving the sequestered state, whereas agents that promote aggregate dissolution (e.g., Hsp70 inducers) will synergize with Bcl‑2 inhibitors to increase senescent cell death.

Testable predictions: (1) In human senescent fibroblasts treated with ABT‑263, immunofluorescence will show a rapid loss of co‑localization between aggregated ubiquitin‑positive proteins and mitochondrial markers (TOM20) within 2–4 h, preceding caspase‑3 activation. (2) Co‑treatment with an aggregation inhibitor (e.g., EPPS) will attenuate both aggregate release and cell death, measured by Annexin V/PI flow cytometry, without affecting Bcl‑2 inhibition of BAX/BAK. (3) Conversely, pretreatment with an Hsp70 inducer (e.g., YM‑1) will increase cytosolic aggregate burden and enhance ABT‑263‑induced senescence‑associated secretory phenotype (SASP) suppression, quantified by IL‑6 and IL‑8 ELISA. (4) In vivo, aged mice receiving ABT‑263 plus EPPS will exhibit fewer senescent cell clearance markers (reduced p16^INK4a^‑positive cells in kidney and adipose) compared with ABT‑263 alone, while showing no change in off‑target toxicity (liver enzymes, blood counts).

This hypothesis extends the seed idea by framing aggregation not merely as a passive end‑point but as an active, mitochondrially anchored defense that senolytics specifically undermine. It also explains why dasatinib‑quercetin, which does not target Bcl‑2, shows less selective senolysis and can induce chromatin changes in young cells: its mechanism does not disrupt the mitochondrial‑aggregate tether, leaving the sequestration system intact. Confirming these predictions would reposition aggregate dissolution as a potential adjuvant to improve senolytic selectivity and reduce required dosing.