Hypothesis: In aged tissues, senolytic removal of senescent cells exacerbates neurodegeneration unless the HSP70/HSP110 disaggregation machinery is simultaneously boosted. Senescent cells act as permanent sequestration sites for misfolded proteins, converting toxic oligomers into inert amyloid‑like deposits. When these cells are eliminated, the deposited proteins are released. If the disaggregation capacity is insufficient, the released material remains as soluble oligomers, which are the primary drivers of toxicity in Alzheimer’s, Parkinson’s and Huntington’s disease. Conversely, enhancing HSP110‑mediated disaggregation before senolysis will convert the liberated aggregates into harmless monomers that can be refolded or degraded, thereby protecting surrounding neurons.

Mechanistic rationale: The Hsp70 system requires a nucleotide exchange factor (NEF) to drive cycles of substrate binding and release. HSP110 functions as a potent NEF that, together with HSP70 and HSP40, can extract monomers from the ends of amyloid fibrils and promote their solubilization. In young cells, high HSP110 levels ensure that any fibrils liberated during stress are rapidly disassembled. Aging reduces HSP110 expression while total HSP70 remains relatively stable, shifting the equilibrium toward fibril persistence. When senolytic drugs clear senescent cells under these conditions, the sudden influx of fibrils overwhelms the limited disaggregation machinery, leading to accumulation of soluble oligomers that seed further misfolding and trigger synaptic dysfunction.

Testable predictions:

1. In aged tau‑transgenic mice, treatment with a senolytic (e.g., navitoclax) alone will increase soluble tau oligomer levels in the cortex and hippocampus and worsen cognitive performance relative to vehicle controls.
2. Co‑administration of an HSP110 inducer (such as Arimoclomol) prior to senolytic treatment will prevent the rise in soluble oligomers and rescue behavioral deficits.
3. In vitro, primary neurons exposed to lysates from senescent cells will show increased oligomer‑dependent calcium dysregulation; adding recombinant HSP110/HSP70/HSP40 complexes to the lysate will abolish this effect.
4. Genetic knockdown of HSP110 in young mice will phenocopy the aged condition, making senolytic treatment toxic even when chaperone networks are otherwise robust.

These experiments directly link the functional state of the disaggregation machinery to the outcome of senescent cell clearance. If the data confirm that boosting HSP110 activity is required for safe senolysis, it would redefine therapeutic strategies: senolytics must be paired with proteostasis‑enhancing agents in aging contexts to avoid converting a protective aggregate sink into a source of toxic oligomers.

[1] https://doi.org/10.1073/pnas.2105548118/-/DCSupplemental [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC12067921/ [3] https://pmc.ncbi.nlm.nih.gov/articles/PMC3001306/ [4] https://elifesciences.org/articles/48240 [5] https://pmc.ncbi.nlm.nih.gov/articles/PMC6744273/ [6] https://doi.org/10.1038/s41467-021-25966-w