Which specific SASP components drive neurodegeneration versus neuroprotection in different brain regions?

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Description

The temporal SASP modulation hypothesis assumes certain SASP factors are beneficial while others are harmful, but the debate revealed no clear evidence for this distinction in neurological contexts. Understanding this balance is critical for designing senomorphic therapies.

Source: Debate session sess_SDA-2026-04-02-gap-senescent-clearance-neuro (Analysis: SDA-2026-04-02-gap-senescent-clearance-neuro)

Resolution criteria

Resolution requires: (1) multiplexed cytokine/chemokine profiling (Olink or Luminex) of SASP components from senescent astrocytes vs microglia vs neurons, identifying >=5 factors that distinguish neuroprotective from neurodegenerative SASP profiles; (2) regional brain organoid model where SASP from different brain regions produces opposing effects on neuronal survival (Live/Dead assay), establishing region-specific SASP duality; (3) in vivo blocking experiments using neutralizing antibodies or senomorphic drugs (rapamycin, JAK inhibitors) that cross BBB, demonstrating region-specific efficacy differences (>=40% variation) in tau or A-beta mouse models. Single-region studies are insufficient to resolve the neurodegeneration vs neuroprotection question.

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