NKG2D CAR-T cells successfully eliminated senescent astrocytes and reduced inflammatory secretions in the central nervous system of ALS mice, yet failed to improve motor function or extend survival. The engineered immune cells specifically targeted NKG2D ligands on senescent cells, effectively reducing cellular senescence markers like p16INK4a and suppressing the inflammatory senescence-associated secretory phenotype. This represents a significant finding in the senolytic field, as it challenges the assumption that clearing senescent cells automatically translates to therapeutic benefit in neurodegenerative diseases. The results suggest ALS pathology operates through multiple interconnected mechanisms beyond cellular senescence alone. While previous research has shown promise for senolytics in aging-related conditions, this study reveals the complexity of neurodegeneration where senescence may be downstream of primary pathological processes rather than a primary driver. The authors' suggestion for early intervention or combination therapies acknowledges that senescence clearance might require integration with other therapeutic approaches. This finding has important implications for the broader senolytic research agenda, indicating that disease context and timing of intervention may be critical factors determining therapeutic success.