Elimination of senescent cells fails to attenuate disease progression in an ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving progressive motor neuron degeneration, resulting in muscle weakness and paralysis. Current therapeutic options provide only modest benefit, and the etiology of ALS remains incompletely understood. Emerging evidence implicates cellular senescence in the central nervous system (CNS) of ALS pathogenesis, with senescent astrocytes identified in both animal models and patients.

We employed transgenic mice overexpressing the human superoxide dismutase 1 gene with a glycine-to-alanine substitution at codon 93 (hSOD1^G93A) as the experimental model. To eliminate senescent cells, mouse-derived natural killer group 2, member D (NKG2D) chimeric antigen receptor T (CAR-T) cells were engineered to target NKG2D ligands (NKG2DLs) ⁺ senescent cells. The efficacy of senescent cell clearance was assessed by SA-β-gal staining on frozen tissue sections and by quantifying the expression of senescence-associated markers (e.g., p16^INK4a, p21). Disease progression in mice was evaluated by monitoring changes in body weight, behavioral performance, and motor function.

We found that NKG2DLs⁺ senescent cells accumulate in symptomatic transgenic mice. NKG2D CAR-T cells can selectively eliminate senescent cell populations in symptomatic hSOD1^G93A mice. A single infusion effectively reduced senescent cell burden and suppressed Senescence-Associated Secretory Phenotype (SASP) features within central nervous system tissues. However, no significant improvements in motor function or survival were observed.

These results indicate that while senescence is a pathogenic feature of ALS, it operates within an integrated disease network. Early senolytic intervention or combinatorial approaches may represent promising future strategies for ALS.