Although aging is the primary risk factor for Alzheimer’s disease (AD), the precise molecular mechanisms by which pathological aging drives neurodegeneration remain unclear. Recent studies have shown that senescent cells accumulate in the brains of individuals with AD, and mitochondrial dysfunction is a key pathological feature of the disease. Since telomere shortening is a well-established trigger of cellular senescence, we used a telomerase-deficient mouse model (Terc-/-) to characterize the molecular signatures of brain senescence. Proteomic and transcriptomic analyses of hippocampal tissue from third-generation Terc-/- mice (G3Terc-/-) revealed multiple alterations at both the mRNA and protein levels, which we are currently investigating as potential novel biomarkers of brain senescence. Among the affected pathways, oxidative phosphorylation (OXPHOS) showed the most significant dysregulation. These findings were further validated through functional analyses. Electron flow assays using Seahorse technology revealed significant activity impairments in mitochondrial electron transport chain (ETC) complexes I to IV in mitochondria isolated from young G3Terc-/- and older G2Terc-/- mice. Similarly, aged G2Terc-/- mice displayed clear signs of energy imbalance. Notably, the hippocampal region exhibited greater vulnerability to these defects than the cortical region. Primary neurons derived from senescent mice displayed similar energy impairments, along with increased production of reactive oxygen species (ROS). Overall, our findings point to a distinct mitochondrial signature associated with brain cellular senescence. Previous work from our laboratory demonstrated that telomere-induced senescence promotes intracellular accumulation of amyloid beta, as well as tau phosphorylation and aggregation. Together, these results underscore the appearance of mitochondrial alterations during cellular senescence and their potential contribution to AD pathogenesis.
Caballol et al. (Wed,) studied this question.