MULTI-OMICS CHARACTERIZATION OF TELOMERASE DEFICIENT MICE REVEALED MITOCHONDRIAL DYSFUNCTION AS A HALLMARK OF BRAIN SENESCENCE

Neurodegenerative diseases are the most prevalent age-related pathologies, including Alzheimer’s disease (AD). Recent studies suggest that telomere attrition, the main trigger of cellular senescence, may contribute to brain dysfunction and neurodegeneration. Recent evidence also indicates that senescent cells accumulate in AD brains. However, the precise molecular mechanisms by which pathological aging leads to neurodegeneration remain unclear.
To unravel the molecular signatures of brain senescence, we used a telomerase-deficient mouse model (Terc^-/-), which presents telomere attrition and premature ageing. Transcriptomic and proteomic analyses of hippocampal tissue from third-generation Terc^-/- mice (G3Terc^-/-) uncovered multiple alterations at both the mRNA and protein levels, which might potentially become novel biomarkers of brain senescence. Pathway enrichment analyses identified the oxidative phosphorylation (OXPHOS) pathway as the most significantly impaired.
These findings were further validated through functional analyses. Electron flow assays (Seahorse technology) revealed significant activity impairments in mitochondrial electron transport chain (ETC) complexes I to IV in mitochondria isolated from adult G3Terc^-/- and older G2Terc^-/- mice. Likewise, aged G2Terc^-/- mice displayed signs of energy imbalance. Notably, the hippocampal region exhibited greater vulnerability to these metabolic defects than the cortical region. Primary neurons derived from Terc^-/- mice displayed similar energy impairments, along with increased production of reactive oxygen species (ROS).
Overall, our study identified a distinct mitochondrial signature associated with brain cellular senescence. In line with previous work from our laboratory showing that telomere-driven senescence promotes intracellular accumulation of amyloid beta and exacerbates tau pathology, these results suggest that mitochondrial dysfunction may contribute to AD pathogenesis.