Senolytics Target Brain Aging Pathways to Fight Neurodegeneration

Brain aging is the leading risk factor for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), yet no disease-modifying therapies exist. A central mechanism driving this risk is the accumulation of senescent cells (SnCs)—cells locked in irreversible cell-cycle arrest that resist apoptosis and chronically inflame their microenvironment. This 2025 review comprehensively examines how senolytics, a class of compounds that selectively eliminate SnCs, might address this gap.

The authors detail the biology of cellular senescence: SnCs arise from DNA double-strand breaks, mitochondrial dysfunction, oxidative stress, and telomere shortening. They are maintained by cyclin-dependent kinase inhibitors p16/INK4a and p21, and they persist by activating senescent cell anti-apoptotic pathways (SCAPs). Critically, SnCs secrete a senescence-associated secretory phenotype (SASP)—a cocktail of IL-1α/β, IL-6, IL-8, TNF-α, TGF-β, CCL2, and matrix proteases—that propagates senescence to neighboring healthy neurons in a paracrine fashion, fueling the 'inflammaging' state characteristic of the aging brain.

The review maps four key signaling axes through which senolytics act. First, mTOR inhibition (via the mTORC1-S6K1 axis) reduces SASP production, particularly IL-1β, and restores autophagic clearance of misfolded protein aggregates such as amyloid-β and tau. Second, AMPK activation enhances mitochondrial biogenesis and autophagic flux, counteracting the metabolic dysfunction of SnCs. Third, SIRT1 activation promotes DNA repair and reduces oxidative damage by deacetylating key substrates. Fourth, Nrf2-Keap1 pathway activation upregulates antioxidant defense genes, lowering ROS burden. Senolytics such as dasatinib (a tyrosine kinase inhibitor), quercetin and fisetin (natural flavonoids), and navitoclax (a Bcl-2 family inhibitor) engage these pathways to selectively kill SnCs while sparing healthy cells.

Preclinical evidence cited includes 4-month-old mice treated with dasatinib plus quercetin or with fisetin alone showing improved spatial memory performance. The review also highlights an emerging senolytic class—mitoTAMs—that targets mitochondria with elevated membrane potential (ΔΨm), a hallmark of SnCs, representing a novel targeting strategy. Mitochondrial sirtuins SIRT3 and SIRT5 are discussed as regulators of ETC function whose decline drives ROS overproduction and senescence.

The authors acknowledge that most evidence remains preclinical, human clinical translation is limited, and the heterogeneity of SnC types across brain cell populations (neurons, astrocytes, microglia, oligodendrocytes) complicates uniform senolytic strategies. Nonetheless, they position senolytics as a mechanistically coherent therapeutic avenue that addresses root cellular causes rather than downstream symptoms of neurodegeneration.