Title : Clearing the fog: Can senolytics wipe out alzheimer’s one cell at a time?
Abstract:
Alzheimer's disease (AD) constitutes a complex neurodegenerative disorder characterized by progressive cognitive decline and brain aging. Early preclinical data suggest a putative role of cellular senescence in AD pathogenesis, leading to speculations that senescent cells might actually contribute towards tau accumulation and neuroinflammation. This thought, in turn, prompted investigations into senolytic therapy as a candidate for a novel therapeutic approach. Senolytic therapy refers to targeting and eliminating senescent cells which are thought to promote inflammation and, therefore, probably contribute towards the progression of the disease. Data from several studies using senolytics in AD models have indicated decreased brain senescence profiles with reductions in tau pathology and normalized cognitive function seemingly. Clinical trials are currently ongoing, which include early-stage AD patients receiving some senolytic combinations such as dasatinib and quercetin, thus providing some initial evidence of CNS penetration and possible mechanistic benefit. Dasatinib and quercetin (D + Q) are amongst some of the most studied senolytic combinations, safe and possibly efficacious in early-stage AD patients. Yet another nascent pair of candidates deserving attention is navitoclax (ABT-263) and fisetin. Navitoclax is a BCL-2 family inhibitor that, in aged monkeys, has been found to diminish senescent and SASP biomarkers, with some trends indicating improvement in neuroinflammation and neuronal damage markers15. Fisetin is a flavonoid with senolytic properties that further provides promise in the liberation of senescent cells as a target across several age-related diseases. The therapeutic rationale for senolytics has a broader scope because these address the mechanisms of cellular damage and other underlying mechanisms directly contributing to AD pathology, thereby representing a disease modification strategy. If it can effectively eliminate pro-inflammatory and pro-aging senescent cells, senolytics might also confer beneficial effects against the progression of other age-associated disorders. However, it is essential to research the long-term safety and efficacy of senolytic therapy in human patients and to obtain further insights about its possible synergistic interactions with ongoing treatments for AD.
