Pharmacological Targeting of Senescence with Senolytics as a New Therapeutic Strategy for Neurodegeneration.

Abstract

Cellular senescence is a state of permanent cell-cycle arrest. Early in life, senescence has a physiologic role in tumor suppression and wound healing. However, gradually, as these senescent cells accumulate over the lifespan of an organism, they contribute to inflammation and the progression of age-related diseases, including neurodegeneration. Targeting senescent cells using a class of drugs known as "senolytics" holds great promise for the management of Alzheimer's and Parkinson's disease. Already, several senolytic compounds have been shown to ameliorate cognitive deficits across several preclinical models of neurodegeneration. Most of these senolytics (e.g., dasatinib) are repurposed clinical or experimental anticancer drugs, which trigger apoptosis of senescent cells by interfering with pro-survival pathways. However, outside of their senolytic function, many first-generation senolytics also have other less appreciated neuroprotective effects, such as potent antioxidant and anti-inflammatory activity. In addition, some senolytic drugs may also have negative dose-limiting toxicities, including thrombocytopenia. In this review, we discuss the various biologic pathways targeted by the leading senolytic drugs, namely dasatinib, quercetin, fisetin, and navitoclax. We further evaluate the clinical transability of these compounds for neurodegeneration, assessing their adverse effects, pharmacokinetic properties, and chemical structure. SIGNIFICANCE STATEMENT: Currently, there are no effective disease-modifying treatments for the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Some of the drugs currently available for treating these diseases are associated with unwanted side-effects and/or become less efficacious with time. Therefore, researchers have begun to explore new innovative treatments for these belligerent diseases, including senolytic drugs. These agents lead to the apoptosis of senescent cells thereby preventing their deleterious role in neurodegeneration.