A guide to senolytic intervention in neurodegenerative disease. (December 2021)

• Record Type: Journal Article
• Authors: Lee, Suckwon; Wang, Ellen Y.; Steinberg, Alexandra B.; Walton, Chaska C.; Chinta, Shankar J.; Andersen, Julie K.
• Is Part Of: Mechanisms of ageing and development. Volume 200(2021)
• Publication Date: 2021-12
• Subjects: ALISE Accumulation of lipids in senescence -- ADEPT antibody-directed prodrug enzyme therapy -- AD Alzheimer's disease -- Apaf-1 apoptotic protease activating factor 1 -- Bcl-2 B-cell lymphoma 2 -- Bcl-XL B-cell lymphoma extra-large -- Bleo Bleomycin -- Bleo (IV) Bleomycin administered in vivo -- BMDMC Bone Marrow Derived Mesenchymal Cells -- CAR-T chimeric antigen receptor T-cells -- CPC Cardiac Progenitor Cells -- CRBN cereblon -- CRS Cytokine release syndrome -- Doxo Doxorubicin -- DQ Dasatinib and Quercetin -- DTR diphtheria toxin receptor -- Eto Etoposide -- Ercc1−/Δ" mouse model of human progeroid syndrome -- FDA Food and Drug Administration -- FKB-Casp8 FK506 binding protein-caspase 8 -- FT2AEC Fibrotic Type II Alveolar Epithelial Cells -- FTD Frontotemporal dementia -- GCV ganciclovir -- GMD galactose-modified duocarmycin -- HSV-TK truncated herpes simplex virus thymidine kinase -- HUVEC human umbilical endothelial cell -- IR Ionizing radiation -- Mcl1 Myeloid Leukemia 1 -- MS Multiple sclerosis -- MEF mouse embryonic fibroblast -- MSC Mesenchymal Stem Cells -- NFT Neurofibrillary tangles -- NK Natural Killer Cell -- NPC Neural precursor cells -- NSC Neural stem cell -- OPC Oligodendrocyte Precursor Cells -- OS Oxidative Stress -- OXR1 oxidation resistance 1 -- PA Preadipocytes -- PD Parkinson's disease -- PL piperlongumine -- PQ Paraquat -- PROTAC bispecific proteolysis targeting chimera -- PSP Progressive supranuclear palsy -- Raf-1 Raf1 proto-oncogene, serine/threonine kinase -- REC Renal Epithelial Cells -- ROS reactive oxygen species -- RS Replicative Senescence -- SA-β-Gal senescence associated β galactosidase -- SASP Senescence-associated secretory phenotype -- T2AEC Type II Alveolar Epithelial Cells -- uPAR urokinase-type plasminogen activator receptor -- WBRT Whole-brain radiation therapy; Aging -- Senescence -- Senolytic -- Neurodegeneration -- Immune surveillance -- Senescence-associated secretory phenotype -- Neurodegenerative diseases; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2021.111585
• Languages: English
• ISSNs: 0047-6374

Abstract

Highlights: Evidence suggests that senescent cell killing by senolytic compounds may be a new intervention in neurodegeneration. Senolytics differ on their mechanism of action and different senolytics can kill different cell types. The heterogeneity of senolytics has been overlooked in neurodegeneration research and may explain existing controversies. The present review provides a guide to the use of senolytics in the brain to aid in future studies. Abstract: Cellular senescence is a potential tumor-suppressive mechanism that generally results in an irreversible cell cycle arrest. Senescent cells accumulate with age and actively secrete soluble factors, collectively termed the 'senescence-associated secretory phenotype' (SASP), which has both beneficial and detrimental effects. Although the contribution of senescent cells to age-related pathologies has been well-established outside the brain, emerging evidence indicates that brain cells also undergo cellular senescence and contribute to neuronal loss in the context of age-related neurodegenerative diseases. Contribution of senescent cells in the pathogenesis of neurological disorders has led to the possibility of eliminating senescence cells via pharmacological compounds called senolytics. Recently several senolytics have been demonstrated to elicit improved cognitive performance and healthspan in mouse models of neurodegeneration. However, their translation for use in the clinic still holds several potential challenges. This review summarizes available senolytics, their purported mode of action, and possible off-target effects. We also discuss possible alternative strategies that may help minimize potential side-effects associated with the senolytics approach.