Therapeutic targeting of senescent cells in the CNS

Abstract

Senescent cells accumulate throughout the body with advanced age, diseases and chronic conditions. They negatively impact health and function of multiple systems, including the central nervous system (CNS). Therapies that target senescent cells, broadly referred to as senotherapeutics, recently emerged as potentially important treatment strategies for the CNS. Promising therapeutic approaches involve clearing senescent cells by disarming their pro-survival pathways with 'senolytics'; or dampening their toxic senescence-associated secretory phenotype (SASP) using 'senomorphics'. Following the pioneering discovery of first-generation senolytics dasatinib and quercetin, dozens of additional therapies have been identified, and several promising targets are under investigation. Although potentially transformative, senotherapies are still in early stages and require thorough testing to ensure reliable target engagement, specificity, safety and efficacy. The limited brain penetrance and potential toxic side effects of CNS-acting senotherapeutics pose challenges for drug development and translation to the clinic. This Review assesses the potential impact of senotherapeutics for neurological conditions by summarizing preclinical evidence, innovative methods for target and biomarker identification, academic and industry drug development pipelines and progress in clinical trials.

Fig. 1 |. Senescence initiation and spread across brain cells.

a, Age and disease-associated stressors that drive inflammation, reactive oxygen species, toxic protein accumulation, metabolic dysregulation or DNA damage may cause senescence in many cell types, including neurons. b, Senescent neurons exhibit altered excitability and/or activity, display ‘eat me’ signals and secrete deleterious molecules (the senescence-associated secretory phenotype (SASP)) that negatively impact neuronal, vascular and glial cells. They may also contain aggregate-prone, neurotoxic proteins that they transmit to other cells as neuronal SASP^,. c, Activated microglia expressing phagocytic receptors recognize neuronal phagoptosis ‘eat me’ signals. d, Activated microglia engulf senescent neurons and their content, including difficult-to-digest protein aggregates, which may cause microglial senescence. e, Senescent microglia exhibit reduced phagocytic and surveillance function. They release partially digested, neurotoxic fragments of protein aggregates and SASP factors that cause astrocytes, microglia^,, vasculature and oligodendrocyte precursor cells to become senescent. Aβ, amyloid-β; Htt, huntingtin; PrP, prion protein; PS, phosphatidylserine; SOD1, superoxide dismutase 1; TDP43, TAR DNA-binding protein 43.

Fig. 2 |. Cellular phenotypes of postmitotic senescent neurons.

Cellular phenotypes of postmitotic senescent neurons include morphological changes, lysosomal and mitochondrial dysfunction, DNA damage, increased nuclear size, decreased expression of lamin B1, increased expression of p21, p16 and p19, changes in membrane potential and a senescence-associated secretory phenotype (SASP). The black arrows indicate axonal and dendritic retraction, which is a feature of postmitotic senescent neurons that does not occur in non-neuronal cell types. Processes highlighted in blue are being explored as senotherapeutic targets across senescent cell types. Increased β-galactosidase, lipofuscin accumulation, proliferation arrest and telomere attrition are senescence phenotypes that may occur in replicative or stress-induced senescence but are not specific markers for postmitotic senescent neurons and are not shown. p16: p16^INK4a; p19: p19^INK4d; p21: p21^CIP1.

Fig. 3 |. Potential molecular drug targets for CNS senotherapeutics.

Senescent cells feature upregulated pro-survival pathways and a senescence-associated secretory phenotype (SASP). Several molecular players in these pathways are under investigation as potential targets for senotherapeutic strategies. Drug-targeting approaches to activate (red arrows), inhibit (red inhibitory lines) or promote (dashed arrows) protein transport within the cell can result in cell clearance (senolytics) or modulate the SASP (senomorphics). A combination of dasatinib and quercetin, which target Src tyrosine kinase signalling, were the first generation of potential senolytics to be discovered. Other promising approaches include targeted inhibition of the pro-survival BCL-2-related pathways, or NF-κB signalling to ameliorate the expression of SASP genes. Selected compounds are shown as examples (red boxes); see Table 2 for further details. Note that galacto-oligosaccharide (gal)-encapsulated drugs, which target raised β-galactosidase levels in the lysosomes of senescent cells, might not be suitable for central nervous system (CNS) applications owing to high β-galactosidase expression in non-senescent neurons. COX2, cyclooxygenase 2; DPP4, dipeptidyl peptidase 4; GPNMB, glycoprotein nonmetastatic melanoma protein B; HDAC, histone deacetylase; HSP90, heat shock protein 90; OXR1, oxidation resistance gene 1; RTK, receptor tyrosine kinase; Ub, ubiquitin; uPAR, urokinase-type plasminogen activator receptor; USP7, ubiquitin-specific peptidase 7.