A guide to senolytic intervention in neurodegenerative disease

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.

Keywords: Aging; Immune surveillance; Neurodegeneration; Neurodegenerative diseases; Senescence; Senescence-associated secretory phenotype; Senolytic.

Figure 1.. Non-cellular autonomous features of cellular senescence.

Senescent cells can develop a SASP which can be deleterious for the surrounding microenvironment. Senescent cells can also induce cellular senescence in neighboring cells in what is known as secondary senescence, senescence-induced senescence, or paracrine senescence.

Figure 2.. Avenues for the selective killing of senescent cells.

A. Genetic deletion models encode a protein (skull) that can be exogenously activated by the addition of an activator compound (AP20187, GCV, DT) to trigger cell death under promoters that regulate major elements of the senescence signaling cascade. B. Resistance to cell death in senescent cells is bestowed by the up-regulation of pro-survival and or anti-apoptotic networks. Senolytic compounds target different elements of these networks to kill senescent cells. C. Chimeric antigen receptors cytotoxic T cells (CAR-T) have been implemented as a novel senolytic approach. CARs are design to target surface proteins, which then activates the cytotoxic function of the T-cell. By targeting membrane-bound ligands present only on senescent cells, CAR-T can be used as a live cell senolytic intervention strategy. The skull represents INK-ATTAC product FK506 binding protein-caspase 8 (FKB-Casp8) fusion protein, the p16-3MR product truncated herpes simplex virus thymidine kinase (HSV-TK), and the ARF-DTR product diphtheria toxin receptor (DTR). AP20187 is a synthetic drug that induces the dimerization of FKB-Casp8 and initiates apoptosis (Baker et al., 2012). GCV, ganciclovir, DT, diphtheria toxin. In p16-3MR mice, HSV-TK phosphorylates GCV, a nucleotide analogue, and converts it into a toxic DNA chain terminator (Laberge et al., 2013; Ray et al., 2004). In ARG-DTR mice, DT activated the DTR which initiates cell death (Hashimoto et al., 2016).

Figure 3.

Senescence immune surveillance: SASP-producing senescent cells recruit immune cells that in turn eliminate the senescent cells and terminate the SASP. Loss of senescence immune surveillance could result in the accumulation of senescent cells with age and support of a chronic SASP. Senescent cells are reported to escape from immune surveillance by preventing the activation immune cell receptors that lead to cytotoxic effector functions, recruitment of immunosuppressive cells and by the loss of function of immune cells with aging or immunosenescence.