Senescent cell clearance by the immune system: Emerging therapeutic opportunities

Abstract

Senescent cells (SCs) arise from normal cells in multiple organs due to inflammatory, metabolic, DNA damage, or tissue damage signals. SCs are non-proliferating but metabolically active cells that can secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype (SASP). Senescent cell anti-apoptotic pathways (SCAPs) protect SCs from their own pro-apoptotic SASP. SCs can chemo-attract immune cells and are usually cleared by these immune cells. During aging and in multiple chronic diseases, SCs can accumulate in dysfunctional tissues. SCs can impede innate and adaptive immune responses. Whether immune system loss of capacity to clear SCs promotes immune system dysfunction, or conversely whether immune dysfunction permits SC accumulation, are important issues that are not yet fully resolved. SCs may be able to assume distinct states that interact differentially with immune cells, thereby promoting or inhibiting SC clearance, establishing a chronically pro-senescent and pro-inflammatory environment, leading to modulation of the SASP by the immune cells recruited and activated by the SASP. Therapies that enhance immune cell-mediated clearance of SCs could provide a lever for reducing SC burden. Such therapies could include vaccines, small molecule immunomodulators, or other approaches. Senolytics, drugs that selectively eliminate SCs by transiently disabling their SCAPs, may prove to alleviate immune dysfunction in older individuals and thereby accelerate immune-mediated clearance of SCs. The more that can be understood about the interplay between SCs and the immune system, the faster new interventions may be developed to delay, prevent, or treat age-related dysfunction and the multiple senescence-associated chronic diseases and disorders.

Keywords: Chemokines; Cytokines; Immune system; Senescent cells; Senolytics.

Fig. 1.

Senescent cell clearance mediated by the immune system cells: what is known and what has yet to be confirmed. Recent studies suggest several ways through which SCs may be cleared by immune cells. In a healthy immune surveillance scenario, SCs produce factors and provide signals that promote SC clearance. Interactions that could suppress SC clearance are shown in green and interactions that promote SC clearance are in red. Possible mechanisms are in Italics. NK = Natural Killer Cell; SC = Senescent Cell; DAMPs = Damage-Associated Molecular Patterns; T-CD8⁺ CTL = CD8⁺ Cytotoxic T Lymphocyte; MDA = Oxidative Adduct Malondialdehyde; T_reg = T-CD4⁺ Regulatory Cell; SASP = Senescence-Associated Secretory Phenotype.

Fig. 2.

Effects of immune clearance of SCs in health and aging. Whether SC accumulation causes or is a consequence of age-related immune system dysfunction is an open question. Possible chains of events are shown. In younger individuals, there is continuing surveillance for SCs by the immune system, with clearance of SCs leading to attenuation of damage signals and the SASP. In older individuals, clearance of SCs by the immune system is impaired. SCs could accumulate and cause dysfunction of immune cells or, conversely, age-related changes in the immune system could allow SCs to accumulate. Once sufficient SCs accumulate and immune cell function becomes impaired by this SC accumulation, a feedforward cycle of further SC accumulation and immune system dysfunction might ensue.