The ageing immune system as a potential target of senolytics

Abstract

Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target senescent cells, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting senescent cells are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful senescent cells could have great potential to promote healthy immune function in ageing populations.

Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis

“…Senolytics can selectively induce the death of senescent cells by selective apoptosis in senescent cells, with the potential to prevent onset of age-related diseases [ 112 ]. Since senescence is driven by chronic oxidative stress, antioxidants, including novel molecules and mammalian target of rapamycin (mTOR) signaling inhibitors, might be used as senostatics [ 113 , 114 ]. The flexible nature of senolytics could have great potential to promote healthy immune function in aging populations.…”

Senescent cell-derived vaccines: a new concept towards an immune response against cancer and aging?

“…Of note, several senolytic compounds are currently under clinical trials [ 42 ]. Moreover, senolytics are also promising in overcoming the decline in the immune fitness of the elderly, which is partially caused by immune cell senescence [ 43 ].…”

Accelerated Aging and the Life Course of Individuals Born Preterm

“…Aging is associated with declining function of the immune system, increasing the risk of cancer and infectious diseases [116]. Levels of protein mediators of inflammation tend to increase with advancing age [117].…”

“…Inflammation is a vital immune defense mechanism that can be activated by pathogens or damaged tissues [136]. As discussed above, aging is associated with the declining function of immune defenses against cancer and infectious diseases [116], but also with increasing levels of inflammation-related proteins [117]. Accelerated aging phenotypes, such as insulin resistance and increased adiposity [137] are pro-inflammatory.…”