Efferocytosis in the Context of Aging and Age-Related Disease

There is something of a tradition in the aging research community of writing reviews that attempt to summarize everything that is known of a single specific cellular behavior in the context of the panoply of cell and tissue dysfunction observed in aging. Today it is the turn of efferocytosis, the clearance of dying cells and their immediate debris by phagocytes such as macrophages of the innate immune system. It is fairly straightforward to mount an argument to suggest that more efficient efferocytosis is a good thing, as unwanted consequences attend the presence of lingering cell corpses cluttering up tissue. Like autophagy, the mechanisms making up efferocytosis are fairly well mapped, but unlike autophagy, there is no great effort underway in the research community to find ways to improve efferocytosis for functional benefit.

Efferocytosis is carried out by professional phagocytes, such as macrophages, dendritic cells, and other nonprofessional cells, to engulf apoptotic cells (ACs). Initially, phagocytes expeditiously and securely eliminate the membrane structure of the deceased cell before its disintegration and subsequent release into adjacent tissue. This process serves to safeguard the surrounding tissue against the deleterious effects induced by toxic enzymes, oxidants, and intracellular components, such as protease antibodies and caspases within ACs. Additionally, efferocytosis can generate a significant number of biological factors, including vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which are hypothesized to facilitate cellular regeneration within the body. In addition, efferocytosis elicits subsequent intracellular signalling cascades, including anti-inflammatory, anti-protease, and growth-promoting actions.

The coordination of many processes is essential for the proper differentiation of ACs from healthy cells and their subsequent elimination through efferocytosis. When these deceased cells remain uninterrupted, they undergo a disruptive process, resulting in harm to the organism, triggering an inflammatory reaction, and perhaps giving rise to a range of ailments. Numerous human diseases, such as atherosclerosis, cancer, systemic lupus erythematosus, diabetes, obesity, rheumatoid arthritis, and aging, have been observed to exhibit associations with deficiencies or alterations in the processes of efferocytosis. Efferocytosis is a multistep physiological process and enhancing any one of these steps can promote efferocytosis while suppressing tissue inflammation.

Hence, the concurrent implementation of strategies aimed at augmenting efferocytic mechanisms and anti-aging treatments has the potential to serve as a potent intervention for extending the duration of a healthy lifespan. In this review, we comprehensively discuss the concept and physiological effects of efferocytosis. Subsequently, we investigated the association between efferocytosis and the hallmarks of aging. Finally, we discuss growing evidence regarding therapeutic interventions for age-related disorders, focusing on the physiological processes of aging and efferocytosis.

Link: https://doi.org/10.1016/j.jare.2024.03.008