The efferocytosis process in aging: Supporting evidence, mechanisms, and therapeutic prospects for age-related diseases

Abstract

Background: Aging is characterized by an ongoing struggle between the buildup of damage caused by a combination of external and internal factors. Aging has different effects on phagocytes, including impaired efferocytosis. A deficiency in efferocytosis can cause chronic inflammation, aging, and several other clinical disorders.

Aim of review: Our review underscores the possible feasibility and extensive scope of employing dual targets in various age-related diseases to reduce the occurrence and progression of age-related diseases, ultimately fostering healthy aging and increasing lifespan. Key scientific concepts of review 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.

Keywords: Aging; Efferocytosis; Inflammation; Senescence.

Graphical abstract

Fig. 1

The mechanisms of efferocytosis. The smell phase: “find-me” signals are released by apoptotic cells to attract macrophages to the site of death. The eating phase: Phosphatidylserine (PS) is the predominant “eat-me” signal utilized by macrophages to identify apoptotic cells. There are two distinct mechanisms by which this process takes place: direct binding of PS to macrophage surface receptors (e.g., Stabilin2, Tim4, and BAI-1), and indirect binding to PS in the presence of bridging molecules. Additionally, calreticulin functions as an eat-me signal by binding directly to LRP1 on the macrophage surface. The digestion phase: phagocytosis follows the canonical process, which involves the gradual transformation of the early phagosome into the late phagosome, with the latter undergoing fusion with the lysosomal compartment so as to form phagolysosomes. The supplemental pathway comprises the phagocytosis mechanism that is facilitated by light chain 3 (LC3) of microtubule-associated protein 1A/1B. The phagocytosed cell corpses are decomposed by proteases and other enzymes contained within the newly formed phagolysosome; the digested products are either excreted from the body or reused by macrophages. Created with BioRender.com.

Fig. 2

The interconnection between efferocytosis and hallmarks of ageing. Efferocytosis and hallmarks of aging interact with each other. As shown in the figure, aging markers interact with each other. On the one hand, they can directly affect the physiological function and polarization of phagocytes represented by macrophages; on the other hand, they can also indirectly affect phagocytes and efferocytosis through inflammatory factors and SASP. Finally, aging markers and efferocytosis jointly promote the occurrence and development of age-related diseases.

Fig. 3

Efferocytosis, ageing and ageing-related diseases. Efferocytosis and ageing markers are correlated and interact with each other, which includes mitochondrial dysfunction, cellular senescence, altered intercellular communication, and chronic inflammation. This eventually leads to a range of age-related diseases. Created with BioRender.com.

Fig. 4

Intervention and treatment opportunities for age-related diseases. The strategies encompassing the promotion of a healthy lifestyle and the implementation of therapeutic interventions, such as small molecules, gene therapies, and cell transplantation, are among the several approaches employed. Created with BioRender.com.