Aging is a gradual process involving the decline of both physiological and psychological aspects in humans. This progression is influenced by several key factors, including cellular senescence, chronic inflammation, and altered intercellular communication, among others (Lopez-Otin et al., 2023). Cellular senescence, first described in 1961, is defined as a permanent state of cell cycle arrest, which is influenced by senescent cells and the microenvironment they reside in. In addition to senescent cells, the senescent microenvironment encompasses both cellular and acellular elements, comprising blood vessels, fibroblasts, immune cells, and the extracellular matrix. Immunosenescence, characterized by the deterioration in the structure and function of the body's immune system, manifests as an accumulation of memory and non-functional immune cells, compromised signaling due to a limited repertoire of receptors, an overall pro-inflammatory milieu, and complete dysregulation of the immune system. Infiltrating macrophages and tissue-resident macrophages are major constituents of the senescent microenvironment, indicating that macrophages are critical mediators of immunosenescence (Burton and Stolzing, 2018).

Macrophages (also called phagocytes), with a stellate morphology and high phagocytic activity, are key players in the regulation of innate and adaptive immunity. Initially, through the ingestion of particles and/or other cells, phagocytosis was heralded as a protective mechanism against pathogens (Metchnikoff, 1907). In most aging-related disorders, macrophage dysfunctions have been associated with degenerative lesions in tissues or organs, limited therapeutic responses, and poor prognostic outcomes. Senescence-associated macrophages are not a homogeneous cell population but a highly dynamic, heterogeneous population that is regulated by specific local stimuli. Macrophages possess the capacity to perceive and react to the microenvironments within all organs, participating in a multitude of cellular processes (Guilliams et al., 2022, Qi et al., 2022). This establishes them as more than just innate immune cells (Mosser et al., 2021). The phenotypes of macrophages exhibit significant adaptability and are subject to influence from diverse factors, encompassing microenvironmental cues, immune conditions, tumor presence, and hypoxic conditions (Dong et al., 2021). Moreover, various endogenous and exogenous stresses, such as telomere dysfunctions, DNA damage, and oncogenesis activate cellular senescence, which is characterized by irreversible growth arrest and senescent phenotypes. The senescent cell motility and microenvironment sensing are reshaped by senescence-associated secretory phenotypes (SASPs), a new mechanism that links senescence to tissue malfunction (He and Sharpless, 2017, Malaquin et al., 2019). SASP, which is characterized by a substantial increase in pro-inflammatory factors, contributes to a progressive decline in the functional capacity of organ systems. Aberrant accumulation of SASP from senescent or damaged cells is associated with ageing and contributes to frailty as well as age-associated disorders, including cancer, autoimmunity, cardiovascular disease, and degenerative diseases (He and Sharpless, 2017, Lewis-McDougall et al., 2019).

During ageing, clearance of aged and senescent cells is vital for inhibiting their harmful effects (Ge et al., 2021). Macrophage recruitment and interactions with SASP senescent cells is crucial for the maintenance of tissue homeostasis (Huang et al., 2021). Removal of aged and senescent cells by macrophages (along with other immune cells) is a continuous process that recycles about 2 million red blood cells each second, and releases their iron into the systemic iron pool (Hampton-O'Neil et al., 2020, Korolnek and Hamza, 2015). Apart from phagocytosis, studies have revealed links between tissue homeostasis, and inflammasome activation (Camell et al., 2017), autophagy (Chen et al., 2022), as well as efferocytosis (Juhas et al., 2018), indicating that macrophages have efficacious regulatory mechanisms in response to senescence microenvironments. Thus, the ability of macrophages to sense and alter cell states in senescence microenvironments can be leveraged to develop strategies for improving the diagnosis, prognosis, and treatment of various diseases, including ageing and age-associated disorders.

The growing field of immune-targeted therapies has elucidated on how various novel treatments influence the host immune system. However, the high plasticity and heterogeneity of macrophages are practical obstacles in development of anti-ageing therapies (Blacher et al., 2022). Recently, macrophage immunotherapy, aimed at ablation or re-education of macrophages (Ramesh et al., 2021), has emerged as a powerful component of combination therapies designed to target senescent cells and reverse cognitive ageing (Minhas et al., 2021), and to inhibit cancer development (Li et al., 2019). Most of the published reviews on senescence-associated macrophages have focused on how they modulate microenvironment inflammation (Neves and Sousa-Victor, 2020), influence cell senescence (Campbell et al., 2021), or on how they interplay with senescent cells (Behmoaras and Gil, 2021). A limited number of reviews have discussed the application of macrophage-specific therapies in the treatment of cancer (Belgiovine et al., 2016), age-related liver diseases (Stahl et al., 2018), and metabolic diseases (Peterson et al., 2018). Furthermore, the exact importance of macrophages in anti-aging strategies remains incompletely understood. We discuss several therapeutic mechanisms underlying the anti-ageing effects of macrophages, as well as the clinical strategies and future directions in the study of macrophages in senescence and associated disorders.