Macrophage function in the elderly and impact on injury repair and cancer

Abstract

Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6. However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role. In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases/co-morbidities where macrophages are known to play a key role, focussed on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.

Keywords: Age‐related diseases; Cancer; Inflammation; Injury repair; Macrophages.

Fig. 1

Age-related changes to macrophages during musculoskeletal repair and cancer . Following musculoskeletal injury or tumor growth, there may be changes associated with tissue-resident macrophages and tissue site during ageing (1). This may lead to decreased or altered chemotactic signals (2), driven by factors such as CSF-1, CCL2 or CCL5. Bone marrow and splenic myeloid cells are increased during ageing (3) and can supply macrophages to the tumor and injury site, however this could be further impacted by inflammageing factors such as TNF, IL-1β and IL-6. Macrophages during ageing generally display reduced capacity for phagocytosis (4). This may lead to altered transitioning from pro-inflammatory to reparative macrophages (5), which can also be driven by factors such as IL-4, IL-10 and TGF-β1. Studies are conflicting during ageing as to whether there are increased or decreased macrophages following musculoskeletal injury or during tumor growth (6). Age-associated changes are shown as increased (↑); decrease (↓); unknown (?). This Figure was created with BioRender.com

Fig. 2

Strategies to target macrophages during age-related diseases. Potential strategies to target macrophages during ageing could include inhibiting recruitment via CSF-1R blockade (1), restoring metabolic function via inhibition of CD38 (2), targeting inflammageing via rapamycin/senolytics (3), anti-TNF (4), transfer of young serum/plasma/blood products (5), or reducing intracellular MAPK signalling leading to increased efferocytosis (6). Age-associated changes are shown as increased (↑); decrease (↓); unknown (?). This Figure was created with BioRender.com