Ageing-related bone and immunity changes: insights into the complex interplay between the skeleton and the immune system

Abstract

Ageing as a natural irreversible process inherently results in the functional deterioration of numerous organ systems and tissues, including the skeletal and immune systems. Recent studies have elucidated the intricate bidirectional interactions between these two systems. In this review, we provide a comprehensive synthesis of molecular mechanisms of cell ageing. We further discuss how age-related skeletal changes influence the immune system and the consequent impact of immune system alterations on the skeletal system. Finally, we highlight the clinical implications of these findings and propose potential strategies to promote healthy ageing and reduce pathologic deterioration of both the skeletal and immune systems.

Fig. 1

Age-related transformations in bone structure involve a decrease in bone mass and alterations in microarchitecture. The ageing process results in a reduction in the population of MSCs and osteoblasts, while there is an increase in osteoclasts and adipocytes, along with heightened levels of pro-inflammatory cytokines

Fig. 2

Aged-related changes on bone cell. During the ageing process, BMSCs experience ageing, which triggers the activation of NF-κB, leading to ROS production, thereby inhibits osteoblast precursor differentiation. This phenomenon is further exacerbated by elevated levels of CCL2 and CCL5, which contribute to the ageing of osteoblasts. Moreover, the decline in the levels of Sirt in aged MSCs promotes adipocyte differentiation. This results in an increase in ROS levels, leading to adipocyte ageing. This, in turn, contributes to secondary ageing in osteoblasts and vascular cells. The cumulative effect of these changes includes increased production of inflammatory cytokines and reduced oxygen availability in the vasculature, resulting in vascular stiffness and a disruption of blood flow within the bone microenvironment. Furthermore, a deficiency in molecular cathepsin K and integrins may lead to ageing in osteoclasts while preserving their bone resorption capacity

Fig. 3

Age-related alterations affect both the adaptive and innate immune systems. In the adaptive immune system, there is a decline in the population of naive CD4⁺ T cells, CD8⁺ T cells, Treg cells, and B cells, whereas memory cells become more prevalent. In the innate immune system, the functionality of monocytes/macrophages is compromised, and neutrophils exhibit reduced capabilities in terms of NET formation, phagocytosis, and chemotaxis, along with an increased susceptibility to apoptosis. Furthermore, there is an increase in CD56^dim NK cells and a decrease in CD56^bright NK cells. The population of dendritic cells also decreases, and their anti-phagocytic abilities weaken with age

Fig. 4

Aged bone marrow cells secrete SASP, with IL-6, IL-8, and IL-15 promoting inflammation and negatively impacting immune cell functions, including T cells, dendritic cells, B cells, NK cells, and neutrophils

Fig. 5

Immune cell ageing is marked by distinctive features, including mitochondrial dysfunction, DNA damage, cell cycle arrest, telomere dysfunction, and elevated levels of reactive oxygen species (ROS) and SASP factors. Moreover, aged immune cells release detrimental cytokines, contributing to an increased presence of osteoclasts and adipocytes while diminishing osteocyte numbers, consequently resulting in the development of bone fragility