The aging of the immune system arises from the underlying causes of aging, but in and of itself causes significant further pathology. Here, for example, researchers discuss immune aging as a shared underlying cause of degenerative conditions of bone and joint tissues, and how this relates to the more traditional view of the cause of these conditions. In general, aging is not a neat straight line of cause and consequence, but rather a network of interacting processes of damage and dysfunction. In many cases the consequence can accelerate the cause. Consider senescent cells, for example, implicated in degenerative bone and joint conditions: the accumulation of senescent cells contributes to immune aging, which is a matter of both cellular senescence in immune cell populations and inflammatory signaling generated by senescent cells of all types, but immune aging is also one of the factors that allows senescent cells to accumulate, as the immune system is responsible for clearing senescent cells.
Traditional views often attribute osteoporosis to an imbalance in bone remodeling, estrogen deficiency, and increased bone resorption, while osteoarthritis is considered the result of abnormal mechanical loading, cartilage degeneration, and abnormal subchondral bone remodelin. However, osteoporosis (OP) and osteoarthritis (OA) are not simple manifestations within the same disease spectrum but are disease entities with different pathological scales and tissue characteristics: OP reflects systemic bone metabolic abnormalities and decreased bone strength, whereas OA primarily manifests as local joint structural degeneration and dysfunction.
Despite their significant differences, traditional mechanisms are still insufficient to fully explain their frequent co-occurrence and mutual influence in the elderly population. In recent years, an increasing number of studies have suggested that inflammaging, immune imbalance, oxidative stress, mitochondrial dysfunction, and metabolic abnormalities may constitute an important pathological background for their common progression. Among these, inflammaging, as a key biological feature of aging, can provide a new perspective for understanding the pathological link between the two by affecting bone remodeling, cartilage homeostasis, and the local immune microenvironment.
The osteochondral unit, composed of articular cartilage, calcified cartilage, and subchondral bone, is an important structural basis for maintaining joint mechanical transmission and tissue homeostasis. Recent studies have found that bone and joint tissues are not independent pathological units but form a dynamic interaction network through cell communication, immune regulation, and changes in metabolic status. Therefore, bone loss and joint degeneration may not occur completely independently but influence each other against the background of common microenvironmental changes and cellular functional imbalances.
Immune metabolic reprogramming provides a new theoretical framework for understanding OP-OA comorbidity. The metabolic status of immune cells and osteochondral-related cells can affect their functional phenotypes and participate in bone remodeling, inflammatory regulation, and tissue repair processes. In recent years, alterations in glycolysis, oxidative phosphorylation, lipid metabolism, and NAD+-related metabolic regulation have been implicated in bone metabolic imbalance in OP and in cartilage and synovial pathology in OA, respectively. However, current evidence mainly comes from studies focusing on OP or OA in isolation, and there is still insufficient evidence to establish that these form a common causal regulatory network in human OP-OA comorbidity. Therefore, immune metabolic reprogramming is more suitable as a candidate integrative framework for explaining the links among inflammaging, bone metabolic abnormalities, and osteochondral unit imbalance, rather than an established comorbidity-driving mechanism.
Link: https://doi.org/10.3389/fimmu.2026.1941310
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