The aging secretome as a candidate driver of bone remodeling imbalance: myokines, adipokines, and senescence-associated secretory factors
TL;DR
The aging secretome should be viewed as an organizing framework whose individual pathways and relative contributions require further validation in human bone, and provides a common context for comparing pathway-specific interventions, such as activin type II receptor blockade and sclerostin inhibition, with broader approaches targeting senescence or inflammation.
Abstract
Bone homeostasis depends on the spatial and temporal coupling of osteoclastic resorption to osteoblastic formation. With aging, this balance shifts toward net bone loss alongside sarcopenia, marrow adipose expansion, and chronic low-grade inflammation. These parallel changes may be linked by a shared set of secreted signals, termed here the aging secretome. We distinguish functional remodeling imbalance, defined as a sustained shift between formation and resorption, from direct uncoupling, in which a resorption-to-formation coupling signal is demonstrably disrupted. The aging secretome comprises three principal arms: muscle-derived signals, including myostatin, irisin, and myogenic extracellular vesicles; fat-derived signals, including leptin, adiponectin, and marrow adipocyte lipotoxicity; and senescence-associated secretory factors, particularly those involving senescent osteocytes, TNF-α, and IL-6. Inflammaging is treated as a shared contextual amplifier rather than a separate signaling arm. These pathways converge on key regulators of skeletal remodeling, including RANKL, Wnt–sclerostin, and IGF-1. This framework also provides a common context for comparing pathway-specific interventions, such as activin type II receptor blockade and sclerostin inhibition, with broader approaches targeting senescence or inflammation. An early phase 2 senolytic trial was negative overall, with only an exploratory signal in women with high senescent-cell burden. The aging secretome should therefore be viewed as an organizing framework whose individual pathways and relative contributions require further validation in human bone.