Age-related inflammation triggers skeletal stem/progenitor cell dysfunction

Significance As we age, our capacity for tissue repair and regeneration in response to injury declines. Accordingly, bone repair is delayed and impaired in older patients. At the cornerstone of bone healing is the skeletal stem/progenitor cell (SSPC), whose function and number diminishes with age. However, the mechanisms driving this decline remain unclear. Here, we identify age-associated inflammation (“inflamm-aging”) as the main culprit of SSPC dysfunction and provide support for a central role of NF-κB as a mediator of inflamm-aging. Our results show that modification of the inflammatory environment may be a translational approach to functionally rejuvenate the aged SSPC, thereby improving the regenerative capacity of the aged skeleton. Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.