Senescent Mesenchymal Stromal Cells Drive Stem Cell Aging Through Dysregulated Chemokine Synthesis

ABSTRACT Aging is accompanied by a progressive decline in tissue regenerative capacity, driven by intrinsic stem cell dysfunction and age‐associated deterioration of the surrounding stem cell niche. Mesenchymal stromal cells (MSCs) are ubiquitous components of stem cell niches, where they integrate structural, metabolic, inflammatory, and paracrine cues to regulate stem cell quiescence, activation, and differentiation. With age, MSCs undergo functional decline and senescence, altering their secretory and signaling profiles. Across tissues, MSC senescence emerges as an intermediate amplifier of aging: molecular, metabolic, epigenetic, and inflammatory stressors promote the senescent state, which converts these upstream insults into chemokine imbalance, chronic inflammation, and progressive loss of stem cell support. Here, we synthesize classical and emerging literature to examine how age‐associated changes in MSC chemokine synthesis contribute to stem cell aging, and we propose a synthesis‐based model in which MSCs translate age‐associated stressors into altered chemokine repertoires that disrupt stem cell‐supportive signaling. We also discuss therapeutic strategies, including chemokine‐directed therapies, senolytics, and MSC rejuvenation, that may restore regenerative capacity by normalizing MSC‐derived signals. Together, the evidence identifies dysregulated chemokine synthesis as a conserved mechanism linking tissue‐resident MSC aging to declining regenerative capacity.