Platelet factor 4 in cognitive, immune and hematopoietic aging: emerging evidence and translational challenges

Platelet Factor 4 (PF4) is a CXC chemokine abundantly sequestered within platelet α-granules. Its modulatory roles in age-related dysfunction across cognitive, immune, and hematopoietic systems have garnered increasing research attention in recent years. PF4 modulates an array of biological pathways associated with the attenuation of aging-related cellular defects; these pathways are activated by physical activity, young plasma exposure, and Klotho-related signaling cascades. Mechanistically, PF4 engages CXCR3 and LDLR to activate downstream PI3K/Akt and MAPK signaling axes, exerting neuroprotective and immunomodulatory effects and restoring function in aged hematopoietic stem cells (HSCs). Collectively, these actions exert multifaceted effects on aging-associated cellular dysfunction. Within the central nervous system, PF4 mitigates hippocampal neuroinflammation, enhances synaptic plasticity, and promotes adult hippocampal neurogenesis to ameliorate age-dependent learning and memory deficits. In the peripheral immune system, PF4 restores balanced T-cell subset distribution and reduces circulating levels of pro-senescent inflammatory mediators. Within the bone marrow hematopoietic niche, PF4 preserves HSC quiescence, facilitates DNA damage repair, and maintains lymphoid differentiation potential. Clinical observational studies have identified correlations between circulating PF4 levels and multiple age-associated pathologies, including Alzheimer's disease, sarcopenia, stroke, and coronary artery disease, suggesting its potential as an adjunct diagnostic biomarker. Nevertheless, published findings regarding age-related changes in PF4 levels remain inconsistent, largely due to heterogeneous sample preparation protocols and detection methodologies. Furthermore, PF4 carries inherent thrombotic, profibrotic, and autoantigenic risks. Unresolved questions surrounding long-term safety, standardized dosing regimens, and tissue-targeted delivery systems represent major barriers to clinical translation. This review systematically delineates the multilayered modulatory mechanisms of PF4 in age-related cognitive, immune, and hematopoietic dysfunction, as well as its translational prospects, unresolved discrepancies, and key research gaps. We further outline prospective research directions, including protein structural optimization, refined targeted delivery strategies, and combinatorial intervention regimens, to establish a theoretical framework for future preclinical studies of PF4 as a modulator of discrete aging-related cellular phenotypes.