PF4 in rejuvenation therapy: neuroprotection and cognitive enhancement

Abstract

Platelet factor 4 (PF4), a platelet-derived chemokine found in the blood, has been identified as a critical factor in modulating the rejuvenation of the aged brain. Increasing evidence suggests that PF4 secretion is a prerequisite for the cognitive benefits associated with young blood transfusion, the longevity factor klotho, and exercise. Systemic administration of exogenous PF4 has been shown to reduce circulating pro-aging immune factors and restore peripheral immune function in the aged brain by mitigating age-related hippocampal neuroinflammation, promoting molecular changes in synaptic plasticity, and improving cognitive function in aged mice. Clinically, reduced serum PF4 levels have been significantly associated with cognitive decline and core pathological biomarkers in Alzheimer’s disease. Mechanistically, the chemokine receptor CXCR3 partially mediates the cellular, molecular, and cognitive benefits of systemic PF4 administration in the aged brain. However, several critical questions remain, including the potential role of PF4 in blood–brain communication, its interaction with neurotransmitters and neuropharmacological processes, and how these findings might be translated into clinical practice. Further detailed studies are needed to validate and expand upon these insights for therapeutic application.