Cellular senescence is a key driver of age-associated tissue dysfunction through the secretion of pro-inflammatory and pro-senescent factors (SASP). Among these, insulin-like growth factor binding proteins (IGFBPs) have emerged as causal mediators of senescence propagation. Piceatannol (PCT), a naturally occurring stilbene and resveratrol metabolite with superior pharmacokinetic properties, exhibits senomorphic activity in vitro, but its in vivo senotherapeutic potential remains poorly defined. We established a murine model of mild aging using sublethal X-ray irradiation, in which organ function remains largely preserved but molecular and cellular hallmarks of aging, such as senescent cell accumulation, SASP factor elevation, tissue remodeling, and low-grade inflammation, are detectable. This controlled model mimics the early stage of aging seen in many healthy middle-aged individuals, particularly prevalent in Western societies, and provides a relevant platform for testing preventive senotherapeutics. Mice were treated with oral PCT at a human-translatable dose and evaluated for behavioral performance, circulating SASP factors, tissue senescence, inflammation and fibrosis. PCT significantly improved motor coordination and spatial memory while reducing systemic inflammation and circulating SASP factors, including the senescence-propagating IGFBPs IGFBP4, IGFBP5, and IGFBP7. In kidney and heart, the organs most affected by radiation-induced aging, PCT reduced senescent cell burden, CD68⁺ inflammatory foci, fibrotic remodeling, and the senescence markers P53 and P21. PCT also preserved mesenchymal stromal cell clonogenic capacity. These multi-organ benefits were achieved without detectable toxicity in healthy animals. Our findings position PCT as a promising, safe, nutritionally derived senotherapeutic candidate for delaying aging-associated deterioration. This mild aging model, capturing preclinical senescence without overt organ failure, may accelerate the development of interventions aimed at preserving health span in middle-aged populations.
