Exercise-induced Circulating Blood Factors Mediate the Benefits of Exercise on the Aged Brain

Author(s): Horowitz, Alana Michelle | Advisor(s): Dubal, Dena | Abstract: Aging is associated with cognitive decline in otherwise healthy older adults. As human lifespan increases, a larger portion of the population is thus at risk for impaired cognition. This highlights the need for therapeutic approaches that restore functionality to the aged brain. The ability to reverse brain aging through systemic interventions such as exercise could provide a unique therapeutic approach to mitigate this vulnerability to cognitive decline. While exercise has long been reported to rejuvenate the aged brain, identification of therapeutic targets by which to transfer such benefits remains elusive. Work by our lab and others has demonstrated that complementary systemic manipulations, such as heterochronic parabiosis (in which the circulatory systems of young and old animals are joined), function through blood-borne factors to rejuvenate regenerative and cognitive capacity in aged mice. Given parallels between the effects of exercise and heterochronic parabiosis, we hypothesized that exercise-induced circulating blood factors could confer the benefits of exercise to the aged brain. Here, we report that circulating factors in blood plasma transfer the rejuvenating effects of exercise on adult neurogenesis and cognitive function to aged mice. We demonstrate that exercise modulates the circulating factors present in blood plasma, and that administration of exercise plasma into sedentary aged mice enhances neurogenesis and cognition. Using mature and aged mice as plasma donors, we show that circulating blood factors mediate the benefits of exercise across ages. Using mass spectrometry, we identify glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) as a liver-derived, exercise-induced circulating blood factor. We demonstrate that increasing systemic Gpld1 in aged mice ameliorates age-related regenerative and cognitive impairments by altering signaling cascades downstream of glycosylphosphatidylinositol (GPI)-anchored substrate cleavage in the aging systemic milieu. Further, we confirm that the enzymatic activity of Gpld1 directly mediates its effects on adult neurogenesis and cognitive function. Altogether, our data identify a liver-brain rejuvenation axis by which blood-based interventions can transfer the benefits of exercise to the aged brain.