Discussion
Cumulatively, our data show that beneficial effects of exercise on the aged brain can be transferred through administration of blood components. We identified the liver-derived factor Gpld1 as one such factor, and we sus- pect that signaling cascades activated by GPI- anchored substrate cleavage activity may also participate. Our results identify a liver-to-brain axis by which circulating blood factors confer the beneficial effects of exercise in old age.
Adult neurogenesis in humans remains controversial (32). Nonetheless, adult neurogenesis is reported in the human hippocampus through the ninth decade of life, with age- related decline exacerbated in Alzheimer’s disease (AD) patients (33) and correlating with cognitive dysfunction (34). In the context of dementia-related neurodegenerative diseases, exercise is correlated with reduced risk for cognitive decline in the elderly, improves cognition in populations at risk for AD, and is associated with better neurobehavioral outcomes even in autosomal dominant AD (35–37). Exercise ameliorates impairments in learning and memory in animal models of AD (38, 39) by increasing adult neurogenesis and abundance of BDNF in the aged hippocampus (39)—benefits that we found to be transferred with injected plasma.
Our data identify decreased uPAR signaling, and associated changes in the coagulation and complement system cascades, as potential pro- aging molecular targets. The effects of liver- derived Gpld1 and exercise are likely the result of changes in multiple signaling cascades. However, a prominent role is emerging for the coagulation and complement pathways in aging. Changes in the coagulation pathway have been identified as part of the senescence- associated secretory phenotype (SASP) (40), and blood-derived complement C1q promotes age-related regenerative decline in peripheral tissues (41). The benefits of targeting members of the coagulation pathway modulated by Gpld1 have been reported in the context of neurodegeneration (42). Genetic mouse models deficient for Plg were protected from demyelination and paralysis in a mouse model of multiple sclerosis (43). Moreover, targeting blood-derived Plg through oligonucleotide technologies decreased amyloid b plaque deposition and neuropathology in a mouse model of AD (42). Given that transfer of young blood simultaneously elicits central (3, 9) and peripheral (44–46) enhancements in regenerative capacity in aged mice, our data raise the possibility that the beneficial effects of exercise could be promoted broadly across tissues through circulating blood factors.
