Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain

Abstract

<jats:p>Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.</jats:p>

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

“…Palmitoyl-protein thioesterase 1 (Ppt1) removes thioester-linked fatty acyl groups like palmitate from modified cysteine residues during lysosomal degradation of proteins [59]. Finally, glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans (GPI-anchor) to release proteins from the membrane and has recently been linked to the cognitive benefits of exercise for the aged brain [49]. Of note, earlier work found that loss of PGRN leads to an accumulation of polyunsaturated triacylglycerides and reduced diacylglycerides and phosphatidylserines in Grn −/− fibroblasts and mouse brains [29].…”

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation

“…This growing body of work positions O-GlcNAcylation, STAT3 signaling and the balance between newly generated neurons and astrocytes as a focal point in combating age-related functional decline in the aging and diseased brain. Of note, the benefits of interventions that ameliorate cognitive-decline during aging and Alzheimer’s disease, such as exercise, have been shown to involve increased adult neurogenesis ( 37 , 38 ). Given recent observations of the persistence of adult neurogenesis in the aged human brain ( 13 , 14 ), the promise of restoring cellular and cognitive plasticity in the elderly by targeting adult NSCs is increasingly evident.…”

A new player in the beneficial effects of exercise on the aged brain

“…They show that full integrity of the catalytic activity of Gpld1, which activates downstream pathways related to coagulation cascades, is required to achieve the aforementioned effects. 1 The data obtained by Horowitz et al bring to light the intricate complexity of the brain-body axis and how physical exercise reshapes several aspects of this (bi)directional communication.…”

“…They also demonstrate the importance of this liver-to-brain axis in ameliorating age-related regenerative and cognitive impairments. 1 Physical activity exerts numerous beneficial actions on the brain and body. Exercise improves cardiovascular fitness and ameliorates metabolic syndrome, and other conditions related to a sedentary lifestyle.…”

“…Previous work by Villeda et al 5 demonstrated that transferring blood from young to aged mice rejuvenates the systemic inflammatory milieu, increases AHN and improves cognition. The new study by Horowitz et al 1 takes one step further and shows that the beneficial effects of physical exercise on AHN and cognition can be transferred to sedentary aged mice by injecting them with the plasma of exercised animals (Fig. 1).…”