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

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          Abstract

          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.

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          Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

          Saul Villeda, Kristopher E Plambeck, Jinte Middeldorp … (2014)
          As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
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            Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging.

            Sebastian Lugert, Onur Basak, Philip Knuckles … (2010)
            New neurons are generated in the adult hippocampus throughout life by neural stem/progenitor cells (NSCs), and neurogenesis is a plastic process responsive to external stimuli. We show that canonical Notch signaling through RBP-J is required for hippocampal neurogenesis. Notch signaling distinguishes morphologically distinct Sox2(+) NSCs, and within these pools subpopulations can shuttle between mitotically active or quiescent. Radial and horizontal NSCs respond selectively to neurogenic stimuli. Physical exercise activates the quiescent radial population whereas epileptic seizures induce expansion of the horizontal NSC pool. Surprisingly, reduced neurogenesis correlates with a loss of active horizontal NSCs in aged mice rather than a total loss of stem cells, and the transition to a quiescent state is reversible to rejuvenate neurogenesis in the brain. The discovery of multiple NSC populations with Notch dependence but selective responses to stimuli and reversible quiescence has important implications for the mechanisms of adaptive learning and also for regenerative therapy.
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              Running enhances spatial pattern separation in mice.

              D. Creer, C Romberg, L Saksida … (2010)
              Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.
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                Author and article information

                Journal
                Title: Science
                Abbreviated Title: Science
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date Created: July 09 2020
                Publication date Created: July 10 2020
                Publication date (Electronic): July 09 2020
                Publication date (Print): July 10 2020
                Volume: 369
                Issue: 6500
                Pages: 167-173
                Affiliations
                [1 ]Department of Anatomy, University of California, San Francisco, CA, USA.
                [2 ]Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
                [3 ]Department of Neurology, University of California, San Francisco, CA, USA.
                [4 ]Memory and Aging Center, University of California, San Francisco, CA, USA.
                [5 ]Sandler-Moore Mass Spectrometry Core Facility, University of California, San Francisco, CA, USA.
                [6 ]Department of Physical Therapy and Rehabilitation Science, San Francisco, CA, USA.
                [7 ]Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA.
                Article
                DOI: 10.1126/science.aaw2622
                PMC ID: 7879650
                PubMed ID: 32646997
                SO-VID: fc0708ca-66cd-4fb3-be71-330f5d9717f7
                Copyright © © 2020
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                https://www.sciencemag.org/about/science-licenses-journal-article-reuse

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