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A deterioration in cognitive performance accompanies brain aging, even in the absence of neurodegenerative pathologies. However, the rate of cognitive decline can be slowed down by enhanced cognitive and sensorimotor stimulation protocols, such as environmental enrichment (EE). Understanding how EE exerts its beneficial effects on the aged brain pathophysiology can help in identifying new therapeutic targets. In this regard, the inflammatory chemokine ccl11/eotaxin-1 is a marker of aging with a strong relevance for neurodegenerative processes. Here, we demonstrate that EE in both elderly humans and aged mice decreases circulating levels of ccl11. Interfering, in mice, with the ccl11 decrease induced by EE ablated the beneficial effects on long-term memory retention, hippocampal neurogenesis, activation of local microglia and of ribosomal protein S6. On the other hand, treatment of standard-reared aged mice with an anti-ccl11 antibody resulted in EE-like improvements in spatial memory, hippocampal neurogenesis, and microglial activation. Taken together, our findings point to a decrease in circulating ccl11 concentration as a key mediator of the enhanced hippocampal function resulting from exposure to EE. A deterioration in cognitive performance accompanies brain aging, even in the absence of neurodegenerative pathologies. However, the rate of cognitive decline can be slowed down by enhanced cognitive and sensorimotor stimulation protocols, such as environmental enrichment (EE). Understanding how EE exerts its beneficial effects on the aged brain pathophysiology can help in identifying new therapeutic targets. In this regard, the inflammatory chemokine ccl11/eotaxin-1 is a marker of aging with a strong relevance for neurodegenerative processes. Here, we demonstrate that EE in both elderly humans and aged mice decreases circulating levels of ccl11. Interfering, in mice, with the ccl11 decrease induced by EE ablated the beneficial effects on long-term memory retention, hippocampal neurogenesis, activation of local microglia and of ribosomal protein S6. On the other hand, treatment of standard-reared aged mice with an anti-ccl11 antibody resulted in EE-like improvements in spatial memory, hippocampal neurogenesis, and microglial activation. Taken together, our findings point to a decrease in circulating ccl11 concentration as a key mediator of the enhanced hippocampal function resulting from exposure to EE.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.