Calorie restriction alleviates the age‐related decrease in neural progenitor cell division in the aging brain

Abstract

Production of new neurons from stem cells is important for cognitive function, and the reduction of neurogenesis in the aging brain may contribute to the accumulation of age-related cognitive deficits. Restriction of calorie intake and prolonged treatment with rapamycin have been shown to extend the lifespan of animals and delay the onset of age-related decline in tissue and organ function. Using a reporter line in which neural stem and progenitor cells are marked by the expression of GFP, we examined the effect of prolonged exposure to calorie restriction (CR) or rapamycin on hippocampal neural stem and progenitor cell proliferation in aging mice. We show that CR increases the number of dividing cells in the dentate gyrus (DG) of female mice. The majority of these cells corresponded to Nestin-GFP-expressing neural stem or progenitor cells; however, this increased proliferative activity of stem and progenitor cells did not result in a significant increase in the number of doublecortin-positive newborn neurons. Our results suggest that restricted calorie intake may increase the number of divisions that neural stem and progenitor cells undergo in the aging brain of females.

Cholesterol metabolism changes under long-term dietary restrictions while the cholesterol homeostasis remains unaffected in the cortex and hippocampus of aging rats

“…In the light of recent findings that prolonged exposure to DR increases both the total number of dividing and progenitor cells in the dentate gyrus, the neurogenesis niche in adult rats (Couillard-Despres et al 2011;Park et al 2013), the abovementioned properties of desmosterol may suffice to increase the pool of membrane-active brain sterols. Furthermore, in DHCR24 −/− (24-dehydrocholesterol reductase) mice lacking cholesterol, desmosterol accounts for 99 % of the total sterols, indicating that this precursor takes over the function of cholesterol despite differences in their biophysical and functional properties (Wechsler et al 2003;Vainio et al 2006).…”

“…This could be attributed, at least in part, to neurogenesis that takes place in the adult dentate gyrus (Couillard-Despres et al 2011). Accordingly, the DR-induced increase in desmosterol concentration in the aging hippocampus could at least in part correlate with the increased number of progenitor cells differentiating into neurons following DR (Park et al 2013). Furthermore, the different responses of the key proteins involved in cholesterol homeostasis in the cortex and hippocampus to DR reported herein could be attributed to the specific requirements for cholesterol in different brain regions Trapani and Pallottini 2010;Segatto et al 2012;Perovic et al 2009).…”

“…Both of these brain regions exhibit high responsiveness to the beneficial effects of DR. Studies on the rodent central nervous system (CNS) have revealed that long-term DR can improve learning and memory, and diminish age-related behavioral impairments and cognitive decline (Means et al 1993;Halagappa et al 2007;Adams et al 2008) caused by disruptions of the pivotal brain functions associated with the cortex and hippocampus. Furthermore, DR alleviates t he decline in hippocampal neurogenesis (Park et al 2013) and counteracts the age-related decrease of synaptic plasticity (Fontán-Lozano et al 2008;Mladenovic Djordjevic et al 2010).…”

Long-term intermittent feeding restores impaired GR signaling in the hippocampus of aged rat

“…Among those, we and others have reported that DR promotes neurogenesis [29], enhances plasticity [30,31], and retards ageassociated brain functional impairments [32][33][34]. The exceptionally diverse anti-aging and neuroprotective properties of DR are probably linked to its ability to recruit adaptive cellular stress responses and to modulate the neuroendocrine system both of which are impaired in aged animals.…”

Viral and Transgenic Reporters and Genetic Analysis of Adult Neurogenesis

“…Thus, the use of reporter mice enables efficient dissection of the neuronal differentiation cascade in the DG into distinct steps and assembly of a detailed scheme of entire cascade (Encinas et al 2006(Encinas et al , 2011bEncinas and Enikolopov 2008). As a following step, this scheme can be used to determine the classes of stem and progenitor cells in the DG that are affected by various pro-and antineurogenic factors and stimuli (for examples of such analyses, see Encinas et al 2006Encinas et al , 2011aPark et al 2013).…”