Elsevier

Neurobiology of Aging

Volume 25, Issue 3, March 2004, Pages 333-340
Neurobiology of Aging

Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice

https://doi.org/10.1016/S0197-4580(03)00083-6Get rights and content

Abstract

Age-related changes in neurogenesis and its modulation by caloric restriction (CR) were studied in C57BL/6 mice. To this end, bromodeoxyuridine (BrdU) labeling was used to assess neuronal and glial precursor proliferation and survival in the granular cell layer (GCL) and the hilus of the dentate gyrus of 2-, 12-, 18-, and 24-month-old mice. For both regions, we found an age-dependent decrease in proliferation but not in survival of newborn cells. Interestingly, the reduction in proliferation occurred between 2 and 18 months of age with no additional decline between 18- and 24-month-old mice. Phenotyping of the newborn cells revealed a decrease in the neuron fraction in the GCL between 2 and 12 months of age but not thereafter. The majority of BrdU cells in the hilus colocalized with astrocytic but none with neuronal markers. CR from 3 to 11 months of age had no effect on neurogenesis in the GCL, but had a survival-promoting effect on newly generated glial cells in the hilus of the dentate gyrus. In conclusion, C57BL/6 mice reveal a substantial reduction in neurogenesis in the dentate gyrus until late adulthood with no further decline with aging. Long-term CR does not counteract this age-related decline in neurogenesis but promotes survival of hilar glial cells.

Introduction

The vast majority of cells in the CNS are generated during the embryonic and early postnatal period, but new neurons are continuously added in selected regions of the mammalian brain [2], [10], [13], [19], [22]. Neurogenesis has been described in the subgranular layer of the dentate gyrus [2], [18] and the subventricular zone of the lateral ventricle [3], [21], [27]. Newborn cells in the subgranular layer migrate into the granule cell layer (GCL), where a portion differentiates into neurons, which then extend axons to the CA3 region [14], [30], [43]. Although the functional significance of this ongoing neurogenesis in the dentate gyrus remains to be fully established, evidence has been provided that newly produced neurons play an important role in learning and memory [4], [37], [42]. Because a decline of neurogenesis in the dentate gyrus has been reported with aging [12], [22], a relationship between the age-related decline in neurogenesis and age-dependent cognitive impairments may be suggested [8].

In numerous rodent studies, caloric restriction (CR) has been shown to extend life span, postpone the onset of age-related changes including brain aging, and maintain physiological function at more youthful levels [31], [38]. Thus, it is tempting to speculate that CR may also postpone the age-related decline in neurogenesis. Indeed, short-term CR has been reported to increase neurogenesis in the dentate gyrus of young mice and rats [24], [25].

The aim of the present study was to investigate the effects of aging and CR on neurogenesis in the dentate gyrus of C57BL/6 mice. C57BL/6 mice were selected because this mouse strain has become the most common background for genetically engineered mouse models of age-related neurodegenerative diseases [16], [17]. Moreover, we have previously assessed age-related changes in granule cell number in the dentate gyrus of this mouse strain [7] and thus have provided a basis for the interpretation of age-related changes in neurogenesis in the dentate gyrus of C57BL/6 mice.

Section snippets

Animals

To study age-related changes in neurogenesis, 2-month-old (n=11), 12-month-old (n=13), 18-month-old (n=11), and 24-month-old mice (n=5) male C57BL/6 mice were used. Their respective mean body weights were: 24.4, 31.5, 32.6, and 32.0 g (S.E.M. ±0.7 to ±1.3 g). To examine the effects of the diet manipulation on aging, 11-month-old C57BL/6 mice ad libitum (AL) fed (n=13) and caloric restricted (n=9) were used. Their respective mean body weights were: AL fed, 31.3±0.7 g; CR, 23.8±0.5 g. CR was

Aging and neurogenesis

To study the impact of aging on neurogenesis in the dentate gyrus, C57BL/6 mice of four age groups (2-, 12-, 18-, and 24-month-old) were analyzed 2 h and 4 weeks after the last BrdU injection. Two hours post-BrdU, cell proliferation was predominantly conferred to the subgranular layer (Fig. 1A, C, and E). The BrdU-positive nuclei were often clustered in the subgranular layer and exhibited variable shapes. In contrast, the majority of BrdU-labeled cells 4 weeks after BrdU treatment were located

Discussion

In the present study, we have investigated the impact of aging and CR on neurogenesis in the dentate gyrus of C57BL/6 mice. Proliferation of BrdU-positive cells was assessed 2 h post-BrdU, whereas a 4-week survival period was used to examine cell survival and differentiation.

Acknowledgements

This work was supported by grants from the Roche Research Foundation and the Swiss National Science Foundation.

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    1

    Contributed equally.

    2

    Present address: Medical Teaching Facility, School of Medicine, University of California, San Diego, La Jolla, CA, USA.

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