Aging and Exercise Affect Hippocampal Neurogenesis via Different Mechanisms

<div><p>The rate of neurogenesis is determined by 1) the number of neural stem/progenitor cells (NSCs), 2) proliferation of NSCs, 3) neuron lineage specification, and 4) survival rate of the newborn neurons. Aging lowers the rate of hippocampal neurogenesis, while exercise (Ex) increases this rate. However, it remains unclear which of the determinants are affected by aging and Ex. We characterized the four determinants in different age groups (3, 6, 9, 12, 21 months) of mice that either received one month of Ex training or remained sedentary. Bromodeoxyuridine (BrdU) was injected two hours before sacrificing the mice to label the proliferating cells. The results showed that the number of newborn neurons massively decreased (>95%) by the time the mice reached nine months of age. The number of NSC was mildly reduced during aging, while Ex delayed such decline. The proliferation rates were greatly decreased by the time the mice were 9-month-old and Ex could not improve the rates. The rates of neuron specification were decreased during aging, while Ex increased the rates. The survival rate was not affected by age or Ex. Aging greatly reduced newborn neuron maturation, while Ex potently enhanced it. In conclusion, age-associated decline of hippocampal neurogenesis is mainly caused by reduction of NSC proliferation. Although Ex increases the NSC number and neuron specification rates, it doesn't restore the massive decline of NSC proliferation rate. Hence, the effect of Ex on the rate of hippocampal neurogenesis during aging is limited, but Ex does enhance the maturation of newborn neurons.</p></div

Effects of age and running exercise (Ex) on the maturation of newborn neurons.

<p><b>A</b>) Representative micrographs of DCX⁺ immature neurons in the dentate gyrus of the 9 and 21-month-old mice that received or did not receive Ex training. Examples of tracings (blue line) are used to measure the quality of dendrite of DCX⁺ immature neurons. Sed: sedentary group. Scale bar: 20 μm. <b>B</b>) Quantitative results of the number of branches of DCX⁺ dendrite. <b>C</b>) Quantitative results of the total length of DCX⁺ dendrite. **: Bonferroni post-hoc test: p < 0.01 vs. respective Sed group.</p

Effects of age and running exercise (Ex) on the proliferation rate, neuron lineage specification rate and survival rate of adult hippocampal neurogenesis.

<p><b>A</b>) Proliferation rate, estimated by dividing the number of BrdU⁺ cells by the number of nestin⁺ cells. <b>B</b>) Neuron lineage specification rate, estimated by dividing the number of BrdU⁺DCX⁺ cells by the number of BrdU⁺ cells. <b>C</b>) Survival rate, estimated by dividing the number of BrdU⁺ cells, 2 h after BrdU injection, by the number of BrdU⁺ cells 1 month after BrdU injection.</p

Effects of age and running exercise (Ex) on the number of newly proliferated cells and that of immature neurons in the adult hippocampus.

<p>Representative micrographs of BrdU⁺ newborn cells (<b>A</b>), DCX⁺ immature neurons (<b>D</b>) and BrdU⁺DCX⁺ newborn neurons (<b>G</b>) in the hippocampal dentate gyrus of mice at 3, 9 and 21 months of age. Sed: sedentary group. Bar = 100 μm. Enlarged micrographs of BrdU⁺ cells (<b>B</b>), DCX⁺ immature neurons (<b>E</b>) and BrdU⁺DCX⁺ newborn neurons (<b>H</b>) are presented to illustrate the detail locations of these cells. Bar = 20 μm. SGZ: subgranular zone; GCL: granular cell layer; MoL: molecular layer. Quantitative analyses of BrdU⁺ cells (<b>C</b>), DCX⁺ cells (F) and BrdU⁺DCX⁺ cells (I) in dentate gyrus of mice with different ages. ***: Bonferroni post-hoc test: p < 0.001 vs. respective Sed group.</p