Abstract
Immune senescence is a natural consequence of aging and may contribute to frailty and loss of homeostasis in later life. Calorie restriction increases healthy life-span in C57BL/6J (but not DBA/2J) mice, but whether this is related to preservation of immune function, and how it interacts with aging, is unclear. We compared phenotypic and functional characteristics of natural killer (NK) cells and T cells, across the lifespan, of calorie-restricted (CR) and control C57BL/6 and DBA/2 mice. Calorie restriction preserves a naïve T cell phenotype and an immature NK cell phenotype as mice age. The splenic T cell populations of CR mice had higher proportions of CD11a−CD44lo cells, lower expression of TRAIL, KLRG1, and CXCR3, and higher expression of CD127, compared to control mice. Similarly, splenic NK cells from CR mice had higher proportions of less differentiated CD11b−CD27+ cells and correspondingly lower proportions of highly differentiated CD11b+CD27−NK cells. Within each of these subsets, cells from CR mice had higher expression of CD127, CD25, TRAIL, NKG2A/C/E, and CXCR3 and lower expression of KLRG1 and Ly49 receptors compared to controls. The effects of calorie restriction on lymphoid cell populations in lung, liver, and lymph nodes were identical to those seen in the spleen, indicating that this is a system-wide effect. The impact of calorie restriction on NK cell and T cell maturation is much more profound than the effect of aging and, indeed, calorie restriction attenuates these age-associated changes. Importantly, the effects of calorie restriction on lymphocyte maturation were more marked in C57BL/6 than in DBA/2J mice indicating that delayed lymphocyte maturation correlates with extended lifespan. These findings have implications for understanding the interaction between nutritional status, immunity, and healthy lifespan in aging populations.
Highlights
Obesity, diet, and our aging population are increasingly important public health concerns in many societies [1]
Body weights of control (AL) C57BL/6 mice increased over the entire life course whereas weights of ad libitum (AL) DBA mice stabilized at approximately 12 months of age (Figure S2 in Supplementary Material)
On the other hand and in agreement with the previous study [30, 44], we find that CR has a dramatic effect on natural killer (NK) maturation at all ages, increasing the proportions of the relatively immature Stage 2 subset and decreasing the proportions of the most mature Stage 3 and Stage 4 subsets, leading to marked differences in the ratio of Stage 2 to Stage 4 cells in CR mice compared to controls (Figure 5C)
Summary
Diet, and our aging population are increasingly important public health concerns in many societies [1]. Restriction of the calorie intake of C57BL/6J mice by 40% compared to that of mice fed ad libitum (AL), extends median lifespan by more than 35% (i.e., from around 24 months to around 32 months) whereas the lifespan of DBA/2J mice is not extended by calorie restriction [16,17,18] This differential response to calorie restriction may be linked to lower basal metabolic rate, lower oxygen consumption, higher oxidative stress, higher body fat, and continued weight gain throughout adult life in C57BL/6 mice compared to DBA/2 mice fed AL [18, 19] differential effects on nutrient sensing cannot be ruled out [20, 21]
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