Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis

Abstract

The action of nutrients on early postnatal growth can influence mammalian aging and longevity. Recent work has demonstrated that limiting nutrient availability in the first 3 wk of life [by increasing the number of pups in the crowdedlitter (CL) model] leads to extension of mean and maximal lifespan in genetically normal mice. In this study, we aimed to characterize the impact of early-life nutrient intervention on glucose metabolism and energy homeostasis in CL mice. In our study, we used mice from litters supplemented to 12 or 15 pups and compared those to control litters limited to eight pups. At weaning and then throughout adult life, CL mice are significantly leaner and consume more oxygen relative to control mice. At 6 mo of age, CL mice had low fasting leptin concentrations, and low-dose leptin injections reduced body weight and food intake more in CL female mice than in controls. At 22 mo, CL female mice also have smaller adipocytes compared with controls. Glucose and insulin tolerance tests show an increase in insulin sensitivity in 6 mo old CL male mice, and females become more insulin sensitive later in life. Furthermore, ␤-cell mass was significantly reduced in the CL male mice and was associated with reduction in ␤-cell proliferation rate in these mice. Together, these data show that early-life nutrient intervention has a significant lifelong effect on metabolic characteristics that may contribute to the increased lifespan of CL mice.

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice

“…This difference from the results obtained by Sagagurski et al (Sadagurski et al 2014) may have been due to a strain difference and unexpected increase in the expression of pro-inflammation markers. Although enhanced insulin sensitivity is believed to represent one of the mechanisms of extended longevity of GHR-KO mice, normal males from L litters did not live longer, whereas normal females did.…”

“…In our study, the levels of IL-6 in subcutaneous adipose tissue were increased by litter crowding in both sexes of normal mice (Fig. 5c), which may explain why glucose homeostasis was not significantly improved by mild early-life calorie restriction unlike the results from a litter crowding study (Sadagurski et al 2014). The levels of TNF-α and IL-1 were increased in normal males, but not in females from L litter (Fig.…”

Long-lived crowded-litter mice have an age-dependent increase in protein synthesis to DNA synthesis ratio and mTORC1 substrate phosphorylation

“…1), suggesting that CL mice were calorically restricted during suckling (33,39). However, there were no differences in body weight at either 4 or 7 mo of age (Fig.…”

“…For example, increasing litter size by 50% for the first 3 wk of life, a model termed crowded litter (CL), extends mean and maximal lifespan (39). The increase in litter size presumably imposes a CR period until the pups are weaned and given free access to food (33,39). How a transient nutrient stress at such a young age extends lifespan is unknown.…”

The somatotropic axis and longevity in mice

“…These results suggest that the enhanced sensitivity to insulin is necessary for the slow aging of the GHRKO mice, as few other characteristics measured differed from the GHRKO. Concomitantly, mice raised in crowded litters (12-15 pups) are long-lived and exhibit lower plasma IGF-I and enhanced insulin sensitivity, glucose tolerance, and xenobiotic metabolism compared with mice in normal-size (8 pups) litters (89,98).…”