Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

Abstract

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlated with lifespan extension, though it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

“…The DR‐induced reductions in body weight (BW) and blood glucose level were not influenced by the supplement of any dietary amino acids (Figure 1c,d). Consistent with previous reports (Forster, Morris, & Sohal, 2003; Mitchell et al., 2016), introduction of 40% DR tended to increase mortality in the first 20% of the survival curve but ultimately extended lifespan, when compared with the ad libitum‐fed aged mouse group (Figure 1e). Although the replenishment of NEAA did not affect the DR‐mediated lifespan extension, it is significant that the addition of EAA not only abrogated the beneficial effects of DR on lifespan, but also seemed to have detrimental effects (Figure 1e).…”

“…For study 2, a DR group that was supplemented with EAAs, without methionine ( n  = 20), was also established, and its phenotype was compared with those of simple DR ( n  = 25) and DR plus EAAs ( n  = 30) groups. Based on previous reports (Bluher, Kahn, & Kahn, 2003; Forster et al., 2003; Migliaccio et al., 1999; Mitchell et al., 2016; Weindruch & Walford, 1982), the survival rate of male C57BL/6 mice is approximately 50%–60% at 24 months old. Thus, we decided to use 24 months as the end‐point of this study, which enabled us to analyze the effect of each dietary regimen on survival, cardiac function, glucose metabolism, muscle function, histology, and serum parameters in living middle aged and older mice, but not in very old mice.…”

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

“…Starvation seems to restore KIFC3 levels in old lysosomes and thus partially restore defective autophagy in old cells. Changes in motor protein enrichment at the lysosomal membrane could explain the previously described beneficial effect on autophagy in old mice of nutritional interventions, such as caloric restriction (Cavallini, Donati, Gori, Pollera & Bergamini, 2001; Mitchell et al., 2016). In fact, low protein diets alleviate motor symptoms in mice with mutant dynein‐mediated neurodegeneration (Wiesner et al., 2015), suggesting that upregulation of autophagy through nutritional intervention might be beneficial in dynein‐related diseases.…”

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

“…However, methionine, cysteine, phenylalanine, glutamine, asparagine, lysine and tryptophan pathways appeared modulated at varying levels of CR in the present analysis. This is in concordance with studies that found changes in a wide range of different amino acids in the liver with CR in both C57BL/6 and DBA2 mice (Collino et al ., 2013; Mitchell et al ., 2016b). Pathway analyses did not reveal that amino acid pathways were particularly altered with CR, this is in contrast with the results of (Mitchell et al ., 2016b); however, in that study CR was lifelong, and the most significant amino acid changes in C57BL/6 mice appeared in the females.…”

“…This is in concordance with studies that found changes in a wide range of different amino acids in the liver with CR in both C57BL/6 and DBA2 mice (Collino et al ., 2013; Mitchell et al ., 2016b). Pathway analyses did not reveal that amino acid pathways were particularly altered with CR, this is in contrast with the results of (Mitchell et al ., 2016b); however, in that study CR was lifelong, and the most significant amino acid changes in C57BL/6 mice appeared in the females. As our mice were male and the duration of restriction shorter, it may be that less significant amino acid changes are seen after 3 months of restriction.…”