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Calorie restriction (CR) extends lifespan and healthspan in diverse species. Comparing ad libitum - and CR-fed mice is challenging due to their significantly different feeding patterns, with CR-fed mice consuming their daily meal in 2 h and then subjecting themselves to a prolonged daily fast. Here, we examine how ad libitum - and CR-fed mice respond to tests performed at various times and fasting durations and find that the effects of CR—insulin sensitivity, circulating metabolite levels, and mechanistic target of rapamycin 1 (mTORC1) activity—result from the specific temporal conditions chosen, with CR-induced improvements in insulin sensitivity observed only after a prolonged fast, and the observed differences in mTORC1 activity between ad libitum - and CR-fed mice dependent upon both fasting duration and the specific tissue examined. Our results demonstrate that much of our understanding of the effects of CR are related to when, relative to feeding, we choose to examine the mice. [Display omitted] • The observed effects of calorie restriction (CR) depend upon when the mice last ate • CR mice are insulin resistant relative to ad libitum mice when examined post-prandially • CR does not suppress muscle and hepatic mTORC1 activity • CR animals reprogram their metabolism to adapt to a daily fast Pak et al. find that many canonical effects of calorie restriction, including insulin sensitivity, result from the specific temporal conditions chosen. Feeding time, fasting duration, and the time of day the study is conducted have critical effects on the metabolic and molecular response to calorie restriction. [ABSTRACT FROM AUTHOR]

The inhibitory G protein alpha-subunit (Gαz) is an important modulator of beta-cell function. Full-body Gαz-null mice are protected from hyperglycemia and glucose intolerance after long-term high-fat diet (HFD) feeding. In this study, at a time point in the feeding regimen where WT mice are only mildly glucose intolerant, transcriptomics analyses reveal islets from HFD-fed Gαz KO mice have a dramatically altered gene expression pattern as compared with WT HFD-fed mice, with entire gene pathways not only being more strongly upregulated or downregulated versus control-diet fed groups but actually reversed in direction. Genes involved in the "pancreatic secretion" pathway are the most strongly differentially regulated: a finding that correlates with enhanced islet insulin secretion and decreased glucagon secretion at the study end. The protection of Gαz-null mice from HFD-induced diabetes is beta-cell autonomous, as beta cell-specific Gαz-null mice phenocopy the full-body KOs. The glucose-stimulated and incretin-potentiated insulin secretion response of islets from HFD-fed beta cell-specific Gαz-null mice is significantly improved as compared with islets from HFD-fed WT controls, which, along with no impact of Gαz loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass, supports a secretion-specific mechanism. Gαz is coupled to the prostaglandin EP3 receptor in pancreatic beta cells. We confirm the EP3γ splice variant has both constitutive and agonist-sensitive activity to inhibit cAMP production and downstream beta-cell function, with both activities being dependent on the presence of beta-cell Gαz. [ABSTRACT FROM AUTHOR]

Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention. [Display omitted] • Isoleucine restriction (IleR) improves metabolic health in both sexes • IleR reprograms hepatic metabolism in a sex- and age-dependent manner • IleR reduces frailty and increases lifespan, with stronger effects on male lifespan • Amino acid restriction begun at 6 months extends healthspan but not lifespan Green et al. find that dietary isoleucine is a key regulator of metabolic health and lifespan in genetically heterogeneous mice. Restriction of isoleucine improves metabolic health, reduces frailty, and increases the lifespan of both male and female mice, with greater benefits for males. [ABSTRACT FROM AUTHOR]

There is significant interest in identifying compounds that mimic the effects of dietary restriction on healthy aging. In the latest issue of Cell Metabolism , Le Couteur et al. (2021) use a nutritional geometry approach to survey the effects of three such compounds on the hepatic proteome across a changing dietary landscape. There is significant interest in identifying compounds that mimic the effects of dietary restriction on healthy aging. In the latest issue of Cell Metabolism , Le Couteur et al. use a nutritional geometry approach to survey the effects of three such compounds on the hepatic proteome across a changing dietary landscape. [ABSTRACT FROM AUTHOR]

Low-protein diets promote metabolic health in humans and rodents. Despite evidence that sex and genetic background are key factors in the response to diet, most protein intake studies examine only a single strain and sex of mice. Using multiple strains and both sexes of mice, we find that improvements in metabolic health in response to reduced dietary protein strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, we observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, we identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, providing molecular insight into the differential response to protein restriction. Our results highlight the importance of sex and genetic background in the response to dietary protein level, and the potential importance of a personalized medicine approach to dietary interventions. [Display omitted] • Protein restriction (PR) promotes metabolic health in mice • The benefits of PR are influenced by sex, strain, and the degree of restriction • The role of FGF21 in the effects of PR is sex and strain dependent • PR improves metabolic health in aged mice Green et al. find that restricting dietary protein promotes metabolic health in mice but that the specific benefits observed are dependent upon sex, strain, the level of restriction, and age. Using a multi-omics approach, the authors gain molecular insight into the physiological effects of dietary protein and find that the role of the hormone FGF21 depends upon both sex and strain. [ABSTRACT FROM AUTHOR]

Identifying the causal gene(s) that connects genetic variation to a phenotype is a challenging problem in genome-wide association studies (GWASs). Here, we develop a systematic approach that integrates mouse liver co-expression networks with human lipid GWAS data to identify regulators of cholesterol and lipid metabolism. Through our approach, we identified 48 genes showing replication in mice and associated with plasma lipid traits in humans and six genes on the X chromosome. Among these 54 genes, 25 have no previously identified role in lipid metabolism. Based on functional studies and integration with additional human lipid GWAS datasets, we pinpoint Sestrin1 as a causal gene associated with plasma cholesterol levels in humans. Our validation studies demonstrate that Sestrin1 influences plasma cholesterol in multiple mouse models and regulates cholesterol biosynthesis. Our results highlight the power of combining mouse and human datasets for prioritization of human lipid GWAS loci and discovery of lipid genes. • Systematic method to combine mouse liver network and human lipid GWAS for discovery • Identification of a conserved liver cholesterol module across mouse populations • Prioritization of genes replicated in mouse and associated with human lipid traits • Validation of Sestrin1 as a gene that regulates cholesterol biosynthesis Here, Li et al. develop a systematic approach that integrates mouse liver co-expression networks together with human lipid GWAS datasets to identify lipid metabolism genes. Using this approach, they pinpoint Sestrin1 as a gene associated with cholesterol levels in humans and demonstrate that Sestrin1 protein can regulate cholesterol biosynthesis. [ABSTRACT FROM AUTHOR]

Summary A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network. Finally, we show that sarcosine can activate autophagy in cultured cells and enhances autophagic flux in vivo , suggesting a potential role in autophagy induction by DR. Thus, these data identify circulating sarcosine as a biomarker of aging and DR in mammalians and may contribute to age-related alterations in the metabolome and in proteostasis. Graphical Abstract Highlights • Dietary restriction is a stronger modulator of the rat metabolome than age • Sarcosine is similarly decreased by age and increased by DR in rodents and humans • Sarcosine is elevated in serum of long-lived Ames dwarf mice • Sarcosine activates macroautophagy in vitro and in vivo In a comparative metabolic screen of rodents and humans, Walters et al. show that circulating sarcosine is similarly reduced with aging and increased by dietary restriction. They demonstrate that sarcosine activates macroautophagy in cultured cells and in vivo , suggesting a role in improved proteostasis via dietary restriction. [ABSTRACT FROM AUTHOR]

Primates tend to be long-lived for their size with humans being the longest lived of all primates. There are compelling reasons to understand the underlying age-related processes that shape human lifespan. But the very fact of our long lifespan that makes it so compelling, also makes it especially difficult to study. Thus, in studies of aging, researchers have turned to non-human primate models, including chimpanzees, baboons, and rhesus macaques. More recently, the common marmoset, Callithrix jacchus , has been recognized as a particularly valuable model in studies of aging, given its small size, ease of housing in captivity, and relatively short lifespan. However, little is known about the physiological changes that occur as marmosets age. To begin to fill in this gap, we utilized high sensitivity metabolomics to define the longitudinal biochemical changes associated with age in the common marmoset. We measured 2104 metabolites from blood plasma at three separate time points over a 17-month period, and we completed both a cross-sectional and longitudinal analysis of the metabolome. We discovered hundreds of metabolites associated with age and body weight in both male and female animals. Our longitudinal analysis identified age-associated metabolic pathways that were not found in our cross-sectional analysis. Pathways enriched for age-associated metabolites included tryptophan, nucleotide, and xenobiotic metabolism, suggesting these biochemical pathways might play an important role in the basic mechanisms of aging in primates. Moreover, we found that many metabolic pathways associated with age were sex specific. Our work illustrates the power of longitudinal approaches, even in a short time frame, to discover novel biochemical changes that occur with age. [ABSTRACT FROM AUTHOR]