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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., Competing Interests: Declaration of interests D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases., (Published by Elsevier Inc.)

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., Competing Interests: Declaration of interests D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases., (Published by Elsevier Inc.)

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes., Competing Interests: Declaration of interests D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. UW-Madison has applied for a patent based in part on the findings reported here, for which N.E.R. and D.W.L. are inventors., (Published by Elsevier Inc.)

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

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., Competing Interests: Declaration of Interests D.W.L. has received funding from, and is a scientific advisory board member of, Aeonian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)