Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging.

In defiance of the paradigm that calories from all sources are equivalent, we and others have shown that dietary protein is a dominant regulator of healthy aging. The restriction of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan when initiated in young or adult mice. However, many interventions are less efficacious or even deleterious when initiated in aged animals. Here, we investigate the physiological, metabolic, and molecular consequences of consuming a diet with a 67% reduction of all amino acids (Low AA), or of isoleucine alone (Low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diet regimens effectively reduce adiposity and improve glucose tolerance, which were benefits that were not mediated by reduced calorie intake. Both diets improve specific aspects of frailty, slow multiple molecular indicators of aging rate, and rejuvenate the aging heart and liver at the molecular level. These results demonstrate that Low AA and Low Ile diets can drive youthful physiological and molecular signatures, and support the possibility that these dietary interventions could help to promote healthy aging in older adults.

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.

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.

Protein restriction slows the development and progression of Alzheimer's disease in mice.

Over the last decade, it has become evident that dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and we and others have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction.

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.

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice.

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21-/- and wild-type control mice either ad libitum (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice.

Calorie restriction (CR) promotes healthy ageing in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced caloric intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.

The Second Annual Symposium of the Midwest Aging Consortium: The Future of Aging Research in the Midwestern United States.

While the average human life span continues to increase, there is little evidence that this is leading to a contemporaneous increase in "healthy years" experienced by our aging population. Consequently, many scientists focus their research on understanding the process of aging and trialing interventions that can promote healthspan. The 2021 Midwest Aging Consortium consensus statement is to develop and further the understanding of aging and age-related disease using the wealth of expertise across universities in the Midwestern United States. This report summarizes the cutting-edge research covered in a virtual symposium held by a consortium of researchers in the Midwestern United States, spanning topics such as senescence biomarkers, serotonin-induced DNA protection, immune system development, multisystem impacts of aging, neural decline following severe infection, the unique transcriptional impact of calorie restriction of different fat depots, the pivotal role of fasting in calorie restriction, the impact of peroxisome dysfunction, and the influence of early life trauma on health. The symposium speakers presented data from studies conducted in a variety of common laboratory animals as well as less-common species, including Caenorhabditis elegans, Drosophila, mice, rhesus macaques, elephants, and humans. The consensus of the symposium speakers is that this consortium highlights the strength of aging research in the Midwestern United States as well as the benefits of a collaborative and diverse approach to geroscience.

Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.

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.

ARDD 2020: from aging mechanisms to interventions.

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.

The Metabolic Response to a Low Amino Acid Diet is Independent of Diet-Induced Shifts in the Composition of the Gut Microbiome.

Obesity and type 2 diabetes are increasing in prevalence around the world, and there is a clear need for new and effective strategies to promote metabolic health. A low protein (LP) diet improves metabolic health in both rodents and humans, but the mechanisms that underlie this effect remain unknown. The gut microbiome has recently emerged as a potent regulator of host metabolism and the response to diet. Here, we demonstrate that a LP diet significantly alters the taxonomic composition of the gut microbiome at the phylum level, altering the relative abundance of Actinobacteria, Bacteroidetes, and Firmicutes. Transcriptional profiling suggested that any impact of the microbiome on liver metabolism was likely independent of the microbiome-farnesoid X receptor (FXR) axis. We therefore tested the ability of a LP diet to improve metabolic health following antibiotic ablation of the gut microbiota. We found that a LP diet promotes leanness, increases energy expenditure, and improves glycemic control equally well in mice treated with antibiotics as in untreated control animals. Our results demonstrate that the beneficial effects of a LP diet on glucose homeostasis, energy balance, and body composition are unlikely to be mediated by diet-induced changes in the taxonomic composition of the gut microbiome.