Protein-restricted diets promote health and longevity in many species. While the precise components of a protein-restricted diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of protein restriction 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 life span and a reduction in frailty in male, but not female, wild-type mice when they undergo lifelong feeding. Our results demonstrate that restricting dietary BCAAs can increase health span and longevity in mice and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

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.

The COVID-19 pandemic has made an impact on how health care/support services are accessed with up to 60% decline in visits to primary care providers. This study evaluated the impact of COVID-19 on participant engagement with asthma navigators and asthma outcomes in a school-centered asthma program. Step Up Asthma program is implemented in 40 Colorado schools. Asthma navigators enrolled 2 cohorts (Cohort 1/2018-2019 and Cohort 2/2019-2020) of students with poorly controlled asthma to participate in a comprehensive asthma navigator program. Study visits were scheduled every 3 months over a 12-month period. Due to COVID-19 school closures, we transitioned to telehealth visits beginning in March 2020. We compared participation rates and indicators of asthma control (ACT score, ED and hospitalizations) before and during the COVID-19 crisis to identify if there was an impact on program engagement. We compared rates for participation at 3-time points: start of school year, mid-year, and end of school year. Cohort 1 (n=113) had participation rates of 100%, 99.1% and 88.5% respectively and Cohort 2 (n=119) had rates of 100%, 87.4% and 70.6%. The results demonstrate an 11.5% decline from start of year to end of year for Cohort 1, compared to a 29.4% decline for Cohort 2 during the COVID-19 crisis. No change in asthma outcomes was noted. Our school-centered asthma program maintained high levels of participant engagement through telehealth mechanisms. This study demonstrates the effectiveness of asthma navigators in maintaining close monitoring. Anecdotally, families expressed how important these outreach visits were to them.

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.

Obesity and diabetes are increasing problems in the United States and worldwide. While even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Plasma branched‐chain amino acids (BCAAs) are elevated in obese humans and rodents, and high protein or BCAA consumption is implicated in impaired metabolic health. We and others have found that reduced BCAA consumption is associated with reduced fat mass gain when begun at a young age. Here, we examined the hypothesis that reducing dietary BCAAs would promote weight normalization and improve blood glucose control in mice with pre‐existing metabolic syndrome, without requiring a reduction in caloric intake.C57BL/6J mice were pre‐conditioned with a high calorie, high‐fat, high‐sugar Western diet for 12 weeks until they were obese and pre‐diabetic. Mice were then randomized into several groups and fed amino acid defined diets with reduced or increased levels of the three BCAAs (Leucine, Isoleucine, Valine), in the context of either a normal calorie diet or a high‐calorie “Western” diet. We examined weight, body composition, glucose and insulin tolerance, food intake, activity and energy expenditure, over the following 4 months, as well as examining the effects of altering dietary BCAAs on the taxonomic composition of the gut microbiome.We find that specifically reducing dietary BCAAs rapidly reverses diet‐induced obesity and improves glucoregulatory control in diet‐induced obese mice. Mice switched to a diet with reduced levels of BCAAs lost weight and fat mass rapidly until returning to a normal weight, while mice consuming isocaloric diets with normal or increased levels of BCAAs remained obese. This normalization of weight was mediated by increased energy expenditure, and was accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Subsequent experiments suggest this latter effect may be mediated by changes to the gut microbiome.Our results demonstrate that diets with decreased levels of BCAAs promote metabolic health and energy balance in obese animals, and link dietary protein quality – the specific amino acid composition of the diet – to metabolic health as well as the composition of the gut microbiome. Specifically reducing dietary BCAAs may represent a translatable option for the treatment of obesity and insulin resistance.Support or Funding InformationThe Lamming lab is supported by the NIH (AG041765, AG051974, and AG056771), a Glenn Foundation Award for Research in the Biological Mechanisms of Aging, and a New Investigator Program Award from the Wisconsin Partnership Program. This research was conducted while DWL was an AFAR Research Grant recipient. NEC is supported by a training grant from the UW Institute on Aging (T32 AG000213). EMW was supported by the Shapiro Summer Research Program. DY is supported in part by a fellowship from the AHA (17PRE33410983). This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Key points We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high‐fat, high‐sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets. AbstractObesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched‐chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin‐resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet‐induced obese mice with pre‐existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet‐induced obesity and improves glucoregulatory control in diet‐induced obese mice. Most dramatically, mice eating an otherwise unhealthy high‐calorie, high‐sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.

Calorie restriction (CR) is the nutritional ‘gold standard’ in lifespan extension, improving metabolic health in many metabolic organisms. This intervention is extremely difficult to sustain, especially in a population struggling with both obesity and readily available food sources. While CR limits the intake of all macronutrients, it's unclear what macronutrient drives these benefits. An attractive alternative to restricting all calories is to limit only certain macronutrients, changing the ratio of macronutrient intake. A low protein, high carbohydrate diet can increase lifespan and improve metabolic health in both rodents and humans. However, the specific amino acid composition of protein intake may have more of an impact on metabolism and aging than researchers and physicians previously thought.Our lab has previously determined that a diet restricted in branched chain amino acids (BCAAs; leucine, isoleucine, and valine) improves glycemic control and metabolic health in young, wild‐type mice. In addition, we have determined that reduced consumption of BCAAs does not induce the production of fibroblast growth factor 21 (FGF21), a hormone produced in fasting and protein restriciton, but does result in specific inhibition of the mechanistic Target of Rapamycin Complex 1 (mTORC1). We have since expanded our research to explore the effects of BCAA restriction in aged and metabolically disadvantaged mice.We find that Low BCAA diets rapidly reverse diet induced obesity, improving glucoregulatory control and inducing weight loss. When BCAAs or total protein are restricted in a progeroid mouse, we promote longevity and rescue some aspects of cardiac function. BCAA restriction improves weight and glycemic control of aged, wild‐type mice. Our results suggest that a reduction in dietary BCAAs promotes metabolic health and longevity, and may represent a highly translatable option to treat age‐related disease.Support or Funding InformationThe Lamming lab is supported by a K99/R00 Pathway to Independence Award to D.W.L. from the National Institute of Health/National Institute on Aging (AG041765), a New Investigator Program Award from the Wisconsin Partnership Program, and an Innovator Award from the Progeria Research Foundation, as well as startup funds from the UW‐Madison School of Medicine and Public Health and the UW‐Madison Department of Medicine. N.E.C. is supported in part by a training grant from the UW Institute on Aging (NIA T32 AG000213). This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government.