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A growing number of geroprotectors have demonstrated healthspan extension in young animals, but the effectiveness of these therapies when commenced in midlife or later has been under-studied. We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either 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 diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphatidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.

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. Pak et al. show that prolonged fasting is required for the effects of calorie restriction on insulin sensitivity, fuel utilization and ageing in mice.

Lower intake of dietary protein is associated with improved metabolic health and reduced rates of age-associated diseases in humans, while low protein (LP) diets improve fitness and extend the lifespan of diverse animal species. Paradoxically, many athletes and bodybuilders consume high protein (HP) diets and protein or branched-chain amino acid supplements, yet remain fit and metabolically healthy. Here, we examine the effect of weight pulling, a validated progressive resistance exercise training regimen in mice fed either a LP diet or an isocaloric HP diet. We find that sedentary HP-fed male C57BL/6J mice gain significantly more fat mass than sedentary mice fed a LP diet, despite not consuming more calories. Resistance exercise was protective against this effect, blocking excess fat gain overall and in specific fat depots in HP-fed mice, but did not alter fat mass gain or distribution in LP-fed mice. In accordance with the widespread belief that high protein diets help promote muscle mass gain, the HP diet augmented the hypertrophy of the soleus, flexor digitorum longus (FDL) and the forearm flexor complex that occurred in response to exercise. While strength increased more rapidly in HP-fed mice, the maximum strength pulled by LP and HP-fed mice after 12 weeks was indistinguishable. Our results confirm the widespread belief that HP diets can augment muscle hypertrophy and strength gain induced by resistance exercise without negative metabolic consequences, while demonstrating that LP diets may be relatively advantageous in the sedentary. The results here highlight the need to consider both dietary composition and activity levels, not simply calories, when taking a precision nutrition approach to health.

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

Mitochondrial NAD

Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.

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.

Much of our foundational knowledge of cellular biology comes from studies in budding yeast, often described as a simple unicellular eukaryotic model. In this issue of Cell, Correia-Melo et al. describe an unappreciated feature of yeast biology involving intra-cellular metabolite exchange, where cells adapt and respond as part of a community, and go on to show that sharing of resources linked to methionine metabolism enhances longevity of cooperating cells.

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 feedingFgf21-/-and wild-type control mice eitherad 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 ofFgf21blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss ofFgf21significantly 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.

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. The authors find that mice fed a diet with reduced levels of branched-chain amino acids have improved metabolic health, and in males but not females, lifelong feeding of such a diet reduces frailty and extends life span.

SummaryMitochondrial NAD+-dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/-) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower physical activity and favor fatty acid oxidation during the postprandial period, leading to a pseudo-fasting condition that extends the fasting period. This study shows uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity), and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and a low protein diet promotes leanness and glycemic control in both rodents and humans. While the effects of a LP diet on glycemic control are mediated by reduced dietary levels of the branched- chain amino acids (BCAAs), we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces weight gain of young, lean male mice, reducing both adipose and lean mass gain, without altering glucose metabolism. Specifically reducing dietary histidine rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity; this normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. We find that the effects of histidine restriction surprisingly does not require the energy balance hormone Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary levels of histidine may be a highly translatable option for the treatment of obesity.Key PointsProtein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan.Restriction of specific individual essential amino acids can recapitulate the benefits of PR.Reduced histidine promotes leanness and increased energy expenditure in mice.Reduced histidine does not extend the lifespan of mice when begun in mid-life.Dietary levels of histidine are positively associated with BMI in humans.

The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie-and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality-the specific composition of dietary protein-may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.

Obstructive sleep apnea (OSA) is more common in patients with asthma, and inhaled corticosteroids may contribute to OSA pathogenesis in these patients. This study tested the effects of orally inhaled fluticasone propionate (FP) on extrinsic tongue muscles. Unanesthetized rats were treated with FP or placebo for 28 days. On day 29, tongue retrusive and protrusive functions were tested via hypoglossal nerve stimulation under a state of anesthesia, followed by genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscle extraction, after euthanasia, for histology [myosin heavy chain (MHC) fibers and laminin content reflecting extracellular matrix (ECM)]. On protrusive testing, FP increased percent maximum tetanic force at 40 Hz ( P = 0.03 vs. placebo) and endurance index ( P = 0.029 vs. placebo). On retrusive testing, FP increased maximum twitch ( P = 0.026 vs. placebo) and tetanic forces ( P = 0.02 vs. placebo) with no effect on endurance index. On histology, FP increased GG cross-sectional area of MHC type IIa ( P = 0.036 vs. placebo) and tended to increase type IIb ( P = 0.057 vs. placebo) fibers and HG MHC IIx fibers ( P = 0.065). The FP group had significantly increased laminin-stained areas, of greatest magnitude in the HG muscle. FP affects tongue protrusive and retrusive functions differently, concurrent with a shift in MHC fibers and increased ECM accumulation. These differential alterations may destabilize the tongue’s “muscle hydrostat” during sleep and promote collapse. NEW & NOTEWORTHY The effects of inhaled corticosteroid on upper airway may contribute to OSA pathogenesis in asthma. In this study, we tested the effects of orally inhaled fluticasone propionate on tongue protrusive and retrusive functions and on tongue extrinsic muscle fiber composition and molecular properties. We found that fluticasone treatment: 1) increased protrusive endurance and retrusive maximum twitch and tetanic force; and 2) on histology, increased cross-sectional area of myosin heavy chain (MHC) type IIa fibers and tended to increase cross-sectional area of MHC type IIb fibers in the protrusive muscle and of MHC IIx fibers in the retrusors. It also increased laminin-stained areas, across extrinsic tongue muscles, of greatest magnitude in the retrusors; and 3) reduced protein degradation and activated pathways associated with increased protein synthesis in the protrusor. These differential effects on the protrusors and retrusors may destabilize the tongue’s “muscle hydrostat” properties during sleep and promote collapse.

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.

As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as well as the ability of protein calories to displace allegedly unhealthy calories from fats and carbohydrates. However, clinical studies find that consumption of dietary protein is associated with an increased risk of multiple diseases, especially diabetes, while studies in rodents have demonstrated that protein restriction can promote metabolic health and even lifespan. Emerging evidence suggests that the effects of dietary protein on health and longevity are not mediated simply by protein quantity but are instead mediated by protein quality - the specific amino acid composition of the diet. Here, we discuss how dietary protein and specific amino acids including methionine, the branched chain amino acids (leucine, isoleucine, and valine), tryptophan and glycine regulate metabolic health, healthspan, and aging, with attention to the specific molecular mechanisms that may participate in these effects. Finally, we discuss the potential applicability of these findings to promoting healthy aging in humans.

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.

Although the beneficial effects of calorie restriction (CR) on health and aging were first observed a century ago, the specific macronutrients and molecular processes that mediate the effect of CR have been heavily debated. Recently, it has become clear that dietary protein plays a key role in regulating both metabolic health and longevity, and that both the quantity and quality - the specific amino acid composition - of dietary protein mediates metabolic health. Here, we discuss recent findings in model organisms ranging from yeast to mice and humans regarding the influence of dietary protein as well as specific amino acids on metabolic health, and the physiological and molecular mechanisms which may mediate these effects. We then discuss recent findings which suggest that the restriction of specific dietary amino acids may be a potent therapy to treat or prevent metabolic syndrome. Finally, we discuss the potential for dietary restriction of specific amino acids - or pharmaceuticals which harness these same mechanisms - to promote healthy aging.

Understanding how nutrient-sensitive signaling pathways regulate development and aging is an active area of research. In this issue of Developmental Cell, Zhu and colleagues (2021) identify a specific monomethylated branched-chain fatty acid that overrides nutrient deprivation signaling and activates mTORC1 in C. elegans and mammalian cells.

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) signaling promotes health and longevity in diverse model organisms. Over the past decade, excitement has built over the possibility that treatment with the mTORC1 inhibitor rapamycin can be utilized to treat or prevent age-related disease in humans. However, concerns over the side effects of rapamycin on immunity and metabolism have precluded the routine use of rapamycin as a geroprotective therapy. Here, we discuss the evidence that these negative side effects of rapamycin are largely mediated by off-target inhibition of a second mTOR Complex (mTORC2). Further, we discuss how intermittent treatment with rapamycin, specific dietary regimens, and new molecules may provide routes to the safer and more selective inhibition of mTORC1. We conclude that the time is ripe for the development of therapies based on the safe and selective inhibition of mTORC1 for the treatment or prevention of diseases of aging.

The transition from &beta, cell compensation to &beta, cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional &beta, cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation&mdash, a strong genetic model of T2D&mdash, were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated &beta, cell dysfunction.

When is a calorie not just a calorie? In the current issue of Nature Metabolism, Roy et al. use recombinant inbred strains of mice to investigate the role of genetic background in the response to dietary fat. Notably, both lifespan and weight gain have been found to be highly dependent on genotype, thus highlighting the need for a personaliz ed approach to dietary interventions.

Mammalian skin impacts metabolic efficiency system-wide, controlling the rate of heat loss and consequent heat production. Here we compare the unique fat depots associated with mouse and human skin, to determine whether they have corresponding function and regulation. For human, we assay a skin-associated fat (SAF) body-wide depot to distinguish it from the subcutaneous fat pads characteristic of abdomen and upper limbs. We show that the thickness of SAF is not related to general adiposity; it is much thicker (1.6-fold) in women than men, and highly subject-specific. We used molecular and cellular assays of β-adrenergic induced lipolysis and found that dermal white adipose tissue (dWAT) in mice is resistant to lipolysis; in contrast, the body-wide human SAF depot becomes lipolytic, generating heat in response to β-adrenergic stimulation. In mice challenged to make more heat to maintain body temperature (either environmentally or genetically), there is a compensatory increase in thickness of dWAT: A corresponding β-adrenergic stimulation of human skin adipose (in vivo or in explant) depletes adipocyte lipid content. We summarize the regulation of skin-associated adipocytes by age, sex, and adiposity, for both species. We conclude that the body-wide dWAT depot of mice shows unique regulation that enables it to be deployed for heat preservation; combined with the actively lipolytic subcutaneous mammary fat pads they enable thermal defense. The adipose tissue that covers human subjects produces heat directly, providing an alternative to the brown adipose tissues.KEY POINTS SUMMARYSeveral distinct strategies produce and conserve heat to maintain body temperature of mammals, each associated with unique physiologies, with consequence for wellness and disease susceptibilityHighly regulated properties of skin offset the total requirement for heat productionWe hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservationWe found that insulating mouse dermal white adipose tissue accumulates in response to environmentally- and genetically-induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat productionIn contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue

Background: One of the primary risk factors for the development of diabetes is obesity. Although moderate weight loss can lead to improvements in metabolic health, reduced-calorie diets are difficult to sustain. A number of groups have shown that low protein diets are associated with metabolic health in both rodents and humans. In particular, the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are associated with insulin resistance and diabetes in humans. Blood levels of the BCAAs decrease in humans fed a low protein diet, and we recently showed that reducing either dietary BCAAs or protein rapidly restored normal body composition and insulin sensitivity to diet-induced obese mice without reducing calorie intake. We are determining the effect of a low BCAA diet in humans with prediabetes and overweight/obesity. Objectives: The primary outcome is the reduction of dietary BCAA intake by at least 50% in subjects in the low BCAA group while maintaining overall baseline calories. Secondary outcomes are compliance and tolerability of the low BCAA protein powder. Method: This is a randomized, controlled, single-blind pilot study. The intervention arm uses a low BCAA protein powder to replace two meals per day for 60 days. The control arm uses a control protein powder with standard amounts of amino acids to replace two meals per day for 60 days. We are enrolling 16 males with the following criteria: ages 35 to 65, BMI 28 to 35, and hemoglobin A1c 5.7%-6.4% or fasting glucose 101-125 mg/dL. A registered dietitian reviews a 4-day food diary prior to diet initiation and creates an individualized meal plan based on those values in order to maintain baseline calories during the study diet. Baseline measurements prior to diet initiation include waist circumference, body mass index, fasting insulin and glucose, an oral glucose tolerance test, resting metabolic rate, body composition testing using dual energy x-ray absorptiometry, jumping mechanography to assess muscle function, and a stool sample to assess the microbiome. These tests are repeated after 60 days on the diet. Safety labs are performed while on the diet and 2-3 weeks after the end of the diet. Weekly safety telephone calls occur while on the diet. The food diaries are repeated after 30 and 60 days on the diet. Results/Conclusion: Ten of sixteen subjects have completed the trial to date. One out of four subjects in the low BCAA group dropped out; the remainder successfully completed the study. BCAA intake was successfully reduced by 50%. Missed beverages were uncommon. No significant safety concerns or side effects have been noted. In conclusion, our early results suggest that replacement of two meals a day with a protein powder lacking BCAA for up to two months is a safe and feasible intervention. Ongoing analysis will determine if this intervention impacts metabolic health.

Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.