Biology subjects

Green, C. L.

Publications and source records attributed to Green, C. L..

8 recordsLinked to original sources

bioRxiv2024

Retrospective Analysis of the Effects of BWF Interdisciplinary Postdoctoral to Faculty Transition Awards on Future Funding Success

Established by the Burroughs Wellcome Fund (BWF) in 2001, the Career Award at the Scientific Interface (CASI) is a career development award for scientists with doctoral training in the physical/mathematical/computational sciences or engineering conducting postdoctoral research in the biological sciences. The goal of the program is to support early career scientists interested in pursuing an independent research career with an interdisciplinary focus. In order to assess the benefit of the CASI award on recipients, the authors undertook a retrospective analysis of the funding data for CASI recipients to evaluate success against matching cohorts. These cohorts included applicants who succeeded to the final interview stage but were ultimately unsuccessful (interviewed), applicants who submitted proposals but did not make it to the final interview stage (proposal declined), and a randomly selected dataset of researchers from a comparable program, the highly competitive Pathway to Independence Award (K99/R00) from the National Institutes of Health (NIH). The results indicate that CASI recipients outperformed unsuccessful applicants and their K99/R00 counterparts in federal grant rates and overall grant dollars. The authors conclusion affirms that the CASI mechanism and BWF support successfully achieve the objective of invigorating the careers of young investigators, resulting in tangible downstream long-term effects.

scientific communication and education↗

bioRxiv2024

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease

Age is the greatest risk factor for Alzheimers disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.

physiology↗

bioRxiv2024

Dietary isoleucine content defines the metabolic and molecular response to a Western diet

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.

physiology↗

bioRxiv2024

Non-canonical Metabolic and Molecular Effects of Calorie Restriction Are Revealed by Varying Temporal Conditions

Calorie restriction (CR) extends lifespan and healthspan in diverse species. However, comparing ad libitum (AL) and CR-fed mice is challenging due to their significantly different feeding patterns. CR-fed mice consume their daily meal in approximately 2 hours, subjecting themselves to a prolonged self-imposed fast each day. To gain deeper insights into the effects of CR, we conducted a comprehensive examination of how AL and CR-fed mice respond to tests performed at various times relative to the completion of their once-daily CR meal. Our findings reveal that many well-known effects of CR, including its impact on insulin sensitivity, result from the specific temporal conditions. CR animals exhibit a divergent response to insulin, and this response varies based on the time elapsed since the CR-fed mice consumed their food. Utilizing an unbiased metabolomics approach, we discovered that the effects of CR on circulating metabolites are heavily dependent upon the time-of-day and feeding regimen. Finally, while it is widely believed that CR functions in part by reducing activity of the kinase mTORC1, our study suggests that the observed differences in mTORC1 activity between AL and CR-fed mice are dependent upon both fasting duration and the specific tissue examined. Furthermore, we find that the metabolic effects of CR are independent of hepatic mTORC1. Our results shed new light on the physiological, metabolic, and molecular effects of a CR diet, and highlight that much of our understanding of the effects of CR are related to when, relative to feeding, we choose to examine the mice.

physiology↗

bioRxiv2023

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

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.

physiology↗

bioRxiv2022

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

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.

physiology↗

bioRxiv2022

SIRT3 deficiency decreases oxidative-metabolism capacity but increases lifespan under caloric restriction

Mitochondrial 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.

molecular biology↗

bioRxiv2022

Regulation of metabolic health by dietary histidine in mice

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 PointsO_LIProtein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. C_LIO_LIRestriction of specific individual essential amino acids can recapitulate the benefits of PR. C_LIO_LIReduced histidine promotes leanness and increased energy expenditure in mice. C_LIO_LIReduced histidine does not extend the lifespan of mice when begun in mid-life. C_LIO_LIDietary levels of histidine are positively associated with BMI in humans. C_LI

physiology↗