Biology subjects

Lamming, D.

Publications and source records attributed to Lamming, D..

7 recordsLinked to original sources

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

Resistance exercise protects mice from protein-induced metabolic dysfunction

Low protein (LP) diets extend the lifespan of diverse species, and are associated with improved metabolic health in both rodents and humans. Paradoxically, many athletes and bodybuilders consume high protein (HP) diets and protein supplements, yet are both fit and metabolically healthy. Here, we examine this paradox using weight pulling, a validated progressive resistance exercise training regimen, in mice fed either an LP diet or an isocaloric HP diet. We find that despite having lower food consumption than the LP group, HP-fed mice gain significantly more fat mass than LP-fed mice when not exercising, while weight pulling protected HP-fed mice from this excess fat accretion. The HP diet augmented exercise-induced hypertrophy of the forearm flexor complex, and weight pulling ability increased more rapidly in the exercised HP-fed mice. Surprisingly, exercise did not protect from HP-induced changes in glycemic control. Our results confirm that HP diets can augment muscle hypertrophy and accelerate strength gain induced by resistance exercise without negative effects on fat mass, and also demonstrate that LP diets may be advantageous in the sedentary. Our results highlight the need to consider both dietary composition and activity, not simply calories, when taking a precision nutrition approach to health.

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

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.

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↗

bioRxiv2020

Contrasting recruitment of skin-associated adipose depots during cold challenge of mouse and human

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 {beta}-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 {beta}-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 {beta}-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 SUMMARYO_LISeveral distinct strategies produce and conserve heat to maintain body temperature of mammals, each associated with unique physiologies, with consequence for wellness and disease susceptibility C_LIO_LIHighly regulated properties of skin offset the total requirement for heat production C_LIO_LIWe 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 conservation C_LIO_LIWe 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 production C_LIO_LIIn contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue C_LI

physiology↗