Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.

Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence of oral dosage forms of peptide-based drugs in clinical settings.

Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells.

Introduction: The enhanced β-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks including altered nutrient sensing (insulin/IGF1 pathway) in β-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human β-cells is a marker of older β-cells; however, its contribution to age-related dysfunction and cellular senescence remains to be determined.

Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation.

Obesity induces chronic inflammation resulting in insulin resistance and metabolic disorders. Cold exposure can improve insulin sensitivity in humans and rodents, but the mechanisms have not been fully elucidated. Here, we find that cold resolves obesity-induced inflammation and insulin resistance and improves glucose tolerance in diet-induced obese mice.

Growth Hormone Signaling Shapes the Impact of Environmental Temperature on Transcriptomic Profile of Different Adipose Tissue Depots in Male Mice.

Growth hormone receptor knockout (GHRKO) mice are smaller, long living, and have an increased metabolic rate compared with normal (N) littermates. However, it is known that thermoneutral conditions (30-32°C) elicit metabolic adaptations in mice, increasing the metabolic rate. Therefore, we hypothesized that environmental temperature would affect the expression profile of different adipose tissue depots in GHRKO mice.

Energy Metabolism and Aging.

Aging is strongly related to energy metabolism, but the underlying processes and mechanisms are complex and incompletely understood. Restricting energy intake and reducing metabolic rate can slow the rate of aging and extend longevity, implying a reciprocal relationship between energy metabolism and life expectancy. However, increased energy expenditure has also been associated with improved health and longer life.

17α-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner.

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice.

CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice.

Brown and brown-like beige/brite adipocytes dissipate energy and have been proposed as therapeutic targets to combat metabolic disorders. However, the therapeutic effects of cell-based therapy in humans remain unclear. Here, we created human brown-like (HUMBLE) cells by engineering human white preadipocytes using CRISPR-Cas9-SAM-gRNA to activate endogenous uncoupling protein 1 expression.

The Link between Stress and IL-6 Is Heating Up.

Psychological stress has long been known to reduce adaptability to inflammatory challenges, although the precise mechanism has remained elusive. In a recent issue of Cell, Qing et al. (2020) demonstrate that psychological stress induces secretion of IL-6 from brown adipose tissue, which promotes hepatic gluconeogenesis, and reduces host fitness to inflammatory insults.

Integrated metabolomics reveals altered lipid metabolism in adipose tissue in a model of extreme longevity.

Adipose tissue plays an essential role in metabolic health. Ames dwarf mice are exceptionally long-lived and display metabolically beneficial phenotypes in their adipose tissue, providing an ideal model for studying the intersection between adipose tissue and longevity. To this end, we assessed the metabolome and lipidome of adipose tissue in Ames dwarf mice.

Analyzing Mitochondrial Function in Brown Adipocytes with a Bioenergetic Analyzer.

Brown adipocytes are a cell type with high mitochondrial content and bioenergetic capacity. A critical means to measure mitochondrial function, macromolecule fuel usage, and other important phenotypes is with a bioenergetic analyzer. Here, we describe how to isolate, culture, and differentiate brown preadipocytes into mature adipocytes.

Lifespan of long-lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning.

Growth hormone receptor knockout (GHRKO) mice are remarkably long-lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO ). Short-term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage.

From White to Brown - Adipose Tissue Is Critical to the Extended Lifespan and Healthspan of Growth Hormone Mutant Mice.

Growth hormone (GH) is a metabolic hormone that has major functions in the liver, muscle, and adipose tissue (AT). In the past 20 years, numerous studies have demonstrated that decreased growth hormone (GH) action is clearly linked to alterations in longevity. Therefore, it is not surprising that mechanisms underlying the extended longevity of GH-mutant animals include alterations in AT function.

12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT).

ComBATing aging-does increased brown adipose tissue activity confer longevity?

Brown and its related beige adipose tissue (BAT) play a definitive role in maintaining body temperature by producing heat through uncoupling protein 1 (UCP1), which acts by dissociating oxidative phosphorylation from ATP production, resulting in the release of heat. Therefore, in order to maintain high thermogenic capacity, BAT must act as a metabolic sink by taking up vast amounts of circulating glucose and lipids for oxidation. This, along with the rediscovery of BAT in adult humans, has fueled the study of BAT as a putative therapeutic approach to manage the growing rates of obesity and metabolic syndromes.

Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice.

Ames dwarf () mice possess a loss-of-function mutation that results in deficiency of growth hormone, prolactin, and thyroid-stimulating hormone, as well as exceptional longevity. Work in other laboratories suggests that increased respiration and lipid utilization are important for maximizing mammalian longevity. Interestingly, these phenotypes are observed in Ames dwarf mice.

Dwarf Mice and Aging.

Dwarf mice have been studied for many decades, however, the focus of these studies shifted in 1996 when it was shown by Brown-Borg and her coworkers that Ames dwarf (Prop1) mice are exceptionally long-lived. Since then, Snell dwarf (Pit1) and growth hormone receptor knockout (GHR-KO, a.k.

Intestinal immunity in hypopituitary dwarf mice: effects of age.

Hypopituitary dwarf mice demonstrate advantages of longevity, but little is known of their colon development and intestinal immunity. Herein we found that Ames dwarf mice have shorter colon and colonic crypts, but larger ratio of mesenteric lymph nodes (MLNs) over body weight than age-matched wild type (WT) mice. In the colonic lamina propria (cLP) of juvenile Ames mice, more inflammatory neutrophils (Ā: 0.

Effects of rapamycin on growth hormone receptor knockout mice.

It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice.

Longevity is impacted by growth hormone action during early postnatal period.

Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life.

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice.

There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding).

GH and ageing: Pitfalls and new insights.

The interrelationships of growth hormone (GH) actions and aging are complex and incompletely understood. The very pronounced age-related decline in GH secretion together with benefits of GH therapy in individuals with congenital or adult GH deficiency (GHD) prompted interest in GH as an anti-aging agent. However, the benefits of treatment of normal elderly subjects with GH appear to be marginal and counterbalanced by worrisome side effects.

Functionally enhanced brown adipose tissue in Ames dwarf mice.

Reduced insulin-like growth factor 1/insulin signaling (IIS) has been linked to extended longevity in species ranging from yeast to mammals. In mammals, this is exemplified in Ames dwarf (Prop1) mice, which have a 40%-60% increase in longevity (males and females, respectively) due to their recessive Prop1 loss-of-function mutation that results in lack of growth hormone (GH), thyroid-stimulating hormone and prolactin. Our laboratory has previously shown that Ames dwarf mice have functionally unique white adipose tissue (WAT) that improves, rather than impairs, insulin sensitivity.

Altered structure and function of adipose tissue in long-lived mice with growth hormone-related mutations.

A major focus of biogerontology is elucidating the role(s) of the endocrine system in aging and the accumulation of age-related diseases. Endocrine control of mammalian longevity was first reported in Ames dwarf (Prop1) mice, which are long-lived due to a recessive Prop1 loss-of-function mutation resulting in deficiency of growth hormone (GH), thyroid-stimulating hormone, and prolactin. Following this report, several other GH-related mutants with altered longevity have been described including long-lived Snell dwarf and growth hormone receptor knockout mice, and short-lived GH overexpressing transgenic mice.

Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice.

Ames dwarf mice (Prop1) are long-lived due to a loss of function mutation, resulting in deficiency of GH, TSH, and prolactin. Along with a marked extension of longevity, Ames dwarf mice have improved energy metabolism as measured by an increase in their oxygen consumption and heat production, as well as a decrease in their respiratory quotient. Along with alterations in energy metabolism, Ames dwarf mice have a lower core body temperature.