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. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life. Our data suggest that developmental programming of aging importantly contributes to (and perhaps explains) the well documented developmental origins of adult disease.DOI: http://dx.doi.org/10.7554/eLife.24059.001

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. Moreover, Ames dwarf mice have functionally altered epididymal white adipose tissue (WAT) that improves, rather than impairs, their insulin sensitivity due to a shift from pro- to anti-inflammatory cytokine secretion. Given the unique phenotype of Ames dwarf epididymal WAT, their improved energy metabolism, and lower core body temperature, we hypothesized that Ames dwarf brown adipose tissue (BAT) may function differently from that of their normal littermates. Here we use histology and RT-PCR to demonstrate that Ames dwarf mice have enhanced BAT function. We also use interscapular BAT removal to demonstrate that BAT is necessary for Ames dwarf energy metabolism and thermogenesis, whereas it is less important for their normal littermates. Furthermore, we show that Ames dwarf mice are able to compensate for loss of interscapular BAT by using their WAT depots as an energy source. These findings demonstrate enhanced BAT function in animals with GH and thyroid hormone deficiencies, chronic reduction of body temperature, and remarkably extended longevity.

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. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.

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). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2 years.Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of 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. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic IGF1 production in male mice without inducing any changes in pulsatile GH secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment

Ames dwarf (Prop1df) 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. We recently demonstrated that Ames dwarf mice have hyperactive brown adipose tissue (BAT), and hypothesized that this may in part be due to their increased surface to mass ratio leading to increased heat loss and an increased demand for thermogenesis. Here, we used increased environmental temperature (eT) to interrogate this hypothesis. We found that increased eT diminished BAT activity in Ames dwarf mice, and led to the normalization of both VO2 and respiratory quotient between dwarf and normal mice, as well as partial normalization (i.e. impairment) of glucose homeostasis in Ames dwarf mice housed at an increased eT. Together, these data suggest that an increased demand for thermogenesis is partially responsible for the improved energy metabolism and glucose homeostasis which are observed in Ames dwarf mice.

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 (VO2). Short‐term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO2 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. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short‐term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C.

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