Ageing, genetics and the somatotropic axis

Research on ageing made a big leap forward when genes regulating lifespan were discovered about a decade ago. First isolated by screening the genome of the nematode Caenorhabditis elegans, most of these genes belong to an essential signalling pathway that is highly conserved during animal evolution. Orthologous genes in vertebrate species are the families of genes coding for insulin, insulin-like growth factors (IGF) and related proteins. Intensively studied and well-known for their pivotal roles in proliferation, differentiation, survival and metabolism of most cells, we now discover their multiples functions with respect to the control of longevity and their ability to modulate the cell's responses to oxidative stress, a major cause of cellular and organismal ageing. The activity of IGF signalling in mammals depends on a complex interplay of endocrine signals that together constitute the somatotropic axis. Accordingly, several components of this hormone axis, like growth hormone or growth hormone releasing hormone receptors, regulate efficiently animal longevity, which has been elegantly demonstrated by studies performed in genetically modified mouse models. From this and other work, it becomes increasingly clear that the control of ageing is a question of hormonal regulations. We here present several of these models and discuss the respective contributions of insulin and IGF signalling to the regulation of lifespan. We review data on the Klotho gene that acts on lifespan via surprising and not yet fully understood molecular mechanisms, connecting this new, hormone-like substance to IGF and insulin signalling. We further report recent evidence showing that human lifespan might be controlled in similar ways. Finally, we shed some light on clinical GH treatment in humans, from an endocrinologist's point of view.     

Salinity acclimation affects the somatotropic axis in rainbow trout

In this study, we set out to examine the role of the somatotropic axis in the ion-regulation process in rainbow trout. Specifically, our objective was to examine whether plasma insulin-like growth factor-binding proteins (IGFBPs) are modulated by gradual salinity exposure. To this end, freshwater (FW)-adapted rainbow trout were subjected to gradual salinity increases, up to 66% seawater, over a period of 5 days. During this acclimation process, minimal elevations in plasma Ca2+ and Cl- were seen in the salinity-acclimated groups compared with FW controls. There were no changes in plasma Na+ levels, and only a minor transient change in plasma cortisol levels was seen with salinity exposure. The salinity challenged animals responded with elevations in plasma growth hormone (GH) and IGF-I levels and gill Na+-K+-ATPase activity. We identified IGFBPs of 21, 32, 42, and 50 kDa in size in the plasma of these animals, and they were consistently higher with salinity. Despite the overall increase in IGFBPs with salinity, transient changes in individual BPs over the 5-day period were noted in the FW and salinity-exposed fish. Specifically, the transient changes in plasma levels of the 21-, 42-, and 50-kDa IGFBPs were different between the FW and salinity groups, while the 32-kDa IGFBP showed a similar trend (increases with sampling time) in both groups. Considered together, the elevated plasma IGFBPs suggest a key role for these binding proteins in the regulation of IGF-I during salinity acclimation in salmonids.     

Age-related changes of the somatotropic axis in cloned Holstein calves

To determine if the development of the somatotropic axis in somatic clones (clones) is similar to that in heifers produced by artificial insemination (controls), serum samples were collected every 30 min for 6 h, once per month, for 7 mo from 4 clones generated from a 13-yr-old cow and from 4 age-matched controls. Average concentrations of growth hormone (GH) were not different between clones and controls, and GH concentrations declined over time in controls. Average concentrations of insulin-like growth factor I (IGF-I) were less in clones than controls, and IGF-I concentrations increased over time in both groups. Concentrations of IGF-binding protein 3 (IGFBP-3) were greater in controls than in clones and did not change over time. Average IGFBP-2 concentrations did not change over time and were not different between clones and controls. Clones and controls were challenged with GH-releasing hormone (GHRH) (3 microg/100 kg body weight) and somatostatin (somatotropin release-inhibiting factor [SRIF]) (1.87 and 5 microg/100 kg body weight) at 14 mo of age. GHRH-induced GH secretion was greater and SRIF inhibition of GHRH-induced GH was less in clones than in controls. We speculate that some of the differences between clones and controls in concentrations of GH, IGF-I, and IGFBP-3 may be related to the genetic merit of the animals. Although there were differences in concentrations of components of the somatotropic axis between these clones and their age-matched controls, the values recorded were all within the range reported for calves of similar ages.     

Effects of dexamethasone and colostrum intake on the somatotropic axis in neonatal calves

Glucocorticoids and colostrum feeding influence postnatal maturation of the somatotropic axis. We have tested the hypothesis that dexamethasone (Dexa) affects the somatotropic axis in neonatal calves dependent on colostrum intake. Calves were fed either with colostrum or with a milk-based formula (n = 14/group), and, in each feeding group, one-half of the calves were treated with Dexa (30 micro g. kg body wt-1. day-1). Pre- and postprandial blood samples were taken on days 1, 2, 4, and 5, and liver samples were taken on day 5 of life. Dexa increased insulin-like growth factor (IGF)-I, but decreased growth hormone (GH) and IGF-binding protein (IGFBP)-1 and -2 plasma concentrations and increased GH receptor (GHR) mRNA levels in liver. Dexa increased IGF-I mRNA levels only in formula-fed calves and increased hepatic GHR binding capacity, but only in colostrum-fed calves. Colostrum feeding decreased IGFBP-1 and -2 plasma concentrations and hepatic IGFBP-2 and -3 mRNA levels. In conclusion, Dexa and colostrum feeding promoted maturation of the somatotropic axis. Dexa effects partly depended on whether colostrum was fed or not.     

Epigenetic mapping of the somatotropic axis in Nile tilapia reveals differential DNA hydroxymethylation marks associated with growth

In vertebrates, the somatotropic axis comprising the pituitary gland, liver and muscle plays a major role in myogenesis. Its output in terms of muscle growth is highly affected by nutritional and environmental cues, and thus likely epigenetically regulated. Hydroxymethylation is emerging as a DNA modification that modulates gene expression but a holistic characterization of the hydroxymethylome of the somatotropic axis has not been investigated to date. Using reduced representation 5-hydroxymethylcytosine profiling we demonstrate tissue-specific localization of 5-hydroxymethylcytosines at single nucleotide resolution. Their abundance within gene bodies and promoters of several growth-related genes supports their pertinent role in gene regulation. We propose that cytosine hydroxymethylation may contribute to the phenotypic plasticity of growth through epigenetic regulation of the somatotropic axis.     

Changes in somatotropic and lactotropic functions of the adenohypophysis of rats with acute alloxan diabetes

Increased growth hormone and prolactin contents of the rat adenohypophysis during the development of experimental diabetes were found by colorimetric studies of stained electrophoregrams. 4 to 5 days after alloxan administration the levels of somatotropic hormone (STH) and prolactin were higher in comparison to those in intact animals by 58% and 43%, respectively. Experiments on the primary cell culture using the precursor 14C-L-leucine revealed an enhanced secretion of somatotropic hormone and prolactin by cells of the rats with alloxan diabetes. A possible role of the adenohypophyseal changes in the development of experimental diabetes is discussed.     

Polymorphism analysis in genes of the somatotropic axis in Nellore cattle selected for growth

The somatotropic axis consists of genes that are involved in muscular development. These genes are potential regions of study to identify possible QTL for economically important traits in beef cattle. The aim of this study was to verify the existence of GH1, POU1F1, and GHR polymorphisms in Nellore cattle to verify the influence of selection in these mutations and to analyse the association between molecular markers and body weight at different ages, yearling hip height, carcass fat thickness and loin eye area. Six hundred forty-five animals from the Centro APTA Bovinos de Corte, were genotyped by PCR–RFLP techniques. The association analyses were performed with general mixed models taking into consideration the effect of one marker, and other model taking into consideration interactions between two molecular markers. Only the molecular markers rs81109601 on GH1 and rs109136815 on GHR were polymorphic; however, they were not found to be under selection. The association of the GHR rs109136815 marker and loin eye area was observed (p < 0.05), as well as the effect of interaction between the markers and the female body weight at 550 days of age (p < 0.04). The interaction effect should be considered in situations where the interactivity between two genes is known.     

Expression profiles of somatotropic axis genes in lines of chickens divergently selected for 56-day body weight

The objective of this study was to evaluate mRNA expression of somatotropic axis genes in chickens divergently selected for high (HWS) or low (LWS) body weight at 56 days of age. Gene expression was measured on days 16, 18, and 20 of incubation, day of hatch, and days 3, 7, 28, and 56 posthatch. Pituitary growth hormone mRNA raised from prehatch to posthatch, with a similar profile in both lines. Liver growth hormone receptor (GHR) mRNA was high during embryogenesis, declined to low levels at day 3 posthatch, and then increased to day 56. Expression of liver insulin-like growth factor 1 (IGF-1) mRNA increased sharply by day 28 in line HWS and day 56 in line LWS. Pectoralis major muscle GHR mRNA was greater in line LWS than HWS. Muscle IGF-1 mRNA declined during embryogenesis, increased posthatch, and declined after day 7. IGF-1 mRNA was 1,000-fold greater in embryonic muscle than embryonic liver. Muscle IGF-1 receptor mRNA was greater in line LWS than HWS posthatch. These results demonstrate that genetic selection for high or low body weight has altered the expression profiles of somatotropic axis genes in a line-, age-, and tissue-specific manner.     

CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation

Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation. Reactive oxygen species (ROS) is associated with mitochondrial dysfunction and cellular damage. Here, we reported an unexplored role of cyclophilin D (CypD), the major modulator of mitochondrial permeability transition pore (mPTP), and the CypD-mPTP axis in inflammation-induced mitochondrial dysfunction and bone damage. And the protective effects of knocking down CypD by siRNA interference or the addition of cyclosporin A (CsA), an inhibitor of CypD, were evidenced by rescued mitochondrial function and osteogenic function of osteoblast under tumor necrosis factor-α (TNF-α) treatment. These findings provide new insights into the role of CypD-mPTP-dependent mitochondrial pathway in the inflammatory bone injury. The protective effect of CsA or other moleculars affecting the mPTP formation may hold promise as a potential novel therapeutic strategy for inflammation-induced bone damage via mitochondrial pathways.     

Hyaluronan-CD44 axis orchestrates cancer stem cell functions

The prominent role of CD44 in tumor cell signaling together with its establishment as a cancer stem cell (CSC) marker for various tumor entities imply a key role for CD44 in CSC functional properties. Hyaluronan, the main ligand of CD44, is a major constituent of CSC niche and, therefore, the hyaluronan-CD44 signaling axis is of functional importance in this special microenvironment. This review aims to provide recent advances in the importance of hyaluronan-CD44 interactions in the acquisition and maintenance of a CSC phenotype. Hyaluronan-CD44 axis has a substantial impact on stemness properties of CSCs and drug resistance through induction of EMT program, oxidative stress resistance, secretion of extracellular vesicles/exosomes and epigenetic control. Potential therapeutic approaches targeting CSCs based on the hyaluronan-CD44 axis are also presented.     

The FSH-inhibin axis in Prader-Willi Syndrome: heterogeneity of gonadal dysfunction

ABSTRACT: BACKGROUND: We characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults. METHODS: Reproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16-34 years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15 IU/l and undetectable INB (<10 pg/ml); Group B: central hypogonadism (FSH <0.5 IU/l, INB <10pg/ml); Group C: partial gonadal & central dysfunction (FSH 1.5-15 IU/l, INB >20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5-15 IU/l, INB < 10 pg/ml. RESULTS: There were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; P=0.04). Significant differences between the groups were found in mean testosterone (P=0.04), AMH (P=0.003) and pubic hair (P=0.04) in males and mean LH (P=0.003) and breast development (P=0.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups. CONCLUSIONS: Analysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.     

Response of the somatotropic axis to alterations in feed intake of channel catfish (Ictalurus punctatus)

To better understand the effects of reduced feeding frequency on the GH–IGF-I axis, channel catfish (Ictalurus punctatus), were either fed (Fed control, commercial diet fed daily), fed every other day (FEOD, commercial diet fed every other day), or not fed (Unfed, no feed). Pituitary GH mRNA increased whereas hepatic growth hormone receptor (GHR), IGF-I mRNA, and plasma IGF-I decreased in the FEOD and Unfed fish (P < 0.05). In another study, fish were either continually fed (Fed) or fasted and then re-fed (Restricted) to examine the physiological regulation of somatostatin-14 (SS-14) and SS-22 mRNA. Fasting increased (P < 0.05) levels of SS-14 mRNA in the hypothalamus and pancreatic islets (Brockmann bodies) at d 30 while re-feeding decreased SS-14 mRNA to control values in all tissues examined by d 45. Fasting had no effect on levels of SS-22 mRNA in the pancreatic islets whereas SS-22 mRNA was not detected in the stomach or hypothalamus. The results demonstrate that feeding every other day has similar negative impacts on components of the GH–IGF-I axis as fasting. The observed increase in SS-14 mRNA in the hypothalamus and pancreatic islets suggests a role for SS-14 in modulating the GH–IGF-I axis in channel catfish.     

Nutritional assessment of somatolactin function in gilthead sea bream (Sparus aurata): concurrent changes in somatotropic axis and pancreatic hormones

The role of somatolactin (SL) in the regulation of energy homeostasis in gilthead sea bream (Sparus aurata) has been analysed. First, a down-regulation of plasma SL levels in response to gross shifts in dietary amino acid profile and the graded replacement of fish meal by plant protein sources (50%, 75% and 100%) has been observed. Thus, the impaired growth performance with changes in dietary amino acid profile and dietary protein source was accompanied by a decrease in plasma SL levels, which also decreased over the course of the post-prandial period irrespective of dietary nitrogen source. Secondly, we examined the effect of SL and growth hormone (GH) administration on voluntary feed intake. A single intraperitoneal injection of recombinant gilthead sea bream SL (0.1 microg/g fish) evoked a short-term inhibition of feed intake, whereas the same dose of GH exerted a marked enhancement of feed intake that still persisted 1 week later. Further, we addressed the effect of arginine (Arg) injection upon SL and related metabolic hormones (GH, insulin-like growth factor-I (IGF-I), insulin and glucagon) in fish fed diets with different nitrogen sources. A consistent effect of Arg injection (6.6 micromol/g fish) on plasma GH and IGF-I levels was not found regardless of dietary treatment. In contrast, the insulinotropic effect of Arg was found irrespective of dietary treatment, although the up-regulation of plasma glucagon and glucose levels was more persistent in fish fed a fish meal based diet (diet FM) than in those fed a plant protein diet with a 75% replacement (diet PP75). In the same way, a persistent and two-fold increase in plasma SL levels was observed in fish fed diet FM, whereas no effect was found in fish fed diet PP75. Taken together, these findings provide additional evidence for a role of SL as a marker of energy status, which may be perceived by fish as a daily and seasonal signal of abundant energy at a precise calendar time.