ArticleLiterature Review

Growth Hormone Deficiency: Health and Longevity

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Abstract

The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH-deficiency (GHD) or GH-resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH-R mutations, combined deficiency of GH, PRL, and TSH, or global deletion of GH receptors live longer than their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, due to a mutation of the GHRHR gene, in the Itabaianinha County, Brazil, provide unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty, but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years in one case. We believe that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved, may account for the normal longevity and apparent extension of healthspan in these individuals.

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... Studies have reported that the relationship between IGF-1 and BMI is negative [6,7], positive [8] or non-linear [9,10]. Additionally, the relationship between IGF-1 and adiposity may be influenced by its role as a positive marker of growth hormone axis activity, which potentially affects statural growth more than adipose tissue accumulation [11]. ...
... Higher IGF-1 concentrations typically reflect higher IGF-1 secretion and bioaction; but can also reflect IGF-1 resistance (for example, due to damaging mutations in the IGF-1 receptor gene, IGF1R [20]). Therefore, we stratified the IGF-1 genetic instruments by their effect on childhood height, as the established role of IGF-1 is to increase height [11] (Fig. 1). GWAS data for childhood height at age 7 was based on 36,102 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) [21]. ...
... While the term 'IGF-1 resistance' is used here in a broad sense and does not specify any particular condition or biological pathway, IGF-1 resistance has been associated with a potential compensatory mechanism involving increased secretion of growth hormone (GH). Elevated GH levels have been found to have lipolytic effects [11]. Thus, IGF-1 resistance may indirectly contribute to the regulation of adiposity through the upregulation of GH secretion. ...
Article
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Background Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear. Methods We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and ‘biological effect’ filtering of fasting insulin and IGF-1 associated variants. Results Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10⁻³) and lower adult BMI (P = 1.4 × 10⁻⁵). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10⁻³), but effects on adult BMI were inconclusive. Conclusions Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. Our findings demonstrate the need to distinguish between bioaction and resistance when modelling variants associated with biomarker concentrations.
... We have studied extensively for 30 years a cohort of individuals with congenital isolated growth hormone deficiency (IGHD) (21) in the city of Itabaianinha, Brazil (22)(23)(24)(25). These individuals have a normal lifespan (26) with an extended healthspan, i.e., the period of life free from major chronic clinical diseases and disabilities (23). ...
... We have studied extensively for 30 years a cohort of individuals with congenital isolated growth hormone deficiency (IGHD) (21) in the city of Itabaianinha, Brazil (22)(23)(24)(25). These individuals have a normal lifespan (26) with an extended healthspan, i.e., the period of life free from major chronic clinical diseases and disabilities (23). The cohort currently includes 15 individuals with IGHD aged 50 years or older, most of whom have low levels of education. ...
... Developed in South Korea, the LICA instrument can be applied universally if translated into local languages and culturally adapted to the local environment. The version of the instrument presented herein was created from a specific need to evaluate the cognitive performance of older individuals with lifelong, congenital, untreated IGHD (23)(24)(25)(26)(27). After the translation and cultural adaptation of this instrument, we are convinced of its usefulness in evaluating dementia disorders at any stage in Brazil and, after minor adaptations, in other Portuguesespeaking countries with high illiteracy rates (1). ...
Article
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Objectives Individuals with congenital isolated growth hormone deficiency (IGHD) in Northeastern Brazil have a normal lifespan with a prolonged healthspan. We hypothesize that their increased healthspan is accompanied by a reduced cognitive decline during aging. We have recently shown that these individuals have a similar total cognitive function and better attention and executive function than controls. These data were obtained using a Portuguese version of the Literacy Independent Cognitive Assessment (LICA) instrument, whose translation to facilitate cognitive research in Portuguese-speaking countries is described here. Subjects and methods In the first stage, a psychologist and a psychiatrist translated the LICA instrument from English into Portuguese, and an English teacher proofread the translation. The second stage included its synthesis and cultural adaptation, carried out by Brazilian authors, and changes in some words and images. The third stage involved an evaluation round with two referees (independent psychologists). The fourth stage involved a back translation of the instrument, which demonstrated > 95% agreement with the original version. The fifth stage included a study to verify the understanding of the questionnaire by responders. In the sixth stage, an endocrinologist and a psychiatrist approved the final Portuguese version of the instrument, which was then administered to 15 individuals with IGHD and 15 controls older than 50 years. Results The LICA instrument was applied 59 times (5 times in the pilot study, 24 in the variability studies, and 30 in the experimental step). The interobserver and intraobserver variabilities were 99% and 96%, respectively. Cronbach’s alpha was 0.76, indicating good reliability. The mean (± standard deviation) duration of the application was 39 ± 8.6 and 48.5 ± 5.8 minutes in literate and illiterate individuals, respectively. Conclusion The Portuguese version of the LICA instrument was valuable for the cognitive assessment of individuals with Itabaianinha syndrome. Illiteracy; dementia; test; translation into Portuguese; growth hormone
... Prevertebrates grow using a variety of extra pituitary circuits, such insulin, insulin-like growth factors (IGFs) and local production of growth factors. However, vertebrates have developed the somatotrophic axis, with pituitary growth hormone (GH) and circulating IGF type1 (IGF1), coupling their body growth with the increased ability to obtain food and reproduce [1]. The somatotrophic system (the somatotrophic axis and extra pituitary circuits), supports the proper development of bones, muscles, teeth and joints, as well as adequate functioning of the immune system, sense organs, and brain [2]. ...
... We have previously demonstrated that these individuals display wrinkled skin [1], reduced sweating [26], and retain vulnerability to cutaneous cancer [25]. Nevertheless, it remains unclear whether this deficiency may impact other aspects of cutaneous physiology. ...
... The number of skin cancers in these IGHD subjects was similar to the local controls, confirming our previous finding that the skin of these IGHD is vulnerable to cancer [25], while in this cohort, no cases of the most common cancers, such as breast, lung, bowel, and prostate, were identified [1,[16][17][18]. Similarly, no case of cancer was observed in patients with congenital insensitivity to GH (Laron syndrome), suggesting that severe IGF1 deficiency protects against the onset of cancer [29,30]. ...
Article
Full-text available
Purpose The separation between the inside and outside through the skin was fundamental for the evolution of prevertebrates, which grow through extrapituitary circuits, to vertebrates, which grow through the somatotrophic axis, namely pituitary growth hormone (GH). and circulating IGF1.Individuals with untreated isolated growth hormone (GH) deficiency (IGHD) due to a mutation in the GH-releasing hormone receptor (GHRH) gene, residing in Itabaianinha, Brazil, are vulnerable to skin cancer and have reduced sweating. However other aspects of their skin physiology are still unknown. Our objectives were to evaluate the number of skin cancers, skin aging, and functional aspects of the skin in this IGHD cohort. Methods Twenty-six IGHD individuals and 26 controls matched by age, sex, ethnicity, and occupation were submitted to a biochemical, dermatological and a functional skin assessment by the Multi Probe Adapter Cutometer® MPA 580. Results There was no difference in the number of skin cancers and in the degrees of photodamage between the groups. The melanin content in the forearm was similar between the groups but was lower in the buttocks (p = 0.005), as well as skin resistance (p < 0.0001) and elasticity (p = 0.003), lower in the IGHD. There was no difference in hydration and sebum content between the two groups. Conclusion IGHD is apparently associated with a neutral profile in terms of skin cancer and photodamage, with similar melanin on the forearm and lower buttocks, lower skin resistance and elasticity, with hydration and sebum similar to controls.
... Prevertebrates grow using a variety of extra pituitary circuits, like insulin and insulin-like growth factors (IGFs). However, vertebrates have developed the somatotrophic axis with the pituitary growth hormone (GH) and circulating IGF type1 (IGF1), coupling their body growth with the increased ability to obtain food and to reproduce [1]. The somatotrophic system (the somatotrophic axis and extrapituitary circuits), extraordinarily complex and sometimes redundant, supports proper growth and function of bones, muscles, joints as well teeth, skull, and brain development [2]. ...
... The somatotrophic system (the somatotrophic axis and extrapituitary circuits), extraordinarily complex and sometimes redundant, supports proper growth and function of bones, muscles, joints as well teeth, skull, and brain development [2]. Brain function seems to depend more on extra-pituitary circuits, namely insulin [3,4], IGF2 [5], brain GH [6] and brain IGF1 and IGF2 [7,8] than on the classical somatotrophic axis (pituitary GH and circulating IGF1) [1,9]. ...
... + 1G → A) in the GHRH receptor (GHRHR) gene (GHRHR OMIM n.618157) [10]. Most affected adults have not received GH replacement and exhibit normal lifespan [11], with an extended healthspan [1]. Very recently we showed that aging in these IGHD subjects is associated with similar total cognitive performance, but better attention and executive function than local controls, measured by the Literacy Independent Cognitive Assessment (LICA) [12]. ...
Article
Individuals with isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene have a normal life expectancy and above 50 years of age, similar total cognitive performance, with better attention and executive function than controls. Our objectives were to evaluate their brain morphometry and brain aging using MRI. Thirteen IGHD and 14 controls matched by age, sex, and education, were enrolled. Quantitative volumetric data and cortical thickness were obtained by automatic segmentation using Freesurfer software. The volume of each brain region was normalized by the intracranial volume. The difference between the predicted brain age estimated by MRI using a trained neuronal network, and the chronological age, was obtained. p < 0.005 was considered significant and 0.005 < p < 0.05 as a suggestive evidence of difference. In IGHD, most absolute values of cortical thickness and regional brain volumes were similar to controls, but normalized volumes were greater in the white matter in the frontal pole and in the insula bilaterally, and in the gray matter, in the right insula and in left Caudate (p < 0.005 for all comparisons) We also noticed suggestive evidence of a larger volume in IGHD in left thalamus (p = 0.006), right thalamus (p = 0.025), right caudate (p = 0.046) and right putamen (p = 0.013). Predicted brain ages were similar between groups. IGHD is primarily associated with similar absolute brain measurements, and a set of larger normalized volumes, and does not appear to alter the process of brain aging.
... We have discussed this issue in more detail in previous publications [25,26]. ...
... Interestingly, even though life expectancy is not extended by genetic syndromes that block GH signaling, GH-resistant, and GH-deficient individuals are significantly protected from chronic aging-associated diseases including cancer, diabetes, and atherosclerosis, show improvements in the maintenance of various physiological functions into advanced age [60], and in at least one population of IGHD individuals appear to be more likely to achieve exceptional longevity [61]. In terms of average longevity, these protective features of GH-deficient and GH-resistant individuals appear to be counterbalanced by an increased risk of early deaths, particularly deaths related to accidents and alcohol abuse [25,60]. Increased chances of living to very old age were reported also in the "little people of Krk," a population of individuals with a GH deficiency caused by a mutation of the Prop1 gene, the same gene which is mutated in the long-lived Ames dwarf mice [57]. ...
... It is interesting that differences in the pace of life also correlate with the differences in life expectancy among humans with extremely short stature. Thus, short stature due to isolated GH deficiency in the Itabaianinha cohort or to GH resistance is associated with a slow pace-of-life (slow growth, delayed puberty, and reduced fecundity), protection from various age-related diseases and conditions leading to "healthy aging" as well as with normal life expectancy [25,109], while short stature in various populations of pygmies is associated with fast pace-of-life (fast development and early age of first pregnancy) and very short life [110]. A particularly striking example of a reciprocal relationship between the pace of life and longevity is provided by an African fish, Nothobranchius furzeri which lives in ephemeral ponds. ...
Article
Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and longevity have been studied for decades and various unifying “theories of aging” have been proposed to account for the observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity includes a remarkable contrast between the positive correlation in comparisons between different species and the negative correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also the rate of aging are related to the “pace-of-life.” A slow pace-of-life including slow growth, late sexual maturation, and a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation, and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs. The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much further work will be needed to verify this interpretation and to identify mechanisms that are responsible.
... We have discussed this issue in more detail in previous publications [25,26]. ...
... Interestingly, even though life expectancy is not extended by genetic syndromes that block GH signaling, GH-resistant, and GH-deficient individuals are significantly protected from chronic aging-associated diseases including cancer, diabetes, and atherosclerosis, show improvements in the maintenance of various physiological functions into advanced age [60], and in at least one population of IGHD individuals appear to be more likely to achieve exceptional longevity [61]. In terms of average longevity, these protective features of GH-deficient and GH-resistant individuals appear to be counterbalanced by an increased risk of early deaths, particularly deaths related to accidents and alcohol abuse [25,60]. Increased chances of living to very old age were reported also in the "little people of Krk," a population of individuals with a GH deficiency caused by a mutation of the Prop1 gene, the same gene which is mutated in the long-lived Ames dwarf mice [57]. ...
... It is interesting that differences in the pace of life also correlate with the differences in life expectancy among humans with extremely short stature. Thus, short stature due to isolated GH deficiency in the Itabaianinha cohort or to GH resistance is associated with a slow pace-of-life (slow growth, delayed puberty, and reduced fecundity), protection from various age-related diseases and conditions leading to "healthy aging" as well as with normal life expectancy [25,109], while short stature in various populations of pygmies is associated with fast pace-of-life (fast development and early age of first pregnancy) and very short life [110]. A particularly striking example of a reciprocal relationship between the pace of life and longevity is provided by an African fish, Nothobranchius furzeri which lives in ephemeral ponds. ...
Article
Full-text available
Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and longevity have been studied for decades and various unifying “theories of aging” have been proposed to account for the observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity includes a remarkable contrast between the positive correlation in comparisons between different species and the negative correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also the rate of aging are related to the “pace-of-life.” A slow pace-of-life including slow growth, late sexual maturation, and a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation, and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs. The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much further work will be needed to verify this interpretation and to identify mechanisms that are responsible.
... Specifically, Chihuahuas live approximately 80% longer than Great Danes, and it could be argued that the difference in longevity is not extreme enough to result in significant variation in cellular stress resistance. However, the observed difference in longevity among several strains of mice harboring pro-longevity mutations is only approximately 30-70% [44], but there are still marked differences in cellular stress resistance in fibroblast cultures isolated from these mice [45]. Notably, each long-lived strain harbors a mutation that results in a significant lowering of the circulating IGF-1 level [44]. ...
... However, the observed difference in longevity among several strains of mice harboring pro-longevity mutations is only approximately 30-70% [44], but there are still marked differences in cellular stress resistance in fibroblast cultures isolated from these mice [45]. Notably, each long-lived strain harbors a mutation that results in a significant lowering of the circulating IGF-1 level [44]. Similarly, body size has been linked to differences in the circulating IGF-1 level among small versus large breed dogs [46,47]. ...
Article
Small-breed dogs live significantly longer lives than large-breed dogs, while having higher mass-specific metabolic rates and faster growth rates. Underlying this observed physiological difference across domestic dogs, there must also be differences at other levels of organization that could lead to elucidating what accounts for the disparity in aging rates and life span within this species. At the cellular level, a clear mechanism underlying whole animal traits has not been fully elucidated. Here, we cultured dermal fibroblasts from large and small breed dogs from both young and old age categories and examined the degree of resistance to multiple sources of cytotoxic stress. This included heat (42 °C), paraquat, cadmium, and hydrogen peroxide for increasing amounts of time (heat) or increasing concentrations (chemical stressors). We hypothesized that small breed dogs, with longer lifespans, would have greater cellular resistance to stress compared with large breed dogs. Final sample sizes include small puppies (N = 18), large puppy (N = 32), small old (N = 11), and large old (N = 23) dogs. Using a 2 (donor size) by 2 (donor age) between-subjects multivariate analysis of variance, we found that the values for the dose that killed 50% of the cells (LD50) were not significantly different based on donor size (p = 0.45) or donor age (p = 0.20). The interaction was also not significant (p = 0.47). Interestingly, we did find that the degree of resistance to cadmium toxicity was significantly correlated with the degree of resistance to both heat and hydrogen peroxide, but not paraquat (p < 0.01 for both). These data suggest that cellular stress resistance does not differ among domestic dogs as a function of size or age, pointing to other cellular pathways as the mechanistic basis for the observed differences in lifespan.
... Growth hormone (GH) is a significant regulator of growth and metabolism [1]. In the liver, GH stimulates the synthesis and secretion of insulin-like growth factor 1 (IGF-1) [2]. ...
... GH/IGF-1 axis can regulate hepatic glucose and lipid metabolism, including glucose production, the uptake and storage of lipids, and the secretion of triglycerides [3]. Growth hormone deficiency (GHD) is a relatively uncommon endocrine disease caused by a primary deficiency of GH and a secondary deficiency of IGF-1 [1]. Several studies have shown that congenital GHD was associated with an increased risk of metabolic syndromes, such as nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hyperlipidemia [4][5][6]. ...
Article
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Objective: Patients with growth hormone deficiency (GHD) with inadequate growth hormone levels are often correlated with nonalcoholic fatty liver disease (NAFLD). However, potential mechanism of how GHD influences liver function remains obscure. Thus, we aimed to perform hepatic metabolomics in Lewis dwarf rats, a classical model of isolated GH-deficient rat, to evaluate characterizations of hepatic metabolic profiles and explore their relations with liver functions. Methods: Lewis dwarf homozygous (dw/dw) rats at 37 weeks (five females and five males), and Lewis dwarf heterozygous (dw/+) rats at 37 weeks (five females and five males) were analyzed in our study. The body lengths and weights, liver weights, serum ALT, and AST levels were measured. The non-targeted hepatic metabolomics was performed between dw/+ and dw/dw rats. Results: Body weights and lengths, liver weights, and serum IGF-1 levels in dw/dw rats were significantly decreased when compared with dw/+ rats. Dw/dw rats exhibited more obvious hepatic steatosis accompanied by higher serum ALT and AST levels. Hepatic metabolomics showed that a total of 88 and 51 metabolites were identified in positive and negative modes, respectively. Seven metabolites (LPC 16:2, LPC 18:3, LPC 22:6, FAHFA18:1, palmitoyl acid, dehydrocholic acid and 7-Ketolithocholic acid) were significantly altered. These seven differential metabolites were significantly associated with abnormal phenotypes. KEGG pathway analysis showed that arginine and proline metabolism and bile secretion pathways were mainly clustered. Conclusion: Lewis dw/dw rats with isolated growth hormone deficiency (IGHD) showed liver steatosis and abnormal liver function, which could be potentially associated with distinctive hepatic metabolic profiles.
... During pregnancy, their activation in the placenta augments fetal growth in response to maternal nutrient availability (19)(20)(21)(22). There is evidence that mTOR suppression is a mediating pathway linking childhood malnutrition to stunting (23,24), while lower GH/IGF-1 due to genetic mutation has been found to result in shorter stature and delayed puberty (25). mTOR also plays an important role in brain development, including proliferation and differentiation of neurons and glia (26,27). ...
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The rise in chronic diseases over the last century presents a significant health and economic burden globally. Here we apply evolutionary medicine and life history theory to better understand their development. We highlight an imbalanced metabolic axis of growth and proliferation (anabolic) versus maintenance and dormancy (catabolic), focusing on major mechanisms including IGF-1, mTOR, AMPK, and Klotho. We also relate this axis to the hyperfunction theory of aging, which similarly implicates anabolic mechanisms like mTOR in aging and disease. Next, we highlight the Brain-Body Energy Conservation model, which connects the hyperfunction theory with energetic trade-offs that induce hypofunction and catabolic health risks like impaired immunity. Finally, we discuss how modern environmental mismatches exacerbate this process. Following our review, we discuss future research directions to better understand health risk. This includes studying IGF-1, mTOR, AMPK, and Klotho and how they relate to health and aging in human subsistence populations, including with lifestyle shifts. It also includes understanding their role in the developmental origins of health and disease as well as the social determinants of health disparities. Further, we discuss the need for future studies on exceptionally long-lived species to understand potentially underappreciated trade-offs and costs that come with their longevity. We close with considering possible implications for therapeutics, including (1) compensatory pathways counteracting treatments, (2) a Goldilocks zone, in which suppressing anabolic metabolism too far introduces catabolic health risks, and (3) species constraints, in which therapeutics tested in shorter lived species with greater anabolic imbalance will be less effective in humans.
... 25 Weight loss can also trigger changes in neuroendocrine hormones including an increase in growth hormone, 26 which might link to higher mortality risks as observed in transgenic mice and people with acromegaly. 27 Two meta-analyses have shown weight loss associated with increased all-cause mortality risk across ethnicity. 28 29 In particular, unintentional weight loss was positively associated with allcause mortality, and being obese at baseline did not alter the risk imposed by unintentional weight loss. ...
Article
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Background Weight loss at older ages appears to be associated with higher mortality in Western and some East Asian countries, despite differences in the prevalence of obesity; whether it is relevant to China is unknown. We examined the association of body mass index (BMI) trajectories with all-cause mortality in older Chinese adults by sex and baseline age (65–69 years, 70+ years). Methods 54 160 participants aged 65 or above from Hong Kong’s Elderly Health Service Cohort with at least five BMI measurements were included. We identified distinct BMI trajectories using group-based trajectory modelling. We assessed the associations of BMI trajectories with mortality risk using a Cox model stratified by sex and age. Results Compared with ‘normal weight, stable’, the ‘low-normal weight, decreasing’ had higher mortality risk in both sexes and age groups (eg, HR 1.43, 95% CI 1.24 to 1.66 in men aged 65–69 years). The ‘overweight, stable’ and ‘obese, stable’ had lower mortality risk, especially in men at older ages. However, the proportion in the ‘low-normal weight, decreasing’ was greater at 70+ years than at 65–69 years, while the proportion in the ‘overweight, stable’ and ‘obese, stable’ was lower in the older group. Conclusions Decreasing BMI is a likely symptom of ill health in older adults. Inconsistency between the risks and the proportion in each BMI trajectory group by age suggests the observed associations could be driven by changes in weight and preferential recruitment of survivors. Maintaining a healthy weight remains relevant at older ages.
... Therefore, complete elimination of this pathway could disrupt these functions, counteracting localized benefits. It is noteworthy that only few studies have shown lifespan extension from fully ablating core processes; instead, benefits often arise from modulation, as seen with growth hormone signaling [68] or caloric restriction [69]. Thus, the absence of lifespan extension in Mlkl −/− or Ripk3 −/− mice, despite reduced liver inflammation and metabolic improvements, suggests that aging involves complex systemic interactions beyond the liver. ...
Article
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Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in Mlkl −/− or Ripk3 −/− aged mice, supporting a systemic effect of necroptosis inhibition on inflammation. Proteomic analysis of liver tissues emphasizes the critical role of lipid and immune regulatory processes in maintaining liver homeostasis when Mlkl or Ripk3 is absent in aging liver. While Mlkl deletion did not affect the lifespan of mice, Ripk3 deletion shortened it. Additionally, Mlkl deficiency improved insulin sensitivity, whereas Ripk3 deficiency exacerbated glucose intolerance in aged mice. Thus, selective inhibition of Mlkl, not Ripk3, represents a potential therapeutic avenue for mitigating age-related liver disease and enhancing metabolic outcomes in the elderly.
... Particularly, we identified distinct transcriptomic signatures altered by FMT to delineate mechanisms that contribute to improved healthspan. Ames dwarf mice represent a highly valuable animal model to study aging as these mutant mice live approximately 40-60% longer than their normal littermates and maintain increased healthspan through this extraordinary lifespan extension [23][24][25][26][27][28][29][30]. Importantly, our earlier study showed that these df/df mice also have a distinct, healthier microbiome compared to their normal littermate controls [31]. ...
Article
Aging is associated with intestinal dysbiosis, a condition characterized by diminished microbial biodiversity and inflammation. This leads to increased vulnerability to extraintestinal manifestations such as autoimmune, metabolic, and neurodegenerative conditions thereby accelerating mortality. As such, modulation of the gut microbiome is a promising way to extend healthspan. In this study, we explore the effects of fecal microbiota transplant (FMT) from long-living Ames dwarf donors to their normal littermates, and vice versa, on the recipient gut microbiota and liver transcriptome. Importantly, our previous studies highlight differences between the microbiome of Ames dwarf mice relative to their normal siblings, potentially contributing to their extended lifespan and remarkable healthspan. Our findings demonstrate that FMT from Ames dwarf mice to normal mice significantly alters the recipient’s gut microbiota, potentially reprogramming bacterial functions related to healthy aging, and changes the liver transcriptome, indicating improved metabolic health. Particularly, the microbiome of Ames dwarf mice, characterized by a higher abundance of beneficial bacterial families such as Peptococcaceae, Oscillospiraceae, and Lachnospiraceae, appears to play a crucial role in modulating these effects. Alongside, our mRNA sequencing and RT-PCR validation reveals that FMT may contribute to the significant downregulation of p21, Elovl3, and Insig2, genes involved with cellular senescence and liver metabolic pathways. Our data suggest a regulatory axis exists between the gut and liver, highlighting the potential of microbiome-targeted therapies in promoting healthy aging. Future research should focus on functional validation of altered microbial communities and explore the underlying biomolecular pathways that confer geroprotection.
... GH disorders, which can be congenital or acquired later in life, are medical conditions caused by insufficient GH production. Possible causes include genetic abnormalities, injuries, infections, tumors, and radiation therapy [7]. The GH axis, along with its receptor (GHR), IGF-I, and the GHRH, plays a crucial role in growth, development, and cellular homeostasis. ...
Article
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Growth hormone (GH) is a key polypeptide hormone secreted by somatotroph cells in the anterior pituitary gland, essential for postnatal growth, metabolism, and systemic homeostasis. Its secretion is regulated by hypothalamic neuropeptides, including GH-releasing hormone and somatostatin. GH exerts effects through direct interaction with the growth hormone receptor and indirect pathways mediated by the GH-IGF-I axis. GHR activation triggers signaling pathways, such as JAK-STAT, PI3K/AKT, and MAPK, promoting cellular proliferation, differentiation, and metabolic balance. The GH-IGF-I axis is critical for bone growth, lipid and carbohydrate metabolism, and organ-specific physiological functions. Dysregulation of GH results in diverse disorders. Congenital deficiencies, like isolated GH deficiency and syndromic conditions (e.g., Turner syndrome), stem from genetic mutations. Acquired deficiencies arise from trauma, tumors, infections, or autoimmune damage, while GH overproduction causes gigantism in children and acromegaly in adults, often due to pituitary adenomas. Idiopathic deficiencies, lacking identifiable causes, complicate management further. Advances in therapy have transformed outcomes for GH disorders. Recombinant human growth hormone provides effective replacement therapy for deficiencies. Somatostatin analogs, dopamine receptor agonists, and GH receptor antagonists are pivotal for managing GH excess. Surgical and radiotherapeutic interventions remain essential for pituitary adenomas. However, GH therapy requires close monitoring to prevent side effects like insulin resistance and metabolic complications. This review provides a comprehensive evaluation of the molecular mechanisms underlying GH action, its physiological roles, GH-related disorders, and therapeutic approaches to optimize patient outcomes.
... Once an organism has reached its full growth and maturity, it may successfully reproduce and end in senescence (Arking, 2006). The longevity of a species reflects the extent of its biological ageing and represents the average duration of an organism living in its environment (Aguiar-Oliveira & Bartke, 2018). It is consistently linked to an organism's fitness. ...
Article
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Longevity plays a significant role in determining an animal's overall health. Nutrition is a key factor that can influence an animal's longevity. Studying the relationship between wing symmetry and longevity provides a useful approach to understanding how nutrition can affect both longevity and symmetry. The effect of Pomegranate Juice (PJ) and Pomegranate Peel (PP) on longevity and Fluctuating Asymmetry (FA) of wings in male and female Drosophila melanogaster was analysed using Geometric Morphometric Analysis (GMA). The study revealed that PJ and PP-treated flies showed increased longevity and the highest FA compared to control in both males and females. Between PJ and PP-treated flies, PJ had the highest longevity in both males and females whereas PP flies had higher FA in both sexes. Between the sexes, females had lower longevity and FA values compared to males. Overall GMA study reveals shape variation for wings and the presence of a strong FA in PJ and PP flies. Pearson correlation revealed a strong positive association between longevity and wing FA.
... Moreover, in this study, researchers mentioned that mice with GnRH defects exhibit reduced levels of IGF2 [40]. We observed an increase in IGF2 levels. ...
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Background The insulin-like growth factor (IGF) system plays a vital role in regulating gonadotropin-releasing hormone (GnRH), whether the IGF2 can act on the GnRH neurons during the pubertal period is unclear. Methods Central precocious puberty (CPP) rats were induced by danazol, and when the rats met the first diestrus, they were euthanized and tissues were collected. GT1-7 cells were cultured and treated with 0, 1, 10 ng/mL IGF2 for 4 hours and the changes in GnRH were measured. Mice were injected intracerebroventricularly with IGF2 (15 ng/g, 5 μL) or with the same dose of phosphate buffered saline (PBS), after eight hours, they were euthanized and tissues collected. Results CPP rats had increased expression of IGF2 and GnRH mRNA and their respective proteins in the preoptic area (POA) of the hypothalamus. Treatment of GT1-7 cells with 10 ng/mL of IGF2 increased GnRH mRNA and protein expression, and GnRH concentration in the culture medium. Injection of IGF2 protein into the lateral ventricle of mice increased the expression of GnRH mRNA and protein in the POA. Conclusions IGF2 may upregulate the synthesis of GnRH during the pubertal period, and may also take part in the pathology of CPP.
... Congenital isolated growth hormone deficiency (IGHD) is defined as childhood growth retardation because of decreased GH [2]. The demonstration of poor linear growth, delayed skeletal age, and peak levels of GH (< 7ng/ml) in each of the two provocative tests is compatible with diagnosing GH deficiency [3,4]. ...
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Background The purpose of this study is to evaluate the retinal and choroidal microvascular state in children with congenital isolated growth hormone deficiency (IGHD) and determine the effect of recombinant human growth hormone treatment on these structures compared with healthy controls. Methods The study included children with IGHD under recombinant human GH treatment as group one and another group of healthy controls. Both groups were examined using optical coherence tomography angiography (OCTA). Data concerning superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC), and retinal thickness were recorded. Results The study included two equal groups of 30 individuals. Both groups had no statistically significant differences in age, gender, weight, or spherical equivalent. However, subjects of group II were taller than those of group I ( p = 0.011). OCTA images of the SCP, DCP, and CC vessel density revealed statistically non-significant differences between the two groups. Conclusion Children receiving recombinant growth hormone therapy showed no changes in the retinal and choroidal microvasculature or macular thickness. Trial registration number 1094/03/2024 by Minia University Faculty of Medicine Institutional Review Board. Another registration number is UMIN000055654.
... With all these important biological, cellular, and molecular functions, it means any mutation in the gene (positive or negative) will likely have an impact on the functions that the gene and its associated genes control. This has been alluded to by several authors(Kastrup et al., 1978; Schmidt et al., 1996;Ariyasu et al., 2005;Liu et al., 2016;Aguiar-Oliveira et al., 2017Aguiar-Oliveira and Bartke, 2019). The application of functional analysis in the understanding of modern biology and medicine(Barabasi and Oltvai, 2004;Hu et al., 2016;Conte et al., 2020) can therefore, not be discountenanced. ...
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Livestock (farmed domestic animals) play crucial roles in the attainment of several Sustainable Development Goals (SDGs) of the United Nations. There is also an intricate link between one health (human, animal, and environmental) that is advocated by the World Health Organisation and the Sustainable Development Goals which encompasses environmental, economic, and social issues. Many infectious diseases and new or emerging infectious diseases are zoonotic in origin; this includes the current pandemic known as COVID-19. Animal-source foods will increasingly play a huge role in ensuring basic nutrition and health for humans in the coming years, especially in developing countries where the human population will increase rapidly. Three SDGs (Zero hunger, Good health and well-being, and Responsible consumption and production) will thus be addressed by livestock development. Livestock holds the key to sustainable economic growth, addressing two SDGs (Decent work and economic growth and Industry, Innovation, and Infrastructure). The livestock sector contributes 40% of the Agricultural GDP in developing 116 countries and the percentage is growing (FAO, 2021). Equitable livelihoods can be achieved by livestock development, covering four SDGs (No poverty, Quality education, Gender equality, and Peace, Justice, and Strong Institutions). Lastly, livestock can help ensure sustainable ecosystems. Six SDGs can be covered (Clean water, Affordable and Clean Energy, Sustainable cities and communities, Climate Action, Life below water, and Life on land). Global livestock development should therefore be given a pride of place, especially considering their envisaged importance in developing countries.
... The loss of function mutations in PROP1 and PIT1 genes of long-lived Ames and Snell mice cause delayed growth and dwarfism. The loss of function of these genes in humans causes severe developmental abnormalities [32,33] and appear not to increase lifespan [34]. Finally, most gene therapies result in a concomitant burden on the liver and immune system [35,36] and in some cases, the use of certain vectors is limited due to insertional mutagenesis [37,38]. ...
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Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. This outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact. Hence solving the problem of aging may require targeting not one but many of its underlying causes at once. Here we review the challenges and successes of combination therapies aimed at increasing the lifespan of mammals and propose novel directions for their development. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.
... The GH/IGF1 pathway is a well-recognized regulator of lifespan across diverse species, ranging from worms to mammals. Numerous studies have consistently shown that suppressing this pathway effectively inhibits cancer development [26,27]. Remarkably, mutations resulting in the downregulation of this pathway, as observed in Ames and Snell dwarf mice, reduce body mass and size, decrease reproductive capacity, improve metabolic function during aging, and notably extend lifespan [28]. ...
... However, the precise contribution of the different diseases to the endocrinologic disturbance remains unclear. Thus, there are also studies showing that, for example, besides presenting with growth hormone deficiency or GH resistance, laboratory mice indeed live longer than their counterparts [48]. ...
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Purpose It is unclear whether the age-related decline in the somatotropic axis stems from a reduced growth hormone (GH) production in the pituitary gland, or from a peripheral origin akin to an acquired GH resistance. With the help of a GHRH/arginine test, high-aged multimorbid hospitalized patients with IGF-I deficiency are to be tested to determine whether there is primarily a pituitary GH deficiency in the sense of a somatopause. Methods Seventeen multimorbid patients (eleven men and six women) with a mean age of 82 years, with IGF-I concentrations below two standard deviations of 30-year-old men and women were identified. Patients suffered from a variety of common age-related stable diseases including coronary artery disease, chronic liver or kidney disease, chronic heart failure as well as acute conditions e.g., urosepsis or endocarditis. To assess the somatotropic axis they underwent a GHRH/arginine test. Results were evaluated using descriptive statistics. Results In average, the peak concentration of GH after stimulation was 14.8 µg/L with a range from 2.76 to 47.4 µg/L. Taking into account both, gender and BMI (with a mean of 26.5 kg/m²) for each participant, the pituitary gland was adequately stimulated in 16 out of the 17 patients. No patient reported common side effects related to the GHRH/arginine test. Conclusion The somatotroph pituitary gland retains its secretory capacity in the advanced aged. Therefore, age does not seem to be the driving pacemaker for the functional decline of the somatotropic axis within the aged population.
... While the world continues to witness a remarkable increase in the aging population due to considerable advances in medicine, there is an urgent demand for novel strategies to improve the quality of life in these extended years. A key determinant of extended lifespan is delayed puberty which is believed to diminish the risk of mortality by correspondingly preventing the onset of many age-related manifestations including neurodegeneration, type II diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), and cancer (Aguiar-Oliveira & Bartke, 2019;Shadyab et al., 2017;Widen et al., 2012). As such, the period of postnatal development is regarded as a critical stage during an organism's lifetime due to its influence on the future trajectory for health and vitality (Dorn et al., 2019;McMullen & Mostyn, 2009;Zhu et al., 2022). ...
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Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA‐approved medication for type II diabetes mellitus, has recently gained attention for its promising anti‐aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI‐1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI‐1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3‐kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very‐low‐density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age‐related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.
... However, other studies suggest that insulin/IGF signalling pathways protect against proteotoxicity associated with aging. Mice with GH deficiency or GH resistance, and low circulating IGF-I live longer [99]. However, these mice have some tissue IGF-I, including the brain. ...
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The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer’s disease and Parkinson’s disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer’s therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.
... In addition, within the GHRH group, the survival rate of offspring increased uniformly, whereas the rate of stillbirths decreased. The effects of heightened maternal GHRH production on offspring survival and growth are likely attributed to a combination of various factors [19]. The administration of GHRH suggested potential implications for improving the uterine environment [20] and affecting the growth and development of conceptuses in sows. ...
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Simple Summary In the field of veterinary science and animal husbandry, a sow that has given birth more than once is considered “multiparous”. Sows are classified as nulliparous from the moment they arrive at the farm until their first farrowing. During this time, they are frequently referred to as “primiparous”. Growth hormone-releasing hormone (GHRH) plasmid administration had significant effects on serum insulin-like growth factor-1 (IGF-1) levels, birth outcomes, and weaning parameters across different sow categories, indicating its potential for enhancing reproductive performance and postnatal outcomes in sows. Specifically, it affected live births, survival rates, and weaning success without notable effects on birth weight. Abstract The effect of growth hormone-releasing hormone (GHRH) plasmid treatment on sow reproductive performance was examined. Forty pregnant sows (three-way crossbreed: Landrace × Yorkshire × Duroc) at 85 days of gestation were included in the study and consisted of twenty primiparous and twenty multiparous sows (third parity). Sows were randomly assigned to the control and treatment groups. The treatment group received 5 mg dose of GHRH plasmid injection via electroporation, whereas the control group received a phosphate buffer solution. Reproductive indicators, including serum insulin-like growth factor-1 (IGF-1) concentration and weaned piglet data, were assessed. In the GHRH plasmid-treated group, serum IGF-1 concentration significantly increased compared with that in the control group, a trend observed in primiparous and multiparous sows. The key indicator of reproductive performance, litter size, showed that for control primiparous sows (C-PS), it was 10.90 ± 0.99 kg, while for control multiparous sows (C-MS), it was 14.00 ± 0.67 kg. Furthermore, for primiparous sows treated with GHRH plasmid (G-PS), the litter size was 11.60 ± 0.97 kg, and for multiparous sows treated with GHRH plasmid (G-MS), it was 14.00 ± 0.82 kg. The GHRH plasmid-treated group also exhibited a higher number of total births and surviving piglet numbers, along with a decrease in stillborn piglets; however, there was no significant difference in birth weight. The results suggest that GHRH plasmid treatment can enhance the reproductive performance of sows.
... Low IGF-1 levels have been associated with the presence of traditional vascular risk factors, particularly obesity [19] and diabetes [20]. Because of its functional characteristics, IGF-1 also represents a promising target for delaying aging-associated degeneration [21] and modulating neuroprotective responses [22]. However, the cellular mechanisms underlying IGF-1 influences on stroke are not fully understood. ...
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Cytokines and growth factors contribute to nerve growth and angiogenesis and are associated with the development of vascular disease. This Mendelian randomization (MR) study was designed to examine the causal relationship between factors associated with stem cell paracrine mechanisms and with stroke and its subtypes. We used pooled statistics on cytokine levels from three studies (INTERIAL, Olink Proseek CVD array, and KORA) encompassing 7795 participants in Europe. Data for stroke and its subtypes were pooled from these European populations (40,585 cases and 406,111 controls) in a multiprogenitor genome-wide association study (GWAS). MR was performed using established analytical methods, including inverse variance weighting (IVW), weighted median (WM), and MR-Egger. Genetically determined high IGF-1 levels were found to associate negatively with risk of stroke, ischemic stroke (large-artery atherosclerosis), and ischemic stroke (cardiogenic embolism). Meanwhile, high IL-13 levels had a positive causal relationship with ischemic stroke (large-artery atherosclerosis). An additional 27 cytokines were found to have a causal association with stroke or its subtypes. However, these results should be interpreted with caution given that the power efficacy was <80%. This MR study supports the concept of a causal relationship of 29 cytokines with stroke or its subtypes. Our genetic analysis provides new insights into stroke prevention and treatment by demonstrating an association of stem cell paracrine-related cytokines with stroke risk.
... Studies have shown that alterations in insulin and insulin-like growth factor 1 (IGF-1) signaling can affect healthspan and lifespan in a large number of organisms ranging from worms to humans (Min and Tatar, 2018; Aguiar-Oliveira and Bartke, 2019;Bartke, 2021;Bartke, 2022). The lifespan extending effects in mammals are believed to occur through the actions of growth hormone (GH) signaling through the somatotropic axis. ...
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Growth hormone (GH) signaling influences lifespan in a wide variety of mammalian species. We previously reported that a cluster of miRNAs located on the X-chromosome are de-repressed with age in male mouse liver, and a subset, the mir-465 family, can directly attenuate expression of the growth hormone receptor (GHR) in vitro leading to a reduction in GH signaling. Here we show that this cluster of miRNAs is also upregulated in the liver with age in females, and that calorie restriction and the Ames dwarf genotype, both known to delay aging, attenuate the upregulation of the miRNA cluster. Upregulation of mir-465 in vivo leads to a reduction in GHR mRNA in the liver and an attenuation of GH signaling, indicated by a reduction in GHR, IGF-1, IGFBP3, and ALS mRNA expression. There is a corresponding reduction in IGF-1 protein levels in the liver and plasma. These results suggest that the age-associated upregulation of the X-chromosomal cluster of miRNAs could influence lifespan.
... Pathways increased in both depots include the insulin secretion signaling pathway and the senescence pathway. Previous data show decreased senescence with decreased GH action [18,50], so this is an unexpected result, while the decreased WAT browning with decreased GH action agrees with previous reports [51]. Further examination into these results is warranted especially due to the lack of longevity data available for the GHR-KO pigs. ...
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Purpose Growth hormone receptor knockout (GHR-KO) pigs have recently been developed, which serve as a large animal model of Laron syndrome (LS). GHR-KO pigs, like individuals with LS, are obese but lack some comorbidities of obesity. The purpose of this study was to examine the histological and transcriptomic phenotype of adipose tissue (AT) in GHR-KO pigs and humans with LS. Methods Intraabdominal (IA) and subcutaneous (SubQ) AT was collected from GHR-KO pigs and examined histologically for adipocyte size and collagen content. RNA was isolated and cDNA sequenced, and the results were analyzed to determine differentially expressed genes that were used for enrichment and pathway analysis in pig samples. For comparison, we also performed limited analyses on human AT collected from a single individual with and without LS. Results GHR-KO pigs have increased adipocyte size, while the LS AT had a trend towards an increase. Transcriptome analysis revealed 55 differentially expressed genes present in both depots of pig GHR-KO AT. Many significant terms in the enrichment analysis of the SubQ depot were associated with metabolism, while in the IA depot, IGF and longevity pathways were negatively enriched. In pathway analysis, multiple expected and novel pathways were significantly affected by genotype, i.e. KO vs. controls. When GH related gene expression was analyzed, SOCS3 and CISH showed species-specific changes. Conclusion AT of GHR-KO pigs has several similarities to that of humans with LS in terms of adipocyte size and gene expression profile that help describe the depot-specific adipose phenotype of both groups.
... Generally, when downstream targets of Hnf1a are deleted, it results in smaller stature and longer lifespan in both humans and mice. For instance, deficiency in growth hormone or IGF1 confers longer lifespan and healthspan [131,132]. In some instances of Laron syndrome , individuals exhibit insulin resistance and hyperlipidaemia but still have long lives [133,134]. ...
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DNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. Trans-modulated CpGs showed age-dependent changes and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and ageing resulted in a more ‘aged methylome’ for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein–protein interaction enrichment analyses identified the hepatic nuclear factor, Hnf1a (MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variations in body size and metabolic traits, and influence CpG methylation and epigenetic ageing that could have an impact on lifespan.
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Many countries face an unprecedented challenge in aging demographics. This has led to an exponential growth in research of aging, which, coupled to a massive financial influx of funding in the private and public sectors, has resulted in seminal insights into the underpinnings of this biological process. However, critical validation in humans have been hampered by the limited translatability of results obtained in model organisms, additionally confined by the need for extremely time-consuming clinical studies in the ostensible absence of robust biomarkers that would allow monitoring in shorter time frames. In the future, molecular parameters might hold great promise in this regard. In contrast, biomarkers centered on function, resilience and frailty are available at the present time, with proven predictive value for morbidity and mortality. In this review, the current knowledge of molecular and physiological aspects of human aging, potential anti-aging strategies, and the basis, evidence, and potential application of physiological biomarkers in human aging are discussed.
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Skin is the largest organ of the human body and undergoes both intrinsic (chronological) and extrinsic aging. While intrinsic skin aging is driven by genetic and epigenetic factors, extrinsic aging is mediated by external threats such as UV irradiation or fine particular matters, the sum of which is referred to as exposome. The clinical manifestations and biochemical changes are different between intrinsic and extrinsic skin aging, albeit overlapping features exist, eg, increased generation of reactive oxygen species, extracellular matrix degradation, telomere shortening, increased lipid peroxidation, or DNA damage. As skin is a prominent target for many hormones, the molecular and biochemical processes underlying intrinsic and extrinsic skin aging are under tight control of classical neuroendocrine axes. However, skin is also an endocrine organ itself, including the hair follicle, a fully functional neuroendocrine "miniorgan." Here we review pivotal hormones controlling human skin aging focusing on IGF-1, a key fibroblast-derived orchestrator of skin aging, of GH, estrogens, retinoids, and melatonin. The emerging roles of additional endocrine players, ie, α-melanocyte-stimulating hormone, a central player of the hypothalamic-pituitary-adrenal axis; members of the hypothalamic-pituitary-thyroid axis; oxytocin, endocannabinoids, and peroxisome proliferator-activated receptor modulators, are also reviewed. Until now, only a limited number of these hormones, mainly topical retinoids and estrogens, have found their way into clinical practice as anti-skin aging compounds. Further research into the biological properties of endocrine players or its derivatives may offer the development of novel senotherapeutics for the treatment and prevention of skin aging.
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Introduction The diagnosis of Growth Hormone Deficiency (GHD) during childhood has been the subject of much controversy over the last few years. Aiming to accurate medical treatment, there is a need for biomarker discovery. Objective To characterize the metabolic profile of GHD children, examine the effect of GH administration on the metabolic signature, and investigate the correlations between metabolites and IGF-1. Methods Nuclear Magnetic Resonance (NMR)-based untargeted and targeted metabolomic approach applied to study the metabolic profiles of children with GHD. Plasma, serum, and urine samples were collected from twenty-two children diagnosed with GHD and forty-eight age matched controls from the Pediatric Endocrinology Unit of the University Hospital of Patras. Experimental data were examined by both multivariate and univariate statistical analysis. Results The results of this pilot study revealed a different metabolic fingerprint of children with GHD in comparison to age-matched healthy individuals. However, the detected alterations in the metabolite patterns before and after GH treatment were subtle and of minor discriminative statistical power. Conclusions This study provides evidence that metabolome plays a pivotal role in GHD, but large-scale multicenter studies are warranted to validate the results.
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Growth hormone-releasing hormone (GHRH) and its ability to stimulate the production and release of growth hormone from the pituitary were discovered more than four decades ago. Since then, this hormone has been studied extensively and research into its functions is still ongoing. GHRH has multifaceted roles beyond the originally identified functions that encompass a variety of direct extrapituitary effects. In this Review, we illustrate the different biological activities of GHRH, covering the effects of GHRH agonists and antagonists in physiological and pathological contexts, along with the underlying mechanisms. GHRH and GHRH analogues have been implicated in cell growth, wound healing, cell death, inflammation, immune functions, mood disorders, feeding behaviour, neuroprotection, diabetes mellitus and obesity, as well as cardiovascular, lung and neurodegenerative diseases and some cancers. The positive effects observed in preclinical models in vitro and in vivo strongly support the potential use of GHRH agonists and antagonists as clinical therapeutics.
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Osteoarthritis (OA), a chronic joint disease characterized by primary or secondary degeneration of articular cartilage and bone dysplasia, is associated with various risk factors and is the leading cause of musculoskeletal pain and disability, severely impacting the quality of life. Growth hormone (GH), secreted by the anterior pituitary gland, is essential in mediating the growth and development of bone and cartilage. Reportedly, osteoarthritis increases, and the growth hormone decreases with age. A negative correlation between GH and OA suggests that GH may be related to the occurrence and development of OA. Considering that abnormal growth hormone levels can lead to many diseases related to bone growth, we focus on the relationship between GH and OA. In this review, we will explain the effects of GH on the growth and deficiency of bone and cartilage based on the local pathological changes of osteoarthritis. In addition, the potential feasibility of treating OA with GH will be further explored and summarized.
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Adult growth hormone deficiency (AO-GHD) is associated with increased mortality due to a higher risk of cardiovascular complications. Oxidative stress (OS) diminishes antioxidant capacity, leading to endothelial dysfunction and promoting thrombotic and inflammatory mechanisms. This increases the risk of cardiovascular diseases and metabolic disorders. Imbalances in the synthesis or signaling of endothelin-1 (ET-1) and nitric oxide (NO) are linked to hypertension, atherosclerosis, and heart failure. Additionally, elevated levels of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, contribute to vascular endothelial dysfunction, increased vascular tension, higher blood pressure, and the activation of pro-atherogenic mechanisms. This preliminary study aims to investigate the cardiovascular effects of recombinant human growth hormone (rhGH) therapy in AO-GHD. The findings of this research suggest a potential association between rhGH replacement therapy in AO-GHD patients and a reduction in cardiovascular risk through its impact on ET-1, NO, ADMA concentrations, and OS status markers. These results have the potential to inform the optimization of rhGH replacement therapy protocols, thereby exerting a broader influence on the cardiovascular well-being of individuals undergoing such interventions.
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The geroscience research program of the last decade has entailed a shift of focus in research on aging, away from understanding its underlying biology and towards translation into anti-aging treatments—a shift that is premature. [Image: see text]
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Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from day 16 (or ~70 yr in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.
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Disease treatment and prevention have improved the human lifespan. Current studies on aging, such as the biological clock and senolytic drugs have focused on the medical treatments of various disorders and health maintenance. However, to efficiently extend the human lifespan to its theoretical maximum, medicine can take a further proactive approach and identify the inapparent disorders that affect the gestation, body growth, and reproductive stages of the so‐called “healthy” population. The goal is to upgrade the standard health status to a new level by targeting the inapparent disorders. Thus, future research can shift from reaction, response, and prevention to proactive, quality promotion and vigor prolonging; from single disease‐oriented to multiple dimension protocol for a healthy body; from treatment of symptom onset to keep away from disorders; and from the healthy aging management to a healthy promotion design beginning at the birth.
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Growth hormone‐releasing hormone‐deficient (GHRH‐KO) mice have previously been characterized by lower body weight, disproportionately high body fat accumulation, preferential metabolism of lipids compared to carbohydrates, improved insulin sensitivity, and an extended lifespan. That these mice are long‐lived and insulin‐sensitive conflicts with the notion that adipose tissue accumulation drives the health detriments associated with obesity (i.e., diabetes), and indicates that GH signaling may be necessary for the development of adverse effects linked to obesity. This prompts investigation into the ultimate effect of diet‐induced obesity on the lifespan of these long‐lived mice. To this end, we initiated high‐fat feeding in mid and late‐life in GHRH‐KO and wild‐type (WT) mice. We carried out extensive lifespan analysis coupled with glucose/insulin tolerance testing and indirect calorimetry to gauge the metabolic effect of high‐fat dietary stress through adulthood on these mice. We show that under high‐fat diet (HFD) conditions, GHRH‐KO mice display extended lifespans relative to WT controls. We also show that GHRH‐KO mice are more insulin‐sensitive and display less dramatic changes in their metabolism relative to WT mice, with GHRH‐KO mice fed HFD displaying respiratory exchange ratios and glucose oxidation rates comparable to control‐diet fed GHRH‐KO mice, while WT mice fed HFD showed significant reductions in these parameters. Our results indicate that GH deficiency protects against the adverse effects of diet‐induced obesity in later life.
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The success of clinical trials of longevity drugs relies heavily on identifying integrative health and aging biomarkers, such as biological age. Epigenetic aging clocks predict the biological age of an individual using their DNA methylation profiles, commonly retrieved from blood samples. However, there is no standardized methodology to validate and compare epigenetic clock models as yet. We propose ComputAgeBench, a unifying framework that comprises such a methodology and a dataset for comprehensive benchmarking of different clinically relevant aging clocks. Our methodology exploits the core idea that reliable aging clocks must be able to distinguish between healthy individuals and those with aging-accelerating conditions. Specifically, we collected and harmonized 66 public datasets of blood DNA methylation, covering 19 such conditions across different ages and tested 13 published clock models. We believe our work will bring the fields of aging biology and machine learning closer together for the research on reliable biomarkers of health and aging. Code: https://github.com/ComputationalAgingLab/ComputAge Dataset: https://huggingface.co/datasets/computage/computage_bench
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Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the five “common” mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity. Since these common mouse lines outlive their normal-sized littermates - and have protection from age-associated disease - they have become important fixtures in the aging field. On the other hand, the twelve “uncommon” mouse models of GHD described herein have tremendously divergent health outcomes ranging from beneficial aging phenotypes (similar to those described for the common models) to extremely detrimental features (such as improper development of the CNS, numerous sensory organ defects, and embryonic lethality). Moreover, advancements in next generation sequencing technologies have led to the identification of an expanding array of genes that are recognized as causative agents to numerous rare syndromes with concomitant GHD. Accordingly, this review provides researchers with a comprehensive up-to-date collection of the common and uncommon mouse models of GHD that have been used to study various aspects of physiology and metabolism associated with multiple forms of GHD. For each mouse line presented, the closest comparable human syndromes are discussed providing important parallels to the clinic.
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Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone‐releasing hormone knockout (GHRH‐KO) female mice and their littermate controls. Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH‐KO mice, a well‐established model of enhanced longevity. While younger GHRH‐KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one‐third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH‐KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH‐KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH‐KO‐induced transcriptional changes. These findings provide the first evidence of disrupted ceramide metabolism in a long‐lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms influencing lifespan extension.
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The female reproductive system is strongly influenced by nutrition and energy balance. It is well known that food restriction or energy depletion can induce suppression of reproductive processes, while overnutrition is associated with reproductive dysfunction. However, the intricate mechanisms through which nutritional inputs and metabolic health are integrated into the coordination of reproduction are still being defined. In this review, we describe evidence for essential contributions by hormones that are responsive to food intake or fuel stores. Key metabolic hormones—including insulin, the incretins (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), growth hormone, ghrelin, leptin, and adiponectin—signal throughout the hypothalamic-pituitary-gonadal axis to support or suppress reproduction. We synthesize current knowledge on how these multifaceted hormones interact with the brain, pituitary, and ovaries to regulate functioning of the female reproductive system, incorporating in vitro and in vivo data from animal models and humans. Metabolic hormones are involved in orchestrating reproductive processes in healthy states, but some also play a significant role in the pathophysiology or treatment strategies of female reproductive disorders. Further understanding of the complex interrelationships between metabolic health and female reproductive function has important implications for improving women's health overall.
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Individuals with untreated isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene from Itabaianinha Brazil have increased insulin sensitivity, normal life expectancy, and an extended healthspan, i.e., the period of life free from disabilities. We hypothesize that their prolonged healthspan is accompanied by a delayed cognitive decline in senescence. To test this hypothesis, we have administered the Literacy Independent Cognitive Assessment (LICA) to 15 IGHD individuals aged over 50 years and 15 controls matched by age, sex, years of education, and percentage of illiteracy. All individuals were negative for HIV and syphilis serology, and there were no differences in serum levels of folate, vitamin B12 and TSH between the 2 groups, while free T4 was higher in the IGHD group. IGHD subjects had a higher total LICA score than controls, 215 (22.7) vs. 204.2 (18.1), without reaching statistical significance. Scores of memory, visuoconstruction, language and calculation were similar between the two groups, with better attention [9.5 (1.4) vs. 8.3 (1.1), p= 0.01], and executive function [38.3 (4.8) vs. 35.1 (2.5), p= 0.03] scores in IGHD. MANCOVA revealed that group (but no age) had a significant effect on the LICA variables (partial eta squared of 0.455, power of 0.812, p= 0.02). This effect is verified on attention (partial eta squared 0.216, power of 0.749, p= 0.01) and executive function (partial eta squared 0.154, power of 0.570, p= 0.03. In conclusion, IGHD in senescence is associated with similar total cognitive performance, but better attention and executive function than controls.
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Age-related decline results in changes to the architecture of the intestinal epithelium and a loss of barrier function, accompanied by elevated stress and immune signalling and alterations to the intestinal microbial population. Interventions that prevent these phenotypes support longevity across several model organisms. Despite this we do not yet know whether age-related intestinal decline impacts nutrient management, a key function of the intestinal epithelium. Addressing this question is critical given that nutritional interventions hold significant promise in the development of anti-ageing therapies. In this study we have developed Drosophila Undigested Metabolite Profiling (D.U.M.P.) to assess the impact of intestinal ageing on nutrient absorption/excretion balance. We demonstrate that ageing results in a significant increase in amino acid load in the intestinal lumen that shortens lifespan. While the microbiota contributes significantly to intestinal amino acid load, age-related increases remain in sterile flies and are associated with reduced expression of a subset of amino acid transporters. Knockdown of the amino acid transporter slimfast in the intestinal epithelium extends lifespan and confers improved microbial control in aged flies. Our findings demonstrate that age-related intestinal decline may alter the capacity of the epithelium to take up nutrients, resulting in local changes to the nutritional environment that have consequences for health. We emphasise that diet is not the sole determinant of the intestinal nutritional environment, and that the status of the intestinal epithelium and its capacity for nutrient uptake is a key mediator in the response to dietary interventions. Therefore, further understanding the impact of intestinal ageing on nutrient management will be critical to the rational design of nutritional therapies.
Chapter
Thanks to increasing life expectancy with its concomitant number of aging men, medicine is forced to focus more strongly on the endocrine situation of this age group. In men, although there is no climacteric, there is a gradual decline in testosterone, and levels may well remain within the normal range of younger men. In some men, however, levels fall below normal. When this occurs in conjunction with characteristic symptoms, it may be genuine late-onset hypogonadism (LOH) or functional hypogonadism. In these cases, testosterone substitution may be considered and must be closely monitored.
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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.
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Role of growth hormone (GH) in mammalian aging is actively explored in clinical, epidemiological, and experimental studies. The age-related decline in GH levels is variously interpreted as a symptom of neuroendocrine aging, as one of causes of altered body composition and other unwelcome symptoms of aging, or as a mechanism of natural protection from cancer and other chronic diseases. Absence of GH signals due to mutations affecting anterior pituitary development, GH secretion, or GH receptors produces an impressive extension of longevity in laboratory mice. Extension of healthspan in these animals and analysis of survival curves suggest that in the absence of GH, aging is slowed down or delayed. The corresponding endocrine syndromes in the human have no consistent impact on longevity, but are associated with remarkable protection from age-related disease. Moreover, survival to extremely old age has been associated with reduced somatotropic (GH and insulin-like growth factor-1) signaling in women and men. In both humans and mice, elevation of GH levels into the supranormal (pathological) range is associated with increased disease risks and reduced life expectancy likely representing acceleration of aging. The widely advertised potential of GH as an anti-aging agent attracted much interest. However, results obtained thus far have been disappointing with few documented benefits and many troublesome side effects. Possible utility of GH in the treatment of sarcopenia and frailty remains to be explored.
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Equation 3 of the original published version of this article was incorrect. Correct presentation is given below.
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In human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA, PTPN1, PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity.
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Context Acromegaly has been associated with increased risk of cancer morbidity and mortality, but research findings remain conflicting and population-based data are scarce. We therefore examined whether patients with acromegaly are at higher risk of cancer. Design A nationwide cohort study (1978-2010) including 529 acromegaly cases was performed. Incident cancer diagnoses and mortality were compared to national rates estimating standardized incidence ratios (SIRs). A meta-analysis of cancer SIRs from 23 studies (including the present one) was performed. Results The cohort study identified 81 cases of cancer after exclusion of cases diagnosed within the first year (SIR 1.1 [95% confidence interval (CI): 0.9-1.4]). SIRs were 1.4 [95% CI: 0.7-2.6] for colorectal cancer, 1.1 [95% CI: 0.5-2.1] for breast cancer, and 1.4 [95% CI: 0.6-2.6] for prostate cancer. While overall mortality was increased in acromegaly (SIR 1.3 [95% CI: 1.1-1.6]), cancer-specific mortality was not. The meta-analysis yielded a SIR of overall cancer of 1.5 [95% CI: 1.2-1.8]. SIRs were elevated for colorectal cancer: 2.6 [95% CI: 1.7-4.0], thyroid cancer: 9.2 [95% CI: 4.2-19.9], breast cancer: 1.6 [1.1-2.3], gastric cancer: 2.0 [95% CI: 1.4-2.9], and urinary tract cancer: 1.5 [95% CI: 1.0-2.3]). In general, cancer SIR was higher in single-center studies and in studies with < 10 cancer cases. Conclusions Cancer incidence rates were slightly increased in acromegaly patients in our study and this was supported by the meta-analysis of 23 studies, although it also suggested the presence of selection bias in some earlier studies.
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Correlations between behavioral, physiological, and morphological traits linked to life history have been given the label “pace-of-life syndrome” (POLS), hypothesized to arise through variation in the resolution of a trade-off between present and future reproduction. However, other trade-offs over energy allocation may also have effects and influence the present-future trade-off. We analyzed an optimality model of basal metabolic rate (BMR) across variation in food availability and two types of mortality. The model contained three major features: (1) feedback between activity and energy acquisition, (2) links between BMR and the use of energy for other traits, and (3) allocation trade-offs between BMR and all other traits, between activity and defense, and between defense against activity-related risk and activity-independent risk. The model produced an intermediate optimal BMR that was usually highest at an intermediate level of food availability. Food availability and both types of mortality risk interacted to influence the exact value of optimal BMR. Trait correlations expected in the POLS existed under some environmental conditions, but these correlations flipped sign under different conditions and were not always strong. Our model reproduces trait correlations consistent with the POLS, but also generated a “sloppy” syndrome with considerable non-POLS-like variation. In addition, among-individual, non-adaptive variation in BMR produced adjustments of the other traits. These fit a best-of-a-bad job strategy, and the adjustments further weakened trait correlations. The results emphasize that variation in resources and mortality risk creates a diversity of correlation structures. This complexity means the POLS is likely to be a variable construct. Significance statement Many attributes important for reproduction and survival are associated. Such associations may arise through common physiological processes and correlated selection. We modeled metabolic rate within a system in which foraging behavior both depended on and mediated the acquisition of resources necessary for metabolism, while energy was allocated among multiple attributes. Variation in several environmental variables (food availability and two types of mortality risk) influenced basal metabolic rate, activity, and defenses against mortality risk. This variation affected the correlations between the traits in complex ways. When basal metabolic rate was non-optimal, evolution of the allocation of energy to other traits partially compensated, but this further eroded consistent trait correlations. Our results indicate that complexity in how energy is acquired and used can potentially disrupt trait correlations normally associated with the pace-of-life syndrome.
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Significance In various animal species, including mammals, longevity can be extended by rapamycin, an inhibitor of mTOR (mechanistic target of rapamycin). mTOR acts through two complexes: mTORC1 and mTORC2. Antiaging effects of rapamycin are mediated by suppression of mTORC1, while the role of mTORC2 in aging remains to be elucidated. Here, we report that mTORC2 plays a positive role in regulating longevity via maintenance, or enhancement, of whole-body homeostasis. When mTORC2-mediated homeostasis was disrupted by rapamycin in the remarkably long-lived GHR-KO mice (in which mTORC1 signaling is low, while mTORC2 signaling is elevated), their life span was shortened. Hence, a selective approach toward mTORC1 inhibition without impairing mTORC2 is important in devising a strategy for slowing aging.
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Resumo Objetivou-se avaliar o estado nutricional de crianças menores de 5 anos no Brasil no ano de 2009, o associando aos fatores sociais e demográficos. Utilizou-se dados da Pesquisa de Orçamento Familiar (POF 2008/2009), cujo perfil nutricional foi avaliado segundo os índices Peso-para-idade, Estatura-para-idade e Peso-para-estatura (n = 14.569). A associação foi estimada aplicando-se o teste de associação de Pearson, regressões logísticas e análises de correspondência. A análise de correspondência revelou maior associação da magreza com as crianças das regiões Norte e Nordeste, em famílias com menores níveis de renda e de cor/raça preta. O sobrepeso e a obesidade demonstraram maior relação com as crianças residentes nas regiões Sul, Sudeste e Centro-Oeste, do sexo masculino, da zona urbana, de cor/raça branca, com 3 anos de idade e de famílias com faixas de renda intermediárias. O sobrepeso e a obesidade demonstraram distribuição heterogênea quanto a sua espacialização dentre as Unidades da Federação. Aponta-se para uma polarização epidemiológica nutricional, sendo um grande desafio para a saúde coletiva reduzir as carências nutricionais e promover hábitos alimentares saudáveis desde a infância.
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We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity.
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Lifelong 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.
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The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2+/− mice to Ins2+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.
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Context Although pediatric GH treatment is generally considered safe for approved indications, there have been long-held concerns regarding potential for increased risk of neoplasia and, more recently, of stroke and mortality in adults treated with GH during childhood. Objective To assess mortality in children receiving GH. Design Prospective, multi-national, observational study. Setting Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). Patients Children with growth disorders. Interventions GH treatment during childhood. Main Outcome Measure Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population. Results Among 9504 GH-treated patients followed for ≥4 years (67163 person-years of follow-up), 42 deaths were reported (SMR for all diagnoses combined: 0.77 [CI 0.56–1.05]). The SMR was significantly elevated in patients with organic GH deficiency (GHD), mainly influenced by patients with history of malignant neoplasia (n=294, SMR 6.97 [3.81–11.69]). SMRs for patients with history of benign neoplasia (n=158) and idiopathic GHD (n=4324) were 1.44 (0.17–5.20) and 0.11 (0.02–0.33), respectively. SMRs also were not significantly elevated for children with idiopathic short stature (0.20 [0.01–1.10]), short stature associated with small-for-gestational age (SGA) birth (0.66 [0.08–2.37]), Turner syndrome (0.51 [0.06–1.83]), or SHOX deficiency (0.83 [0.02–4.65]). Conclusions No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions.
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The germline mutation rate has been extensively studied and has been found to vary greatly between species, but much less is known about the somatic mutation rate in multicellular organisms, which remains very difficult to determine. Here, we present data on somatic mutation rates in mice and humans, obtained by sequencing single cells and clones derived from primary fibroblasts, which allows us to make the first direct comparison with germline mutation rates in these two species. The results indicate that the somatic mutation rate is almost two orders of magnitude higher than the germline mutation rate and that both mutation rates are significantly higher in mice than in humans. Our findings demonstrate both the privileged status of germline genome integrity and species-specific differences in genome maintenance.
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Objectives: GH releasing hormone (GHRH) exerts hypnotic actions increasing non-rapid eye movement (NREM) sleep. Conversely, GH stimulates REM sleep. GH deficiency (GHD) often leads to sleep problems, daytime fatigue, and reduced quality of life (QoL). GHD may be due to lack of hypothalamic GHRH or destruction of somatotroph cells. We have described a cohort with isolated GHD (IGHD) due to GHRH resistance caused by a homozygous null mutation in the GHRH receptor gene. They have normal QoL and no obvious complaints of chronic tiredness. The aim of this study was to determine the sleep quality in these subjects. Methods: A cross sectional study was carried out in 21 adult IGHD subjects, and 21 age- and gender-matched controls. Objective sleep assessment included polygraphic records of the awake, stages NREM [N1 (drowsiness), N2 and N3 (already sleeping)] and REM (R). Subjective evaluation included the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale. Results: IGHD subjects showed a reduction in sleep efficiency (p=0.007), total sleep time (p=0.028), duration of N2 and R in minutes (p=0.026 and 0.046, respectively), but had increased duration and percentage of N1 stage (p=0.029 and 0.022 respectively), wake (p=0.007), and wake-time after sleep onset (p=0.017). There was no difference in N3, or in sleep quality questionnaire scores. Conclusion: Patients with IGHD due to GHRH resistance exhibit objective reduction in sleep quality, with changes in NREM and REM sleep, with no detectable subjective consequences. GHRH resistance seems have a preponderant role over GHD in the sleep quality of these subjects.
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Background Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. Results We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0?months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. Conclusions This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1186-2) contains supplementary material, which is available to authorized users.
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Background Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging ?clock?, a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1df/df mutation, calorie restriction and rapamycin. Results In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice. Conclusions Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1185-3) contains supplementary material, which is available to authorized users.
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The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.
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Context: Recent studies have highlighted the role of height in complex diseases but conflicting information has been reported on height as a predictor of changes in glycemia and risk of type 2 diabetes. Objective: Our aim was to investigate the association of height with insulin sensitivity, insulin secretion, glycemia, type 2 diabetes and cardiovascular disease in a large prospective population-based study. Design: The study included 8,746 Finnish men (mean±SD, age 57.2±7.1 years, BMI 26.8±3.8 kg/m(2)) selected from a population-based METabolic Syndrome In Men (METSIM) study. Setting: The study was conducted at Kuopio University Hospital and University of Eastern Finland. Participants: The participants were non-diabetic at the recruitment, and 5,401 subjects have participated in the follow-up study. During the follow-up, a total of 693 subjects converted to type 2 diabetes and 351 were diagnosed with a new cardiovascular disease event during the follow-up. Main outcome measures: Incidence of type 2 diabetes and cardiovascular disease Results: Height measured at baseline was significantly associated with lower levels of 2 hour glucose in an oral glucose tolerance test, an increase in insulin secretion, a decrease in the risk of type 2 diabetes (Hazard Ratio 0.83[0.77-0.90]) and cardiovascular disease (HR=0.75[0.67-0.83]) during the follow-up. Conclusion: Short stature is associated with unfavorable changes in glucose metabolism and predicts an increase in the risk of type 2 diabetes and cardiovascular events.
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Background: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Methods: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Results: Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). Conclusion: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.
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Growth hormone (GH) and the insulin-like growth factor I (IGF-I) have cell proliferative and differentiation properties. Whether these hormones have a role in mutagenesis is unknown. Nevertheless, severe IGF-I deficiency seems to confer protection against the development of neoplasms. Here, we report five cases of adult patients with severe and congenital isolated GH deficiency (IGHD) due to the c.57+1G>A mutation in the GHRH receptor gene, who developed tumors. Four GH-naïve subjects presented skin tumors: a 42-year-old man with a fibroepithelial polyp, a 53-year-old woman and two men (59 and 56 years old) with epidermoid skin cancers. One of these died from it after three surgeries and radiotherapy. The fifth patient was a 25-year-old woman, who had intermittently received GH replacement therapy (GHRT) from age 11 to 18, who developed an ependymoma extending from the fourth ventricle to the end of the thoracic spine. She underwent three surgical procedures, without obvious evidence of tumor recurrence during the six years follow up. These observations suggest that severe IGHD does not protect completely from development of tumors.
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Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 40-50 years. Work on the GH receptor (R) knock-out (GHRKO) mice and results of studies on GH resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition, and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.
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Small-for-gestational age (SGA) infants are at risk for short and long term medical and metabolic complications. Most SGA infants (85-90%) demonstrate spontaneous catch-up growth, typically in the first year after birth. Although catch-up growth (CUG) is a desired goal, it is important to note if CUG is too rapid the infants are at increased risk for insulin resistance and type 2 diabetes mellitus as they become adults. On the flip side, infants who do not exhibit CUG are also at increased risk of adverse adult outcomes including those for cardiovascular disease, insulin resistance and type 2 diabetes mellitus, neurodevelopmental and cognitive impairments, in addition to adult short stature. Treatment with growth hormone is safe and effective not only in increasing adult height, but also in improving body composition and decreasing metabolic complications. The aims of this review are to summarize the current knowledge on what constitutes "healthy" catch-up growth in children born SGA as well as provide an update on the role of growth hormone treatment for short children born SGA.
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Along with its inherent properties in growth promotion, cell division and regeneration, growth hormone (GH) exerts a variety of miscellaneous and widespread actions on the human body after binding to its receptor (GHR). Indeed, GH influences the metabolism of carbohydrates, lipids and proteins; shapes body composition, influences cardiovascular profile, quality of life, and induces other direct and indirect physiologic effects. Besides this salutary actions, GH and its derived peptide insulin-like growth factor-I (IGF-I), main product of the GH/GHR interaction, have been implicated in the genesis of diseases such as cancer and insulin-resistant diabetes. The effects of these peptides are difficult to discern in healthy individuals but can be better evaluated in disease states in which their action in target tissues is abnormal. In consequence, we selected acromegaly and Laron syndrome due to GH receptor deficiency (GHRD) as models for excess and absence of GH action, and focused in the role of GH/GHR signaling in the genesis of cancer and diabetes. Considering that malignancy has been linked at epidemiological level to type 2 diabetes and high body mass index, suggesting that hyperinsulinemia is an independent contributor to cancer genesis and progression, we propose that the GH-derived IGF-I is also an independent influence for progression to neoplasia since its absence associates with less DNA damage, diminished mutagenesis and efficient apoptosis. Regarding development of type 2 diabetes, we support the notion that GH, by influencing insulin sensitivity via its counter-regulatory properties on carbohydrate metabolism, is an important contributor for development of this disease.
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Context Data on the association between growth hormone (GH) replacement in patients with GH deficiency (GHD) after malignancies and new neoplasms show conflicting results. Objective To clarify the incidence of new malignant neoplasm in childhood (CO) and adult-onset (AO) adult cancer survivors (CS). Design Retrospective comparison of CO-CS and AO-CS with CO idiopathic GHD (IGHD) and AO non-functioning pituitary adenoma patients (NFPA) and with the general population (standardized incidence ratio, SIR). Setting Data from KIMS study (Pfizer International Metabolic Database) Patients CO-CS (n=349; 50.4% females, mean baseline (MBL) IGF-I SDS -2.4) and IGHD (n=619; 35.7% females, MBL IGF-I SDS -3.4) as well as AO-CS (n=174; 42.5% females, MBL IGF-I SDS -1.4) and NFPA (n=2449; 38.1% females, MBL IGF-I SDS -1.0). Main Outcome Measures SIRs of malignant neoplasms Results After a median follow-up of 5.9 years (2192 patient-years), 15 CO-CS (4.3%) had developed 16 new neoplasms. The SIR was 10.4 (95%CI, 5.9-16.9) and 6.5 (95%CI, 3.0-12.4) after exclusion of 7 patients with skin cancers. In IGHD three malignant neoplasms (0.5%) were observed after a median follow-up of 5.4 years (3908 patient-years, SIR 0.47, 95%CI, 0.09-1.37). New malignant neoplasms occurred in three AO-CS (1.7%; SIR 1.1; 95%CI, 0.2-3.2) and 146 NFPA patients (153 cases, 6.0%, SIR 1.1; 95%CI, 0.9-1.2) after a median follow-up of 4.9 (1024 patient-years) and 5.6 years (15215 patient-years). Conclusions The risk of second malignant neoplasms was increased in CO-CS but not in AO-CS which illustrates the need to closely follow patients on GH replacement due to a prior malignancy.
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Aging is a global decline of physiological functions, leading to an increased susceptibility to diseases and ultimately death. Maximum lifespans differ up to 200-fold between mammalian species. Although considerable progress has been achieved in identifying conserved pathways that regulate individual lifespan within model organisms, whether the same pathways are responsible for the interspecies differences in longevity remains to be determined. Recent cross-species studies have begun to identify pathways responsible for interspecies differences in lifespan. Here, we review the evidence supporting the role of anticancer mechanisms, DNA repair machinery, insulin/insulin-like growth factor 1 signaling, and proteostasis in defining species lifespans. Understanding the mechanisms responsible for the dramatic differences in lifespan between species will have a transformative effect on developing interventions to improve human health and longevity.
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Context Short children born small for gestational age (SGA) have a bone mineral density (BMD) below average. Growth hormone (GH) treatment improves height and BMD in short SGA children. Longitudinal data on BMD in adults born SGA, after GH cessation, are lacking. Objectives To determine BMD in young adults born SGA during 5yrs after GH cessation. Methods In 173 GH-treated adults born SGA (SGA-GH), BMD of total body (BMDTB) and bone mineral apparent density of lumbar spine (BMADLS) were measured longitudinally at adult height (GH-stop), and 6 months, 2yrs and 5yrs thereafter. At 5yrs after GH-stop (age 21yrs), data were compared with 45 untreated short SGA adults (SGA-S), 59 SGA adults with spontaneous catch-up (SGA-CU), and 81 adults born appropriate for gestational age (AGA). Results At GH-stop (mean age 16.4yrs), estimated mean (SE) BMDTB SDS was -0.40 (0.1) in males and -0.51 (0.1) in females followed by a trend towards a decrease of BMDTB in males to -0.59 (0.1) at 5yrs after GH-stop (p=0.06), while it remained stable in females (-0.57 (0.1), p=0.33). At GH-stop, BMADLS SDS was -0.01 (0.1) in males and -0.29 (0.1) in females, followed by a decrease in males and females to -0.38 and -0.55 at 5yrs after GH-stop, resp. (p<0.001). At 5yrs after GH-stop, BMDTB and BMADLS in SGA-GH were similar compared to SGA-S, SGA-CU and AGA. Conclusion After cessation of GH-treatment, there is a gradual decline of BMADLS, but at the age of 21yrs, BMDTB and BMADLS are similar as in untreated short SGA adults.
Article
Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.
Article
Objective Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. Design Cross sectional study. Methods Setting: University Hospital, Federal University of Sergipe, Brazil. Patients: Twenty-five adult (13 males, mean age 50.1 years, range 26 to 70 years old) IGHD subjects homozygous for a null mutation (c.57 + 1G > A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1 years, range 26 to 67 years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. Main outcome measures: Visual acuity, intraocular pressure, refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD), lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). Results IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78% of the control group, mean head circumference was 92% and axial AL was 96%. Conclusions These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD.
Article
Twenty years ago, we described a kindred of 105 individuals with isolated GH deficiency (IGHD) in Itabaianinha County, in Brazilian northeast, due to a homozygous mutation in the GH-releasing hormone receptor gene. These subjects exhibit markedly reduced GH responsiveness to stimulatory tests, and anterior pituitary hypoplasia. Serum concentrations of IGF-I, IGF binding protein type 3, and the acid-labile subunit are markedly reduced, with a lesser reduction of IGF-II. The most striking physical findings of these IGHD individuals are the proportionate short stature, doll facies, high-pitched voice, and visceral obesity with reduced fat free mass. There is neither microphallus, nor neonatal hypoglycemia. Puberty is delayed, climacteric anticipated, but fertility is preserved in both genders. The reduction in bone sizes is not even, with mean standard deviation scores for height of -7.2, total maxillary length of -6.5, total facial height of- 4.3, and cephalic perimeter of -2.7. In addition, the non-osseous growth is not uniform, preserving some organs, like pancreas, liver, kidney, brain, and eyes, and compromising others such as thyroid, heart, uterus, and spleen. They present higher prevalence of dizziness, mild high-tones sensorineural hearing loss, reduction of vascular retinal branching points, increase of optic disc, and genu valgum, and increased systolic blood pressure. Biochemically, they have high LDL cholesterol and C-reactive protein levels, but maintain increased insulin sensitivity, and do not show premature atherosclerosis. Finally, they have normal immune function, and normal longevity. This review details the findings and summarizes 20 years of clinical research carried out in this unique population.
Article
Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igff/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.
Article
A nutritional mismatch in postnatal life of low birth weight offspring increases the risk of developing the metabolic syndrome. Moreover, this is associated with decreased hepaticIgf1 expression, leading to impaired growth and metabolism. Previously, we have demonstrated that the timing of nutritional restoration in perinatal life can differentially program hepatic gene expression. Although microRNAs also play an important role in silencing gene expression, to date, the impact of a nutritional mismatch in neonatal life on their long-term expression has not been evaluated. Given the complementarity of miR-29 to the 3′ untranslated region of Igf1, we examined how protein restoration in maternal protein restriction rat offspring influences hepatic miR-29 and Igf1 expression in adulthood. Pregnant Wistar rats were designated into 1 of 4 dietary regimes: 20% protein (control), 8% protein during lactation only (LP-Lact), 8% protein during gestation only (LP1) or both (LP2). The steady-state expression of hepatic miR-29 mRNAsignificantly increased in LP2 offspring at postnatal day 21 and 130, and this was inversely related to hepatic Igf1 mRNA and body weight. Interestingly, this reciprocal association was stronger in LP-Lact offspring at postnatal day 21. Functional relevance of this in vivo relationship was evaluated by transfection of miR-29 mimics in neonatal Clone 9 rat hepatoma cells. Transfection with miR-29 suppressed Igf1 expression by 12 hours. Collectively, these findings implicate that nutritional restoration after weaning (post liver differentiation) in maternal protein restriction rat offspring fails to prevent long-term impaired growth, in part, due to miR-29 suppression of hepatic Igf1 expression. (Endocrinology 156: 3069–3076, 2015)
Article
Experimental, clinical, and epidemiological findings support the concept of developmental origins of health and disease (DOHAD), suggesting that early-life hormonal influences during a sensitive period around adolescence have a powerful impact on cancer morbidity later in life. The endocrine changes that occur during puberty are highly conserved across mammalian species and include dramatic increases in circulating GH and IGF-1 levels. Importantly, patients with developmental IGF-1 deficiency due to GH insensitivity (Laron syndrome) do not develop cancer during aging. Rodents with developmental GH/IGF-1 deficiency also exhibit significantly decreased cancer incidence at old age, marked resistance to chemically induced carcinogenesis, and cellular resistance to genotoxic stressors. Early-life treatment of GH/IGF-1-deficient mice and rats with GH reverses the cancer resistance phenotype; however, the underlying molecular mechanisms remain elusive. The present study was designed to test the hypothesis that developmental GH/IGF-1 status impacts cellular DNA repair mechanisms. To achieve that goal, we assessed repair of γ-irradiation-induced DNA damage (single-cell gel electrophoresis/comet assay) and basal and post-irradiation expression of DNA repair-related genes (qPCR) in primary fibroblasts derived from control rats, Lewis dwarf rats (a model of developmental GH/IGF-1 deficiency), and GH-replete dwarf rats (GH administered beginning at 5 weeks of age, for 30 days). We found that developmental GH/IGF-1 deficiency resulted in persisting increases in cellular DNA repair capacity and upregulation of several DNA repair-related genes (e.g., Gadd45a, Bbc3). Peripubertal GH treatment reversed the radiation resistance phenotype. Fibroblasts of GH/IGF-1-deficient Snell dwarf mice also exhibited improved DNA repair capacity, showing that the persisting influence of peripubertal GH/IGF-1 status is not species-dependent. Collectively, GH/IGF-1 levels during a critical period during early life determine cellular DNA repair capacity in rodents, presumably by transcriptional control of genes involved in DNA repair. Because lifestyle factors (e.g., nutrition and childhood obesity) cause huge variation in peripubertal GH/IGF-1 levels in children, further studies are warranted to determine their persisting influence on cellular cancer resistance pathways.
Article
Growth hormone receptor knockout mice (GHRKO) are characterized by high insulin sensitivity and extended lifespan. Interestingly, the secretory activity of visceral fat in GHRKO mice is altered, stimulating whole body insulin sensitivity. In this study, we transplanted normal (N) mice with visceral fat pads from GHRKO or N mice to determine the role of visceral fat on the insulin signaling. We found that the transplant of visceral fat from GHRKO mice to N mice (N-GHRKO) improved whole body insulin sensitivity when comparing with sham-operated mice (N-S) and with mice that received visceral fat from N mice (N-N). This was associated with increased hepatic insulin sensitivity as observed by the increased phosphorylated insulin receptor and increased hepatic expression of Pparα and Pparγ. In conclusion, we demonstrated that visceral fat transplant from GHRKO mice into normal mice enhanced insulin sensitivity and glucose tolerance. These results further confirm the differential physiological role played by visceral adipose tissue from GH receptor deficient mice, indicating that the increase of this fat depot can be associated with beneficial effects on insulin signaling and longevity.
Article
The aim of this study was to evaluate the effect of growth hormone (GH) in the maintenance of the ovarian primordial follicle reserve. Ovaries from 16 mo old GH-deficient Ames Dwarf (df/df) and Normal (N/df) mice were used. A subgroup of df/df and N mice received GH or saline injections for six weeks starting at 14 mo of age. In addition, ovaries from 12 mo old mice overexpressing bovine GH (bGH) and controls were used. df/df mice had higher number of primordial and total follicles than N/df mice (p < 0.05), while GH treatment decreased follicle counts in both genotypes (p < 0.05). In addition, bGH mice had lower number of primordial and total follicles than the controls (p < 0.05). pFoxO3a levels were higher in mice treated with GH and in bGH mice (p < 0.05) when comparing with age match controls. These results indicate that increased circulating GH is associated with a reduced ovarian primordial follicle reserve and increased pFoxO3a content in oocytes.
Article
Growth hormone (GH) and insulin like growth factor I (IGF-I) are important for a variety of physiological processes including growth, development and aging. Mice with reduced levels of GH and IGF-I have been shown to live longer than wild type controls. Our laboratory has previously found that mice with aGHreceptor gene knockout (GHRKO) from conception exhibit low rates of cancer, resistance to diet-induced diabetes, and extension of lifespan. The GHRKO mouse as well as other mouse lines with reduced GH action display low IGF-I levels, smaller body size, increased adiposity and increased longevity. To date, nearly all of these mouse strains carry germline mutations. Importantly, the effect of a long-term suppression of the GH/IGF-I axis during adulthood, as would be considered for human therapeutic purposes, has not been tested. The goal of this study was to determine if temporally controlled Ghr gene deletion in adult mice would affect metabolism and longevity. Thus, we produced adult-onset GHRKO mice (aGHRKO) by disrupting the Ghr gene at 6 weeks of age. We found that aGHRKO mice replicate many of the beneficial effects observed in long-lived GHRKO mice. For example, aGHRKO mice, like GHRKO animals, displayed retarded growth and high adiposity with improved insulin sensitivity. Importantly, female aGHRKO animals showed an increase in their maximal lifespan, while the lifespan of male aGHRKO mice was not different from controls.
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Twenty-seven patients with GH insensitivity were identified from 44 possible cases, using a scoring system based on height standard deviation score (SDS), basal GH, insulin-like growth factor-I (IGF-I), IGF-I response to IGF-I generation test, and GH-binding protein (GH-BP) determinations. The 27 cases were from 8 European countries and Australia. Clinical features were as follows: age 2.8-22.6 yr; 12 male, 15 female, 19 prepubertal. Birth weight was median -0.72 SDS (1.75(-)-3.29) and birth length, median -1.59 SDS (0.63(-)-3.63). Hypoglycemia had been documented in 33% of the cases, and micropenis was present in 58% of the males. At assessment, height was median -6.1 SDS (-3.8(-)-10.2), weight was median -3.2 SDS (-0.1 to -5.2), and percentage weight for height, median 111.3 (72-271). Puberty was absent in 2 boys aged 15 yr and in 3 girls aged 13 yr. Bone age was delayed in 19 of the 27 patients. Endocrine investigations showed basal serum GH median 17 micrograms/L (0.5-79), IGF-I values less than 5th p...
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The aim of the current work was to evaluate the ovarian follicle reserve and the ovarian transcriptome in Ames dwarf (df/df) mice. The results suggest a delayed ovarian aging in df/df mice compared to normal (N) mice. Although a high number of genes were differentially expressed during aging of N mice, only a small fraction of these changed with aging in df/df mice. These alterations involved more than 500 categorized biological processes. The majority of these biological processes, including inflammatory/immune responses, were up-regulated with aging in N mice, while old df/df mice were characterized by down-regulation of these same processes in comparison to age matched N mice. However, biological processes related to DNA damage and repairing were commonly down-regulated with aging in both genotypes. In conclusion, delayed ovarian aging in long-living df/df mice was associated with reduced expression of genes related to the inflammatory and immune responses.
Article
Objective: Experimental models demonstrate an important role of GH in retinal development. However, the interactions between GH and the neuro-vascularization of the human retina are still not clear. A model of untreated congenital isolated GH deficiency (IGHD) may clarify the actions of GH on the retina. The purpose of this work was to assess the retinal neuro-vascularization in untreated congenital IGHD (cIGHD). Design: In a cross sectional study, we performed an endocrine and ophthalmological assessment of 25 adult cIGHD subjects, homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene and 28 matched controls. Intraocular pressure measurement, retinography (to assess the number of retinal vascular branching points and the optic disc and cup size), and optical coherence tomography (to assess the thickness of macula) were performed. Results: cIGHD subjects presented a more significant reduction of vascular branching points in comparison to controls (91% vs. 53% [p=0.049]). The percentage of moderate reduction was higher in cIGHD than in controls (p=0.01). The percentage of individuals with increased optic disc was higher in cIGHD subjects in comparison to controls (92.9% vs. 57.1%). The same occurred for cup size (92.9% vs. 66.7%), p<0.0001 in both cases. There was no difference in macula thickness. Conclusions: Most cIGHD individuals present moderate reduction of vascular branching points, increase of optic disc and cup size, but have similar thickness of the macula.