ArticleLiterature Review

Growth Hormone Deficiency: Health and Longevity

December 2018
Endocrine Reviews 40(2)

DOI:10.1210/er.2018-00216

Authors:

Federal University of Sergipe

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.

Likely causal effects of insulin resistance and IGF-1 bioaction on childhood and adult adiposity: a Mendelian randomization study

Article

Full-text available

Aug 2024
INT J OBESITY

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.

Portuguese version of the Literacy Independent Cognitive Assessment (LICA) instrument in the evaluation of individuals aged 50 years or older with Itabaianinha syndrome

Article

Full-text available

Aug 2024

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

Skin assessment in congenital untreated isolated GH deficiency

Article

Full-text available

May 2024
ENDOCRINE

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.

Brain morphometry and estimation of aging brain in subjects with congenital untreated isolated GH deficiency

Article

Apr 2024
J ENDOCRINOL INVEST

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.

Relationships among development, growth, body size, reproduction, aging, and longevity - trade-offs and pace-of-life

Article

Dec 2023
Biokhimiya

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.

Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity – Trade-Offs and Pace-Of-Life

Article

Full-text available

Nov 2023

The resistance of domestic canine skin-derived fibroblasts to oxidative and non-oxidative chemical injury: implications of breed and body size

Article

Sep 2024

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.

The distinct hepatic metabolic profiles and the relations with impaired liver function in congenital isolated growth hormone deficient rats

Article

Full-text available

Mar 2024

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.

An evolutionary medicine and life history perspective on aging and disease: Trade-offs, hyperfunction, and mismatch

Preprint

Full-text available

Apr 2025

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.

Body mass index trajectories and all-cause mortality in older Chinese adults: Hong Kong's Elderly Health Service Cohort

Article

Full-text available

Mar 2025
J EPIDEMIOL COMMUN H

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.

Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan

Article

Full-text available

Feb 2025

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.

Fecal microbiota transplant from long-living Ames dwarf mice alters the microbial composition and biomarkers of liver health in normal mice

Article

Feb 2025

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.

Growth hormone signaling and clinical implications: from molecular to therapeutic perspectives

Article

Full-text available

Feb 2025
MOL BIOL REP

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.

Impact of pomegranate extracts on longevity and wing fluctuating asymmetry in Drosophila melanogaster: A geometric morphometric analysis

Article

Full-text available

Jan 2025

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.

The Regulatory Effect of Insulin-Like Growth Factor-2 on Hypothalamic Gonadotropin-Releasing Hormone Neurons during the Pubertal Period

Article

Full-text available

Nov 2024
J INTEGR NEUROSCI

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.

Retinal and choroidal microvascular assessment of children receiving recombinant growth hormone therapy: Study design: a prospective observational comparative study

Article

Full-text available

Nov 2024

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.

General Information about Journal of Agriculture and Agricultural Technology Background

Article

Full-text available

Nov 2023

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.

Targeting multiple hallmarks of mammalian aging with combinations of interventions

Article

Full-text available

Aug 2024

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.

Early Life Interventions: Impact on Aging and Longevity

Article

Aug 2024

The somatotroph pituitary gland function in high-aged multimorbid hospitalized patients with IGF-I deficiency

Article

Full-text available

May 2024
PITUITARY

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.

Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations

Article

Full-text available

May 2024
AGING CELL

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.

Role of the Insulin-like Growth Factor System in Neurodegenerative Disease

Article

Full-text available

Apr 2024
INT J MOL SCI

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.

Effects of Growth Hormone-Releasing Hormone (GHRH) Plasmid Treatment on the Reproductive Productivity of Sows in Primiparous and Multiparous Sow Breeds

Article

Full-text available

Apr 2024

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.

Causal Association of Cytokines and Growth Factors with Stroke and Its Subtypes: a Mendelian Randomization Study

Article

Full-text available

Nov 2023
MOL NEUROBIOL

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.

A cluster of X-linked miRNAs are de-repressed with age in mouse liver and target growth hormone signaling

Article

Full-text available

Oct 2023

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.

Growth hormone insensitivity and adipose tissue: tissue morphology and transcriptome analyses in pigs and humans

Article

Full-text available

Sep 2023
PITUITARY

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.

Pleiotropic influence of DNA methylation QTLs on physiological and ageing traits

Article

Full-text available

Sep 2023

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.

Histone Modifications as Molecular Drivers of Cardiac Aging: Metabolic Alterations, Epigenetic Mechanisms, and Emerging Therapeutic Strategies

Article

Apr 2025
CURR PROB CARDIOLOGY

Biomarkers of aging: from molecules and surrogates to physiology and function

Article

Full-text available

Mar 2025
PHYSIOL REV

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.

Endocrine Controls of Skin Aging

Article

Feb 2025
ENDOCR REV

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.

Unveiling the metabolomic profile of growth hormone deficiency children using NMR spectroscopy

Article

Full-text available

Feb 2025
METABOLOMICS

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.

Retard de croissance de l’enfant

Article

Jul 2024

Growth hormone-releasing hormone and its analogues in health and disease

Article

Nov 2024

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.

Effects of Growth Hormone on Osteoarthritis Development

Article

Nov 2024

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.

Cardiovascular Effects of Growth Hormone: Preliminary Study on Oxidative Stress in Adults with Growth Hormone Deficiency

Preprint

Full-text available

Sep 2024

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.

Inflated expectations: the strange craze for translational research on aging: Given existing confusion about the basic science of aging, why the high optimism in the private sector about the prospects of developing anti-aging treatments?

Article

Aug 2024
EMBO REP

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]

Characterization of effects of mTOR inhibitors on aging in C. elegans

Article

Aug 2024

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.

Blocking an inflammatory protein slows the pace of ageing

Article

Jul 2024

Richard A. Miller

From Reactive to Proactive – The Future Life Design to Promote Health and Extend the Human Lifespan

Article

Full-text available

Jul 2024

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.

Growth hormone‐releasing hormone deficiency confers extended lifespan and metabolic resilience during high‐fat feeding in mid and late life

Article

Full-text available

Jun 2024
AGING CELL

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.

ComputAgeBench: Epigenetic Aging Clocks Benchmark

Preprint

Full-text available

Jun 2024

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

Common and Uncommon Mouse Models of Growth Hormone Deficiency

Article

Jun 2024
ENDOCR REV

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.

Unveiling ceramide dynamics: Shedding light on healthy aging in growth hormone‐releasing hormone knockout mice

Article

Full-text available

May 2024
AGING CELL

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.

Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction

Article

Mar 2024

Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type II diabetes mellitus (T2DM). Drugs that selectively induce senescent cell removal, “senolytics”, and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, “senomorphics”, appear to delay the onset or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. Over thirty clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.

Why are men healthier but die younger than women?

Chapter

Jan 2024

Ilpo Huhtaniemi

Metabolic hormones are integral regulators of female reproductive health and function

Article

Full-text available

Dec 2023

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.

Cognitive performance during senescence in untreated congenital isolated GH deficiency

Article

Full-text available

Nov 2023

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.

Drosophila Undigested Metabolite Profiling reveals age related loss of intestinal amino acid transport regulates longevity

Preprint

Full-text available

Oct 2023

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.

Senescence and Late-Onset Hypogonadism

Chapter

Oct 2023

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.

Hipopituitarismo - uma revisão abrangente acerca da etiologia, manifestações clínicas, diagnóstico e avaliação, insuficiência adrenal secundária, deficiência de GH, hipogonadismo central, hipotireoidismo central, deficiência de prolactina e diabetes insípido central

Article

Sep 2023

O hipopituitarismo é uma condição médica caracterizada pela insuficiência da glândula pituitária, que leva à deficiência de hormônios essenciais para o funcionamento do organismo. Quanto à etiologia, pode ter várias causas, incluindo tumores pituitários, traumatismo craniano, infecções, distúrbios autoimunes e outras condições que afetam a glândula pituitária. Essas causas podem resultar na diminuição ou interrupção da produção de hormônios pela hipófise. As manifestações clínicas são variadas e dependem dos hormônios que estão em falta. Alguns sintomas comuns incluem fadiga, fraqueza, perda de peso, alterações na pressão arterial, intolerância ao frio, distúrbios menstruais, disfunção erétil, perda de libido, entre outros. O diagnóstico envolve a realização de exames de sangue para medir os níveis de hormônios pituitários e hormônios-alvo no organismo. Exames de imagem, como ressonância nuclear magnética, são frequentemente utilizados para identificar anormalidades na glândula pituitária. Quando a deficiência de hormônio adrenocorticotrófico (ACTH) ocorre, a função das glândulas adrenais é comprometida, levando à insuficiência adrenal secundária. Isso pode resultar em fadiga, fraqueza, hipotensão e outros sintomas relacionados à falta de cortisol. Já a falta de hormônio do crescimento pode levar a atraso no crescimento em crianças e, em adultos, pode causar perda de massa muscular, aumento da gordura corporal e diminuição da densidade óssea. Ainda, o hipogonadismo central resulta da insuficiência dos hormônios gonadotróficos, levando a problemas como disfunção sexual, amenorréia nas mulheres e redução da produção de esperma nos homens. A falta de hormônio estimulante da tireoide (TSH) pode causar hipotireoidismo central, levando a sintomas como fadiga, ganho de peso, pele seca e sensação de frio constante e a insuficiência de prolactina pode interferir na capacidade de amamentação em mulheres, mas os sintomas são geralmente menos evidentes em homens. Também, a falta de hormônio antidiurético (ADH) resulta em sede excessiva e aumento da produção de urina.

Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long‐lived mutant mice

Article

Full-text available

Dec 2010

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

Article

Full-text available

Oct 2018

Ames dwarf (Prop1df) mice possess a loss-of-function mutation that results in deficiency of growth hormone, prolactin, and thyroid-stimulating hormone, as well as exceptional longevity. Work in other laboratories suggests that increased respiration and lipid utilization are important for maximizing mammalian longevity. Interestingly, these phenotypes are observed in Ames dwarf mice. We recently demonstrated that Ames dwarf mice have hyperactive brown adipose tissue (BAT), and hypothesized that this may in part be due to their increased surface to mass ratio leading to increased heat loss and an increased demand for thermogenesis. Here, we used increased environmental temperature (eT) to interrogate this hypothesis. We found that increased eT diminished BAT activity in Ames dwarf mice, and led to the normalization of both VO2 and respiratory quotient between dwarf and normal mice, as well as partial normalization (i.e. impairment) of glucose homeostasis in Ames dwarf mice housed at an increased eT. Together, these data suggest that an increased demand for thermogenesis is partially responsible for the improved energy metabolism and glucose homeostasis which are observed in Ames dwarf mice.

Growth Hormone and Aging: Updated Review

Article

Full-text available

May 2018

Andrzej Bartke

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.

Correction to: Energetic trade-offs and feedbacks between behavior and metabolism influence correlations between pace-of-life attributes

Article

Full-text available

Apr 2018
BEHAV ECOL SOCIOBIOL

Equation 3 of the original published version of this article was incorrect. Correct presentation is given below.

The genetic component of human longevity: New insights from the analysis of pathway-based SNP-SNP interactions

Article

Full-text available

Mar 2018
AGING CELL

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.

Cancer Incidence in Patients With Acromegaly: A Cohort Study and Meta-Analysis of the Literature

Article

Full-text available

Mar 2018

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.

Energetic trade-offs and feedbacks between behavior and metabolism influence correlations between pace-of-life attributes

Article

Full-text available

Mar 2018
BEHAV ECOL SOCIOBIOL

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.

Effects of rapamycin on growth hormone receptor knockout mice

Article

Full-text available

Jan 2018

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.

Estado nutricional de menores de 5 anos de idade no Brasil: evidências da polarização epidemiológica nutricional

Article

Full-text available

Oct 2017

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.

Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice

Article

Full-text available

Oct 2013
eLife

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.

Longevity is impacted by growth hormone action during early postnatal period

Article

Full-text available

Jul 2017
eLife

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.

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

Article

Full-text available

Jul 2017

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.

Mortality in Children Receiving Growth Hormone Treatment for Growth Disorders: Data from the GeNeSIS Observational Program

Article

Full-text available

May 2017

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.

Differences between germline and somatic mutation rates in humans and mice

Article

Full-text available

May 2017

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.

Altered sleep patterns in patients with non-functional GHRH receptor

Article

Full-text available

Apr 2017

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.

Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment

Article

Full-text available

Mar 2017
GENOME BIOL

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.

Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

Article

Full-text available

Mar 2017
GENOME BIOL

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.

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Article

Full-text available

Oct 2016

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.

Short Adult Stature Predicts Impaired β-Cell Function, Insulin Resistance, Glycemia, and Type 2 Diabetes in Finnish Men

Article

Full-text available

Dec 2016

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.

Risk of malignant neoplasms in acromegaly: a case–control study

Article

Full-text available

Oct 2016
J ENDOCRINOL INVEST

PurposeAcromegaly is a chronic disease resulting from pathological oversecretion of growth hormone and subsequently insulin growth factor-1. Several complications of the disease have been reported, including cardiovascular diseases, respiratory disorders but also increased risk of benign and malignant neoplasms. The aim of the study was to evaluate the risk of malignant neoplasms in the patients with acromegaly in comparison with the control group. Patients and methodsMedical documentation of acromegalic patients treated in one medical center between 2005 and 2016 has been analyzed. Results were compared with sex- and age-matched group of subjects with prolactinomas and hormonally inactive pituitary lesions hospitalized in the same department. Results Two hundred patients with acromegaly were included. Control group was composed of 145 patients. Any malignant neoplasm in anamnesis was present in 27 (13.5 %) patients with acromegaly and six (4.1 %) subjects from control group (p = 0.003). Thyroid cancer was present in 14 (7.0 %) patients with acromegaly and two (1.4 %) in control group (p = 0.02). Breast cancer was present in seven women (5.4 % of women) in acromegaly group but none of subjects in control group (p = 0.02). Colon cancer—4 (2.0 %) patients in acromegaly group and 0 in control group (p = 0.14). Conclusions Malignant neoplasms are significantly more common in patients with acromegaly. Particularly, risk of thyroid cancer was increased over fivefold. Systematic screening for neoplastic diseases should be important part of follow-up in these patients. Further case–control studies are strongly indicated to evaluate which neoplasms are more common in acromegalic patients and what is the exact risk of malignancy.

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

Article

Full-text available

Oct 2016

Ames dwarf mice (Prop1(df/df)) are long-lived due to a loss of function mutation resulting in deficiency of growth hormone (GH), thyroid-stimulating hormone and prolactin. Along with a marked extension of longevity, Ames dwarf mice have improved energy metabolism as measured by an increase in their oxygen consumption (VO2) and heat production, as well as a decrease in their respiratory quotient (RQ). Along with alterations in energy metabolism, Ames dwarf mice have a lower core body temperature (Tco). Moreover, Ames dwarf mice have functionally altered epididymal white adipose tissue (eWAT) that improves, rather than impairs, their insulin sensitivity due to a shift from pro- to anti-inflammatory cytokine secretion. Given the unique phenotype of Ames dwarf eWAT, their improved energy metabolism and lower Tco, we hypothesized that Ames dwarf brown adipose tissue (BAT) may function differently than that of their normal littermates. Here, we use histology and RT-PCR to demonstrate that Ames dwarf mice have enhanced BAT function. We also utilize interscapular BAT (iBAT) removal to demonstrate that BAT is necessary for Ames dwarf energy metabolism and thermogenesis, whereas it is less important for their normal littermates. Further, we show that Ames dwarf mice are able to compensate for loss of iBAT by utilizing their WAT depots as an energy source. These findings demonstrate enhanced BAT function in animals with GH and thyroid hormone deficiencies, chronic reduction of body temperature and remarkably extended longevity.

Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline

Article

Full-text available

Oct 2016
J CLIN ENDOCR METAB

Abstract OBJECTIVE: To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline. EVIDENCE: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland

Article

Full-text available

Sep 2016
HUM MUTAT

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910CtextgreaterT, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1000 Greater Belfast (both in NI) and 2094 Republic of Ireland (ROI) volunteers and in 116 acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P textless 0.05), but not in ROI (2/29, 6.8%) vs. non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1275-5000) years. tMRCA-based simulations predicted 432 (90-5175) current carriers, including 86 affected (18-1035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically-targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease. This article is protected by copyright. All rights reserved.

mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice

Article

Full-text available

Sep 2016
AGING CELL

Studies of the mTOR pathway have prompted speculation that diminished mTOR complex-1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long-lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA-KO mice express high levels of two proteins involved in DNA repair, O-6-methylguanine-DNA methyltransferase (MGMT) and N-myc downstream-regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post-transcriptional mechanisms. We show that the CCR4-NOT complex, a post-transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long-lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post-transcriptional regulation involving specific alteration in the CCR4-NOT complex, whose modulation could control multiple aspects of the aging process.

Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity

Article

Full-text available

Sep 2016
AGING CELL

Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128–216) mU L−1] compared with controls [238 (193–284) mU L−1]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39–0.53)] compared with controls [0.66 (0.56–0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.

Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency

Article

Full-text available

Oct 2016
ENDOCRINE

Growth hormone is important for the development and function of the immune system, but there is controversy on whether growth hormone deficiency is associated to immune disorders. A model of isolated growth hormone deficiency may clarify if the lack of growth hormone is associated with increased susceptibility to infections, or with an altered responsiveness of the immune system. We have studied the frequency of infectious diseases and the immune function in adults with congenital, untreated isolated growth hormone deficiency. In a cross-sectional study, 35 adults with isolated growth hormone deficiency due to a homozygous mutation in the growth hormone releasing hormone receptor gene and 31 controls were submitted to a clinical questionnaire, physical examination serology for tripanosomiasis, leishmaniasis, HIV, tetanus, hepatitis B and C, and serum total immunoglobulin G, M, E and A measurement. The immune response was evaluated in a subset of these subjects by skin tests and response to vaccination for hepatitis B, tetanus, and bacillus Calmette-Guérin. There was no difference between the groups in history of infectious diseases and baseline serology. Isolated growth hormone deficiency subjects had lower total IgG, but within normal range. There was no difference in the response to any of the vaccinations or in the positivity to protein Purified Derived, streptokinase or candidin. Adult untreated isolated growth hormone deficiency does not cause an increased frequency of infectious diseases, and does not alter serologic tests, but is associated with lower total IgG levels, without detectable clinical impact.

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Article

Full-text available

Jun 2016
AGING CELL

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.

Physiological underpinnings in life-history trade-offs in man’s most popular selection experiment: the dog

Article

Full-text available

Oct 2016
J COMP PHYSIOL B

Ana Gabriela Jimenez

Animal life-history traits fall within a limited ecological space, a continuum referred to as a “slow-fast” life-history axis. Differences of life-history traits are thought to result from trade-offs between behavioral and physiological aspects in each species as mediated by the biotic and abiotic environment, as well as genetic mechanisms. Domestic animals tend to show inverse relationships between body size and life span. Dogs are a good example of this, with smaller dogs having higher mass-specific metabolic rates and longer lifespans compared with larger dogs. Thus, dogs provide a unique system to examine physiological consequences of life-history trade-offs. I have collected data from the literature to explore implications of these trade-offs at several levels of physiological organization including whole-animal, organ systems, and cells. Small dogs tend to have longer lifespans, fewer pups per litter, faster and shorter developmental trajectories, and higher mass-specific metabolic rates, and in general, larger metabolically active organs compared with large dogs. From work on isolated primary fibroblast cells and telomeres of dogs, I show that selection for body size may influence the attributes of cells that shape proliferative cellular rates and rates of telomere shortening. The potential links between body size, and cellular oxidative stress in dogs as they age are discussed. Furthermore, small size in dogs has been linked to concentrations of reduced insulin growth factor-1 (IGF-1) levels in plasma, a possible metabolic advantage that may provide higher resistance to oxidative stress, a parameter essential to increases in lifespan.

Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity

Article

Oct 2018
MECH AGEING DEV

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.

Occurrence of neoplasms in individuals with congenital, severe GH deficiency from the Itabaianinha kindred

Article

Mar 2018
GROWTH HORM IGF RES

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.

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Article

Feb 2018

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.

Short children born small for gestational age outcomes in the era of growth hormone therapy

Article

Dec 2017
GROWTH HORM IGF RES

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.

GH and GHR signaling in human disease

Article

Dec 2017
GROWTH HORM IGF RES

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.

New Neoplasm During GH Replacement in Adults With Pituitary Deficiency Following Malignancy: A KIMS Analysis

Article

Dec 2017

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.

Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species

Article

Sep 2017
TRENDS ENDOCRIN MET

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.

Bone Mineral Density After Cessation of GH Treatment in Young Adults Born SGA: A 5-Year Longitudinal Study

Article

Jul 2017

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.

Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

Article

Jun 2017

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.

Ocular findings in adult subjects with an inactivating mutation in GH releasing hormone receptor gene

Article

Apr 2017

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.

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GH: lessons from lifetime, untreated isolated GH deficiency due to GHRH receptor mutation

Article

Apr 2017

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.

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

Article

Mar 2017

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.

Higher Hepatic miR-29 Expression in Undernourished Male Rats During the Postnatal Period Targets the Long-Term Repression of IGF-1

Article

Jul 2015
ENDOCRINOLOGY

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)

The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer

Article

Feb 2017

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.

The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling

Article

Jan 2017

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.

Ovarian aging and the activation of the primordial follicle reserve in the long-lived Ames dwarf and the short-lived bGH transgenic mice

Article

Oct 2016
MOL CELL ENDOCRINOL

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.

Disruption of the growth hormone receptor gene in adult mice increases maximal lifespan in females

Article

Oct 2016

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.

Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome).

Article

Dec 1993

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...

Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice

Article

Sep 2016
MOL CELL ENDOCRINOL

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.

Nutrition in early life and age-associated diseases

Article

Sep 2016

Does Growth Hormone Replacement Therapy Reduce Mortality in Adults with Growth Hormone Deficiency? — Data from the Dutch National Registry of Growth Hormone Treatment in Adults

Chapter

Jun 2011

Abnormal vascular and neural retinal morphology in congenital lifetime isolated growth hormone deficiency

Article

Jul 2016

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.

Growth Hormone Deficiency: Health and Longevity

Abstract

No full-text available

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