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Growth Hormone Deficiency: Health and Longevity
Abstract
The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH-deficiency (GHD) or GH-resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH-R mutations, combined deficiency of GH, PRL, and TSH, or global deletion of GH receptors live longer than their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, due to a mutation of the GHRHR gene, in the Itabaianinha County, Brazil, provide unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty, but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years in one case. We believe that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved, may account for the normal longevity and apparent extension of healthspan in these individuals.
... These mechanisms, along with their complex interactions, are apparently responsible for the unique "longevous" phenotypes of GH-deficient and GH-resistant individuals. Discussion of this topic is outside of the scope of the present article and an interested reader is directed to recent reviews (8,(38)(39)(40). ...
... As is described earlier in this article, mice with GH-related lifeextending mutations exhibit slow growth, delayed maturation, and reduced fecundity, which are key features of the slow paceof-life (8,38). Mice with grossly elevated GH levels due to transgenic expression of GH genes exhibit opposite characteristics, including early puberty and large litter size (29,30). ...
... Earlier in this article we have already indicated that, in comparison to other mammalian species, humans are characterized by a slow pace-of-life and long lifespan. Growth hormone-related mutations that slow the pace-of-life and extend longevity in laboratory mice also have been identified in the human (38,58,59), and were reported to influence various aging-related traits, including risk of chronic disease. Individuals with mutations in the GH receptor gene, and the resulting GH resistance (Laron Syndrome), are almost completely protected from cancer (59,60). ...
Mice with genetic growth hormone (GH) deficiency or GH resistance live much longer than their normal siblings maintained under identical conditions with unlimited access to food. Extended longevity of these mutants is associated with extension of their healthspan (period of life free of disability and disease) and with delayed and/or slower aging. Importantly, GH and GH-related traits have been linked to the regulation of aging and longevity also in mice that have not been genetically altered and in other mammalian species including humans. Avai+lable evidence indicates that the impact of suppressed GH signaling on aging is mediated by multiple interacting mechanisms and involves trade-offs among growth, reproduction, and longevity. Life history traits of long-lived GH-related mutants include slow postnatal growth, delayed sexual maturation, and reduced fecundity (smaller litter size and increased intervals between the litters). These traits are consistent with a slower pace-of-life, a well-documented characteristic of species of wild animals that are long-lived in their natural environment. Apparently, slower pace-of-life (or at least some of its features) is associated with extended longevity both within and between species. This association is unexpected and may appear counterintuitive, because the relationships between adult body size (a GH-dependent trait) and longevity within and between species are opposite rather than similar. Studies of energy metabolism and nutrient-dependent signaling pathways at different stages of the life course will be needed to elucidate mechanisms of these relationships.
... GH secretion decreases with age (referred to as somatopause), causing some to consider the use of GH replacement as a means to counteract aging-related conditions. Counterintuitively, diminished GH action in model organisms, either by way of natural mutations or inactivation of the GH or GHR genes, increases lifespan and slows the aging process through reducing IGF-1, mTOR signaling, and cellular senescence while simultaneously enhancing insulin sensitivity and stress resistance [3]. In addition to lifespan extension, removal of GH action in mice extends healthspan, preventing age-related conditions including frailty, cognitive decline, diabetic nephropathy, diet-induced diabetes, and multiple forms of cancer [3]. ...
... Counterintuitively, diminished GH action in model organisms, either by way of natural mutations or inactivation of the GH or GHR genes, increases lifespan and slows the aging process through reducing IGF-1, mTOR signaling, and cellular senescence while simultaneously enhancing insulin sensitivity and stress resistance [3]. In addition to lifespan extension, removal of GH action in mice extends healthspan, preventing age-related conditions including frailty, cognitive decline, diabetic nephropathy, diet-induced diabetes, and multiple forms of cancer [3]. While the link between the GH/IGF-1 axis and aging has proven more challenging to demonstrate in humans, evidence continues to grow. ...
... For example, individuals with Laron Syndrome (GH insensitivity usually caused by inactivating mutations to the GHR) have reduced mTOR signaling [4], are protected against agedependent cognitive decline [5], and are resistant to cancer [4,6]. Likewise, some cohorts of isolated GH deficiency (e.g., type 1B in the Brazilian Itabaianinha cohort) have higher numbers of individuals close to and >100 years of age versus the normal population, further suggesting that the findings in rodents are relevant to humans [3]. GHRKO mice (as well as most other mouse lines with reduced GH action) and humans with LS experience the effects of the inactivated GHR gene mutations from conception; thus, the specific impact of GH on longevity in later life required further investigation. ...
... As it is ancient and universal, singing has its origins prior to the development of spoken language and deserves attention for being integral to human social life (2). For over 25 years, we have been studying subjects with isolated congenital growth hormone (GH) deficiency (IGHD) residing in Itabaianinha in northeastern Brazil and discovered that their IGHD is due to an autosomal recessive null mutation (c.57+1G>A) in the GH-releasing hormone receptor (GHRHR) gene (3)(4)(5). We followed Dr. Chagas's wise prediction by assessing the impact of an artistic activity, choral singing, on the physical and social-emotional aspects of the singer's voice. ...
... Itabaianinha IGHD subjects exhibit very low serum levels of GH and its principal effector IGF-1 throughout their life (9). Despite this, they exhibit an apparent benign phenotype, being quite active with satisfactory muscular function (10), and autonomy even at advanced ages (4). The principal physical findings of these IGHD individuals are severe short stature, central obesity (with reduced muscle mass), wrinkled skin, with a "doll" face or cherubim angel face (due to the disproportion between the calvarium and the face), and a high-pitched voice (4,5,11), with increased values of fundamental frequency (f 0 ) (12,13) and of most formant frequencies (14). ...
... Despite this, they exhibit an apparent benign phenotype, being quite active with satisfactory muscular function (10), and autonomy even at advanced ages (4). The principal physical findings of these IGHD individuals are severe short stature, central obesity (with reduced muscle mass), wrinkled skin, with a "doll" face or cherubim angel face (due to the disproportion between the calvarium and the face), and a high-pitched voice (4,5,11), with increased values of fundamental frequency (f 0 ) (12,13) and of most formant frequencies (14). Their voices have higher values for roughness, breathiness and strain associated with a high frequency of laryngeal constriction (12). ...
Objective:
Currently, not much is known about the interactions between voice and growth hormone (GH). We have described large kindred with isolated GH deficiency (IGHD) due to a GHRH receptor mutation, resulting in severe short stature and high-pitched voice. These IGHD individuals have little interest in GH treatment, as they consider themselves "short long-lived people", rather than patients. Interestingly, they report normal general quality of life, but they rate their Voice-Related Quality of Life (V-RQOL) as low. Here, we assessed the social and auditory-perceptual impacts of artistic-intervention voice therapy with semioccluded vocal tract exercises (SOVTE) and choral singing, on their voices.
Methods:
Seventeen GH-naïve adult IGHD individuals were enrolled in a single-arm interventional pre-post study with 13 weekly sessions of choir singing over 90 days. Outcome measures were V-RQOL scores, self-assessment of voice, and auditory-perceptual analysis (GRBAS scale, G: grade of the severity of dysphonia; R: roughness; B: breathiness; A: asthenia; and S: strain).
Results:
Marked improvements in total (p = 0.0001), physical (p = 0.0002), and socioemotional (p = 0.0001) V-RQOL scores and in self-assessment of voice (p = 0.004) were found. The general grades of vocal deviation (p = 0.0001), roughness (p = 0.0001), breathiness (p = 0.0001) and strain (p = 0.0001) exhibited accentuated reductions.
Conclusion:
Voice therapy with semioccluded vocal tract exercises and choral training improved social impact and perceptual voice assessments in IGHD subjects and markedly improved their voice-related quality of life. This is particularly important in a setting where GH replacement therapy is not widely accepted.
... Growth hormone signaling is thought to be a key aging regulator [34,35]. Lack of GH signaling significantly expands lifespan, slows the aging process, increases the health Figure 2. GHR signaling pathways. ...
... Growth hormone signaling is thought to be a key aging regulator [34,35]. Lack of GH signaling significantly expands lifespan, slows the aging process, increases the health span, reduces body size, delays maturation, and increases life expectancy [35]. ...
Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR), which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR isoform, which lacks exon 3 has recently been related to longevity; individuals carrying this isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the wild type (WT) isoform (flGHR). Further, studies performed in patients with acromegaly, Prader–Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR isoform may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.
... From this perspective researchers also thought progressive decline in GH with ageing (somatopause) might be an adaptive response of the body providing an evolutionary advantage by slowing senescence and increase longevity. The findings in these animal models could not be completely replicated in human models of GH deficiency or resistant states largely because of major difference in energy partitioning, rapidity of postnatal growth and maturation, reproductive strategies, fecundity, and relatively minor role of GH/IGF-1 system in ageing among humans compared to murines [39,40]. Limited data suggests that healthspan and lifespan is normal or increased among patients with isolated GHD syndromes [39]. ...
... The findings in these animal models could not be completely replicated in human models of GH deficiency or resistant states largely because of major difference in energy partitioning, rapidity of postnatal growth and maturation, reproductive strategies, fecundity, and relatively minor role of GH/IGF-1 system in ageing among humans compared to murines [39,40]. Limited data suggests that healthspan and lifespan is normal or increased among patients with isolated GHD syndromes [39]. Offsprings of centenarians tend to have lower GH pulses and serum IGF-1 levels compared to their spouses or partners [41,42]. ...
... Caloric restriction and genetic alterations that reduce function in the GH/IGF-1/insulin pathways have been shown in experimental invertebrate and vertebrate animal models to extend life span. Mouse models of mutants that lack GH release (growth hormone-releasing hormone [GHRH], GHRH receptor, Prop1, and Pouf1) and that are GH insensitive (GHR) live significantly longer, and overexpression of GH reduces life span (bovine GH transgenic) (10). Whether this translates to humans is unclear. ...
... 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 (10). In contrast, dwarfism associated with GH deficiency in patients with GH1 mutations is reported to significantly shorten median life span (11). ...
Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older individuals.
... Interestingly, the absence of GH action in animals and humans, despite short stature, results in resistance to type 2 diabetes mellitus (T2DM) and cancer, and improvements in other indicators of healthspan 4 . With regard to longevity, mice with a reduction or absence in GH action have a robust and reproducible increase in lifespan 5 . Although data from humans is insufficient to draw firm conclusions, some cohorts of individuals with isolated GHD (for example, in the Brazilian Itabaianinha cohort) have attained extreme longevity despite representing a fairly small proportion of the population. ...
... Although data from humans is insufficient to draw firm conclusions, some cohorts of individuals with isolated GHD (for example, in the Brazilian Itabaianinha cohort) have attained extreme longevity despite representing a fairly small proportion of the population. Such observations suggest that the findings in rodents are relevant to humans 5 . The effects of the GH-insulin-like growth factor 1 (IGF1) axis on human ageing, how GH levels change during ageing and the relationship to age-related diseases are discussed in detail elsewhere 6 . ...
Since its discovery nearly a century ago, over 100,000 studies of growth hormone (GH) have investigated its structure, how it interacts with the GH receptor and its multiple actions. These include effects on growth, substrate metabolism, body composition, bone mineral density, the cardiovascular system and brain function, among many others. Recombinant human GH is approved for use to promote growth in children with GH deficiency (GHD), along with several additional clinical indications. Studies of humans and animals with altered levels of GH, from complete or partial GHD to GH excess, have revealed several covert or hidden actions of GH, such as effects on fibrosis, cardiovascular function and cancer. In this Review, we do not concentrate on the classic and controversial indications for GH therapy, nor do we cover all covert actions of GH. Instead, we stress the importance of the relationship between GH and fibrosis, and how fibrosis (or lack thereof) might be an emerging factor in both cardiovascular and cancer pathologies. We highlight clinical data from patients with acromegaly or GHD, alongside data from cellular and animal studies, to reveal novel phenotypes and molecular pathways responsible for these actions of GH in fibrosis, cardiovascular function and cancer.
... The GHR also activates the Src family kinase signaling pathway independently of JAK2 [26]. Growth hormone signaling is thought to be a key aging regulator [27,28]. Lack of GH signaling significantly can expands lifespan, slows the aging process, increases the health span, reduces body size, delays maturation, and increases life expectancy [28]. ...
Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR) gene, which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR variant, which has recently been related to longevity, is associated with enhanced signal transduction and higher receptor function. Many of these studies indicated that the growth response to GH treatment may be affected. Individuals carrying the d3GHR isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the WT isoform. Further, studies performed in patients with acromegaly, Prader-Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR variant may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.
... The embryonic development of the pituitary gland involves a complex and highly regulated network of signaling molecules. The somatotropic axis, including growth hormone (GH) and insulin-like growth factor (IGF-1), is a wellestablished regulator of postnatal growth in mammals (Aguiar-Oliveira et al., 2019). GH is secreted from the pituitary gland and stimulates the liver to synthesize IGF-1 (Schneider et al., 2003). ...
Roundabout guidance receptor 1 (Robo1) has been known to play a role in midbrain development in mice, but its postnatal function remains poorly defined, primarily due to the perinatal lethality observed in mice lacking the gene. In this study, we investigated the postnatal phenotypes of Robo1-/- mice in the B6/129S genetic background. We found that Robo1-/- mice exhibited a slower growth rate and a shorter lifespan compared to their Robo1+/+ littermates. Histological analysis of their skin revealed increased wrinkles, enlarged sebaceous glands, and a reduced subcutaneous fat layer in Robo1-/- mice. Moreover, these mice showed accelerated hair graying, indicating a decrease in melanin production. At 3 weeks of age, Robo1-deficient mice displayed suppressed levels of both growth hormone (GH) and insulin-like growth hormone 1 (IGF-1). However, by 7 weeks of age, the expression of GH and IGF-1 in Robo1-/- mice was similar to that in Robo1 intact mice. These findings suggest that Robo1-mediated hormone regulation is crucial for normal growth during the early stages of puberty and may serve as a vital timepoint to explore the molecular mechanisms of pituitary disorders.
... Conclusions derived from work on longevity in inbred model organisms and mammals maintained under artificial conditions should not simply be extrapolated to long-lived outbred species such as humans. This is extensively reviewed by Aguiar-Oliveira and Bartke (1). ...
The discovery of the growth hormone secretagogues (GHS) and the reverse pharmacology leading to the discovery of GHS receptor which enabled the identification of ghrelin as the natural ligand for the receptor have opened a new horizon in growth hormone (GH) physiology, pathophysiology, and therapeutics. Major progress has been made and we now have orally active GHS which are able to restore optimal pulsatile GH secretion which cannot be overstimulated as insulin-like growth factor feedback regulates the peaks to the optimum level. This enables GH to be restored in the older to levels normally seen in 20- to 30-year-old people; this leads to an increase in fat-free mass and redistribution of fat to the limbs. As these agents are ultimately approved and investigated further, it is likely that they will be shown to restore growth in children with moderate-to-mild GH deficiency; their benefits will be investigated in other indications such as nonalcoholic fatty liver disease, frailty, anemia, osteoporosis, and immune compromise in older subjects. The exquisite regulation of GH secretion reflects the importance of GH pulsatility in the regulation of somatotroph action of GH.
... Life expectancy has increased over the last two centuries, but this has not been accompanied by a comparable increase in healthspan (the period of life free from disease) due to the increase in non-communicable diseases afflicting a growing older population (Garmany et al. 2021, Le Couteur & Barzilai 2022. Inhibition of the GH/IGF1 axis has been highlighted as a key strategy to improve human healthspan by reducing the incidence of chronic age-related diseases such as cancer and diabetes (Berryman et al. 2008, Longo et al. 2015, van der Spoel et al. 2016, Aguiar-Oliveira & Bartke 2019, Lu et al. 2019, Duran-Ortiz et al. 2021, Bartke 2022, Brown-Borg 2022. Supporting this, humans born with Laron syndrome have remarkably reduced incidence of cancer, increased insulin sensitivity and youthful cognitive and motor functions (Laron et al. 2017, Guevara-Aguirre et al. 2020, Werner et al. 2020. ...
Decades of published research supports a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with anticancer therapy or radiation. Here we discuss challenges associated with using growth hormone receptor (GHR) antagonists in preclinical models and considerations for translation, such as the identification of predictive biomarkers for selecting patients and for monitoring drug efficacy. Ongoing research will determine whether suppressing GH signalling pharmacologically will also reduce the risk of developing cancer. An increase in GH-targeted drugs in preclinical development will ultimately provide researchers with new tools to test anti-cancer efficacy of blocking the GH signalling pathway in preclinical models.
... Prevertebrates grow using a variety of extra pituitary circuits, like insulin and growth factors (IGFs). However, to refine this purpose, vertebrates have developed the somatotrophic axis, with the pituitary growth hormone (GH) and circulating IGF type1 (IGF1), coupling their body growth with the increased ability to obtain food and to reproduce [2]. The somatotrophic system (the somatotrophic axis and extrapituitary circuits), extraordinarily complex and sometimes redundant, supports precise functions of the brain, immune system, and sense organs, as well as proper teeth, bones, muscles, and joints [3]. ...
Objectives
The shoulder is the most mobile joint in the entire human body. During arm elevation, it requires the integrity of a set of muscles, bones, and tendons. Individuals with short stature often need to raise their arms above the shoulder girdle and may have functional restriction or shoulder injuries. The impact of isolated GH deficiency (IGHD) on joints remains not well defined. The purpose of this work is to evaluate the function and structure of the shoulder in short-statured adult individuals with untreated IGHD due to the same homozygous mutation in the GHRH receptor gene.
Methods
A cross-sectional study (evidence 3) was carried out in 20 GH-naive IGHD subjects and 20 age-matched controls. They completed the disabilities of the arm, shoulder, and hand (DASH) questionnaire and shoulder ultrasound (US). Thickness of the anterior, medial, and posterior portions of the supraspinatus tendon and of subacromial space was measured, and the number of individuals with tendinosis or tearing of the supraspinatus tendon was registered.
Results
DASH score was similar between IGHD and controls, but IGHD subjects complained less of symptoms (p = 0.002). The number of individual with tears was higher in the controls (p = 0.02). As expected, the absolute US measurements were lower in IGHD, but the magnitude of the reduction was most pronounced in the thickness of the anterior portion of the supraspinatus tendon.
Conclusion
Adults with lifetime IGHD do not have functional shoulder restrictions, complain less of problems in performing upper extremity activities, and have fewer tendinous injuries than controls.
... Reduction in growth hormone (GH) and insulin-like growth factor (IGF) and increased insulin responsiveness correlate with the prolonged life and an apparent reduction in the aging process. [31][32][33] IGFs, insulin receptors (INSR), and insulin receptor substrate-1 (IRS-1) could regulate insulin resistance as well as contribute to metabolic syndrome (Fig. 5). With regard to cardiac aging, the interaction of insulin-like growth factor-1 (IGF-1) with IGF-1 receptor (IGF-1R) accelerates myocardial pathologies in cardiac aging and longevity in mammals. ...
Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However, metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility. Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging, including autophagy, oxidative stress, epigenetic modifications, chronic inflammation, and myocyte systolic phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and chronic inflammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed. Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about metabolic landscapes of cardiac aging, with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.
... Chronic inflammation can lead to several diseases, including cardiovascular disease, and exacerbates the ageing process [72,73]. In addition, the growth hormone receptor (GHR) protein EpiScore was selected; both the receptor and its corresponding protein have been linked to longevity in mouse models [74][75][76][77][78]. Twenty-five of the 28 of the selected EpiScores from Gadd et al. [14] have been associated to multiple diseases, including diabetes, chronic obstructive pulmonary disease, ischaemic heart disease, lung cancer, Alzheimer's, rheumatoid arthritis, stroke, and depression (Additional file 4: Table S10). ...
Background
Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to develop accurate epigenetic predictors of cAge and bAge, whilst improving our understanding of their epigenomic architecture.
Methods
First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to create a cAge predictor, we use methylation data from 24,674 participants from the Generation Scotland study, the Lothian Birth Cohorts (LBC) of 1921 and 1936, and 8 other cohorts with publicly available data. In addition, we train a predictor of time to all-cause mortality as a proxy for bAge using the Generation Scotland cohort (1214 observed deaths). For this purpose, we use epigenetic surrogates (EpiScores) for 109 plasma proteins and the 8 component parts of GrimAge, one of the current best epigenetic predictors of survival. We test this bAge predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women’s Health Initiative study).
Results
Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross-validation framework, we obtain cAge prediction with a median absolute error equal to 2.3 years. Our bAge predictor was found to slightly outperform GrimAge in terms of the strength of its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10⁻⁵², and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 × 10⁻⁶⁰). Finally, we introduce MethylBrowsR, an online tool to visualise epigenome-wide CpG-age associations.
Conclusions
The integration of multiple large datasets, EpiScores, non-linear DNAm effects, and new approaches to feature selection has facilitated improvements to the blood-based epigenetic prediction of biological and chronological age.
... This finding suggests that even prolonged exposure to small amounts of endogenous GH and IGF1 may contribute to carcinogenesis. Of note, these human population studies are in agreement with several animal models in which naturally or experimentally induced suppression of the GH-IGF signaling system has been associated with significant reductions in cancer rates, frequently accompanied by improvement in metabolic indexes and significant increments in their lifespan (Basu et al. 2018, Aguiar-Oliveira & Bartke 2019. ...
The association between growth hormone (GH) and carcinogenesis has long been postulated. The rationale for this association is that several components of the GH axis play an important role in the regulation of cell proliferation, differentiation, apoptosis and angiogenesis and have been tested as targets for cancer therapy. Epidemiological and clinical studies have examined the association between height, growth patterns and IGF-I levels with the most common types of malignancies, while genome-wide association studies have revealed several height-associated genes linked to cancer and/or metastasis-driving pathways. In this context, a permissive role of the GH-IGF signaling system in the link between height and cancer risk has also been investigated. In animal and human models, genetic defects associated with GH deficiency or resistance are associated with protection from tumor development, while risk of malignancies in acromegaly or in patients exposed to recombinant GH therapy has long been a matter of concern and scrutiny. In this review, we present a narrative and historical review covering the potential relations among height, growth patterns, GH axis and cancer.
... There is also in particular a shortage of studies in mammalian models and of research that considers the controls we built in the present work to account for possible age-independent PAAI effects. Contrary to a general expectation that 'anti-aging' treatments should produce a broad change in aging rate across many phenotypes 33,36,53,70,72,[84][85][86][87][88][89][90][91] , our study shows that the PAAIs we examined -that are concerned with some of the very core mechanisms proposed to be involved in aging 4did often not seem to work through targeting age-dependent change (Fig. 9). This is not to say that we did not observe individual anti-aging effects that were consistent with a slowed aging rate; parameters that followed this pattern did, however, represent the minority of cases of anti-aging influences observed in the present study. ...
Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.
... However, earlier study of the same Ecuadorian population found higher mortality before age 7 in dwarfs compared with normal size siblings [9]. There was also no significant longevity difference in a Brazilian cohort with a GHRH receptor mutation, although that population also exhibited reductions in a number of cancer types [10]. In a Croatian population with a disabling mutation in the Prop1 gene, twenty-three untreated heredity dwarfs have been historically identified. ...
In laboratory mice, pituitary dwarfism caused by genetic reduction or elimination of the activity of growth hormone (GH) significantly extends lifespan. The effects of congenital pituitary dwarfism on human longevity are not well documented. To analyse the effects of untreated pituitary dwarfism on human lifespan, the longevity of a diverse group of widely known little people, the 124 adults who played “Munchkins” in the 1939 movie The Wizard of Oz was investigated. Survival of “Munchkin” actors with those of controls defined as cast members of The Wizard of Oz and those of other contemporary Academy Award winning Hollywood movies was compared. According to the Kaplan–Meier survival curves, survival of female and male “Munchkin” actors was shorter than cast controls and Hollywood controls of respective sexes. Cox regression analyses showed that female “Munchkin” actors had significantly higher risk ratios compared to both female cast controls (RR, 1.70; 95% CI, 1.05 to 2.77) and female Hollywood controls (RR, 1.52; 95% CI, 1.03 to 2.24). Similar trends were also discernible for men, albeit point estimates were not significant. The lack of lifespan extension in “Munchkin” actors does not support the hypothesis that hereditary GH deficiency regulates longevity in humans.
... IGF-1 deficiency demonstrates very low prevalence among pediatric patients diagnosed with short stature, constituting approximately 1.2% [4]. Pathological conditions like dwarfism, including Laron syndrome with substantially low levels of IGF-1, allowed us to discover crucial role of that protein in growth and maturation reduction [5]. Laron syndrome is associated with IGF-1 deficiency and mutations in growth hormone (GH) receptor. ...
Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells—very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4–5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients’ data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances.
Graphical abstract
... The GH/Insulin-like growth factors (IGFs) system comprises the somatotrophic axis, critical for body size, including the hypothalamic GH-releasing hormone (GHRH), pituitary GH and circulating IGF-I, and the local production of GH/IGF-I, IGF-II [1], and other peptides like fibroblast growth factor (FGF), vascular ...
Background
The somatotrophic axis, including hypothalamic growth hormone (GH)-releasing hormone (GHRH), pituitary GH and circulating IGF-I, is critical for body size. However, the local production of GH/IGF-I (and IGF-II) and other peptides is relevant for other body functions, such as vascular, brain, and retinal function. The consequences of GH deficiency (GHD) on the retinal structure are still unclear, possibly reflecting the heterogeneity of patients and the different types of assessment in previous publications. Our purpose was to assess quantitative measures of the vascular and neural components of the retina in subjects with severe congenital isolated GHD (IGHD).
Methods
A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, optical coherence tomography (OCT) and OCT angiography (OCTA) were performed.
Results
OCT revealed no difference in the areas of the nerve fiber layer average, nor in the areas of superior, inferior, or nasal quadrants, between the two groups. However, areas of the temporal quadrant (p = 0.041), the optical disc (p = 0.042), the cup (p < 0.0001), as well as the cup/disc ratio (p < 0.0001), were higher in IGHD subjects than controls. The rim area was smaller (p = 0.002), although still normal. In OCTA, there was no difference in the minimum foveal thickness, central fovea, foveal avascular zone, and retinal density in any assessed area.
Conclusions
In conclusion, congenital IGHD does not affect quantitative measures of the vascular and neural retina, and it is associated with increased optical disc in this genetically homogeneous cohort.
... El crecimiento y el desarrollo normales en los mamíferos están estrechamente controlados por numerosos factores genéticos y condiciones metabólicas. El eje hormonal hormona de crecimiento (GH)-factor de crecimiento similar a la insulina-1 (IGF1) es un actor clave en la regulación de estos procesos (42)(43)(44)(45)(46). La desregulación del sistema endocrino GH-IGF1 está relacionada con una serie de patologías, que van desde déficit de crecimiento hasta cáncer. ...
Abstract
The Laron syndrome or Laron-type Dwarfism, aSLo called Growth Hormone Insensitivity, is a rare,
congenital, autosomal recessive disease that does not present differences of affectation by sex. More than 350
cases of the disease have been described worldwide, especially in the Mediterranean (Israel, Saudi Arabia,
Egypt and Iraq) and with the highest incidence in Ecuador, specifically in the province of Loja where 75% of
the total is found cases worldwide. The objective is to document the genetic bases involved in the
pathophysiology and development of the disease, as well as its association with cancer and diabetes mellitus
in the Ecuadorian population. The methodological framework includes a documentary design, through a
systematic bibliographic search of full-text articles, published in the last ten years in journaSL indexed in the
scientific databases and search engines PubMed, MEDLINE, Cochrane, Google Scholar, Scielo, Scopus,
Redalyc, Elsevier and WOS. It is expected to show the most relevant genotypic and phenotypic characteristics
in the Ecuadorian population, as well as possible theories in pathophysiology and its association with a lower
risk of developing diabetes and cancer.
Keywords: Dwarfism, - IGF-1 - Diabetes
... Chronic inflammation can lead to several diseases, including 253 cardiovascular disease and exacerbates the ageing process 60,61 . In addition, the growth hormone 254 receptor (GHR) protein EpiScore was selected; both the receptor and its corresponding protein have 255 been linked to longevity in mouse models [62][63][64][65][66] . 25/28 of the selected EpiScores from Gadd et al 14 individual-level bAge predictions were highly variable. ...
Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understanding of the epigenomic architecture of cAge and bAge. First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to improve cAge prediction, we use methylation data from 24,673 participants from the Generation Scotland (GS) study, the Lothian Birth Cohorts (LBC) of 1921 and 1936 and 8 publicly available datasets. Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection/dimensionality reduction in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross validation framework, we arrive at an improved cAge predictor (median absolute error = 2.3 years across 10 cohorts). In addition, we train a predictor of bAge on 1,214 all-cause mortality events in GS, based on epigenetic surrogates for 109 plasma proteins and the 8 component parts of GrimAge, the current best epigenetic predictor of all-cause mortality. We test this predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women's Health Initiative study) where it outperforms GrimAge in its association to survival (HR GrimAge = 1.47 [1.40, 1.54] with p = 1.08 x 10 ⁻⁵² , and HR bAge = 1.52 [1.44, 1.59] with p = 2.20 x 10 ⁻⁶⁰ ). Finally, we introduce MethylBrowsR, an online tool to visualize epigenome-wide CpG-age associations.
... Growth hormone deficiency (GHD) is a common growth and development disorder in clinical practice, which is triggered by a partial or complete deficiency of growth hormone (GH) synthesis and secretion in the anterior pituitary gland (APG) or by receptor defects and structural abnormalities [1]. With an ever-higher incidence worldwide, childhood GHD has become one of the major health issues affecting children in developing countries [2]. ...
This study aims to explore the magnetic resonance imaging (MRI) findings of the pituitary gland (PG) in children with growth hormone deficiency (GHD) and their correlation with the growth hormone (GH) peak during clinical GH stimulation tests. Sixty-one children with GHD diagnosed and treated between December 2018 and December 2021 were retrospectively analyzed in terms of clinical and pituitary morphological MRI data. MRI measurements of various diameters of the adenohypophysis (AH) were obtained to analyze the differences of the measured values in different genders and age groups, as well as their relationship with the GH peak in GH stimulation tests. Among the 61 children with GHD, the superior PG margin was protuberant in 2 cases, flat in 13 cases, and concave in 46 cases. The three age groups showed similar pituitary morphology and stalk (P>0.05). On T1-weighted images, the proportion of isointensity was lower while the proportion of slightly-low signal intensity was higher in the anterior pituitary gland (APG) of children aged >10 compared with those aged 7–10. The comparison of AH linear parameters and GH peak values of male patients among different age groups showed that the anteroposterior (sagittal) diameter of AH and GH peak were the highest in the >10-year-old group and the lowest in the ≤6-year-old group, with those of the 7–10-year-old group in between (P10-year-old group compared with the ≤6-year-old group (P
... GH exerts its functions by binding to the GHR on target cells, which activates the Jak/STAT/Src pathways and stimulates the production and secretion of IGF1 in many tissues, mainly the liver. In the brain, where it plays an important role in development and function, IGF1 is GH-independent (3,(8)(9)(10). Since IGF1 was identified in 1957, the interest increased, especially when IGF1 was found to mediate the anabolic and mitogenic activities of GH (11). ...
Growth hormone (GH) and insulin‐like growth factor‐1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10‐30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA‐MB‐231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule.
... 6 and 7). These findings ruled out any glucose restriction effect that compromised the cell growth (Fig. 5), however extended the lifespan with a slowgrowth phenotype [49]. However, the extension of lifespan by rapamycin does not require a higher dose that compromises cell growth (Fig. 4). ...
Although aging is the biggest risk factor for human chronic (cancer, diabetic, cardiovascular, and neurodegenerative) diseases, few interventions are known besides caloric restriction and a small number of drugs (with substantial side effects) that directly address aging. Thus, there is an urgent need for new options that can generally delay aging processes and prevent age-related diseases. Cellular aging is at the basis of aging processes. Chronological lifespan (CLS) of yeast Saccharomyces cerevisiae is the well-established model system for investigating the interventions of human post-mitotic cellular aging. CLS is defined as the number of days cells remain viable in a stationary phase. We developed a new, cheap, and fast quantitative method for measuring CLS in cell cultures incubated together with various chemical agents and controls on 96-well plates. Our PICLS protocol with (1) the use of propidium iodide for fluorescent-based cell survival reading in a microplate reader and (2) total cell count measurement via OD600nm absorption from the same plate provides real high-throughput capacity. Depending on logistics, large numbers of plates can be processed in parallel so that the screening of thousands of compounds becomes feasible in a short time. The method was validated by measuring the effect of rapamycin and calorie restriction on yeast CLS. We utilized this approach for chemical agent screening. We discovered the anti-aging/geroprotective potential of 2,5-anhydro-D-mannitol (2,5-AM) and suggest its usage individually or in combination with other anti-aging interventions.
... This could be due to the fact that animal reproduction generally responds quickly to changes in diet or environment. For instance, it has been found that C. elegans, Drosophila, and rat will preferentially impair, delay or abolish fecundity in order to survive better under conditions of dietary restriction or nutritional deficiencies [36][37][38][39][40][41]. A cost of reproduction, where lifespan and fecundity are negatively correlated, is of widespread occurrence. ...
Plasmids are mostly found in bacteria as extrachromosomal genetic elements and are widely used in genetic engineering. Exploring the mechanisms of plasmid–host interaction can provide crucial information for the application of plasmids in genetic engineering. However, many studies have generally focused on the influence of plasmids on their bacterial hosts, and the effects of plasmids on bacteria-feeding animals have not been explored in detail. Here, we use a “plasmid–bacteria–Caenorhabditis elegans” model to explore the impact of plasmids on their host bacteria and bacterivorous nematodes. First, the phenotypic responses of C. elegans were observed by feeding Escherichia coli OP50 harboring different types of plasmids. We found that E. coli OP50 harboring plasmid pEX18Gm unexpectedly increases the fecundity of C. elegans. Subsequently, we found that the plasmid pEX18Gm indirectly affects C. elegans fecundity via bacterial metabolism. To explore the underlying regulatory mechanism, we performed bacterial RNA sequencing and performed in-depth analysis. We demonstrated that the plasmid pEX18Gm upregulates the transcription of methionine synthase gene metH in the bacteria, which results in an increase in methionine that supports C. elegans fecundity. Additionally, we found that a pEX18Gm-induced increase in C. elegans can occur in different bacterial species. Our findings highlight the plasmid–bacteria–C. elegans model to reveal the mechanism of plasmids’ effects on their host and provide a new pattern for systematically studying the interaction between plasmids and multi-species.
... It regulates postnatal longitudinal growth, various aspects of metabolism, and other physiological effects. GH has also been implicated in lifespan [31,32]. Excess GH secretion leads to acromegaly (AC), a devastating medical condition characterized, among other findings, by increased IGF-I serum levels [33]. ...
Objective
Chagas disease (CD) is caused by the protozoan parasite, Trypanosoma cruzi. It affects 6 to 8 million people worldwide and leads to approximately 50,000 deaths per year. In vitro and in vivo studies had demonstrated that Tripanosoma cruzi infection causes an imbalance in the hypothalamic-pituitary-adrenal (HPA) axis that is accompanied by a progressive decrease in growth hormone (GH) and prolactin (PRL) production. In humans, inactivating mutations in the GH receptor gene cause Laron Syndrome (LS), an autosomal recessive disorder. Affected subjects are short, have increased adiposity, decreased insulin-like growth factor-I (IGF-1), increased serum GH levels, are highly resistant to diabetes and cancer, and display slow cognitive decline. In addition, CD incidence in these individuals is diminished despite living in highly endemic areas. Consequently, we decided to investigate the in vitro effect of GH/IGF-I on T. cruzi infection.
Design
We first treated the parasite and/or host cells with different peptide hormones including GH, IGFI, and PRL. Then, we treated cells using different combinations of GH/IGF-I attempting to mimic the GH/IGF-I serum levels observed in LS subjects.
Results
We found that exogenous GH confers protection against T. cruzi infection. Moreover, this effect is mediated by GH and not IGFI. The combination of relatively high GH (50 ng/ml) and low IGF-I (20 ng/ml), mimicking the hormonal pattern seen in LS individuals, consistently decreased T. cruzi infection in vitro.
Conclusions
The combination of relatively high GH and low IGF-I serum levels in LS individuals may be an underlying condition providing partial protection against T. cruzi infection.
... Importantly, delayed and slower aging and extended longevity of these animals are associated with various indices of healthy aging and extension of the healthspan, a period of life free of disease, frailty, and functional impairments (35,38). Overlap of the phenotypic characteristics of these, and other GHrelated, long-lived mouse mutants, with those of GH-deficient and GH-resistant humans was discussed in our recent publications (39,40). The endocrine intervention employed in our studies consisted of twice-daily injections of growth hormone (GH), one of the hormones that these animals fail to produce and was limited to a period of six weeks starting at the age of one or two weeks, when mice are still suckling (21,22). ...
It is well documented that the environment of the developing fetus, including availability of nutrients and presence of toxins, can have major impact on adult phenotype, age-related traits and risk of chronic disease. There is also accumulating evidence that postnatal environment can impact adult characteristics related to evolutionary fitness, health, and aging. To determine whether early life hormonal interventions can alter trajectory of aging, we have examined the effects of early life growth hormone (GH) replacement therapy in Prop1 df (Ames dwarf) mice which are GH deficient and remarkably long lived. Twice-daily GH injections between the ages of two and eight weeks completely normalized (“rescued”) a number of adult metabolic characteristics believed to contribute to extended longevity of these mutants. Importantly, longevity of Ames dwarf mice was reduced by early life GH treatment. This was associated with histone H3 modifications. We conclude that the trajectory of mammalian aging can be modified by early life interventions. Mechanistic links among interventions during postnatal development, adult metabolic characteristics, aging, and longevity, apparently involve epigenetic phenomena.
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.
Human growth hormone (hGH) is a pituitary derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development, and metabolism. Following adulthood, GH is also a regulator of multiple pathologies like fibrosis, cancer, and diabetes. Therefore, there is a significant pharmaceutical interest in developing antagonists of hGH action. Currently there is a single FDA approved antagonist of the hGH receptor (hGHR) prescribed for treating patients with acromegaly and discovered in our laboratory almost three decades ago. Here, we present the first data on the structure and function of a new set of protein antagonists with the full range of hGH actions - dual antagonists of hGH binding to the GHR as well as that of hGH binding to the prolactin receptor. We describe the site-specific poly-ethylene-glycol (PEG) conjugation, purification, and subsequent characterization using MALDI-TOF, size-exclusion chromatography, thermostability, and biochemical activity in terms of ELISA-based binding affinities with GHR and PRLR. Moreover, these novel hGHR antagonists display distinct antagonism of GH induced GHR intracellular signaling in vitro and marked reduction in hepatic insulin-like growth factor 1 output in vivo. Lastly, we observed potent anti-cancer biological efficacies of these novel hGHR antagonists against human cancer cell lines. In conclusion, we propose that these new GHR antagonists have potential for development towards multiple clinical applications related to GH associated pathologies.
Non-pituitary GH (npGH) expression is well established in extrapituitary tissues, but understanding of the physiological role of npGH remains rather limited. Pro-tumorigenic npGH impacting the tumor microenvironment has been reviewed, and we focus here on autocrine/paracrine npGH effects in non-tumorous tissues and discuss its mechanisms of action in the normal tissue microenvironment. We address tissue-specific effects of npGH in regulating stem, endothelial, immune, and epithelial cells and highlight the related role of npGH-associated changes in tissue aging.
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 transacting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. The 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 aging resulted in a more "aged methylome" for BXD strains that 23 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 analysis identified the hepatic nuclear factor, Hnf1a (MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variation in body size and metabolic traits, and influence CpG methylation and epigenetic aging that could have an impact on lifespan.
Lifespan and time of death of dogs died in Switzerland between 2016 and 2020 were evaluated in order to increase the awareness of the public to animal welfare-related consequences of extreme brachycephalic breeding and to clarify the torture breeding problem of dogs suffering from brachycephalic obstructive airway syndrome (BOAS). Skull shape, body size, country of origin and altitude of the registered place of residence at the time of death were analysed in a set of anonymized data from the national animal database Amicus as potential factors influencing the life expectancy. Death rate during summer months and the altitude of the reported place of residence at death were analysed in relation to the skull shape to demonstrate the heat intolerance of brachycephalic dog breeds. The final dataset included 137 469 dogs. The average age of death of the study population was 11,8 years, mixed breeds reaching a higher average age of 12,4 years than purebred dogs with 11,5 years. Bodyweight classification, skull shape and the origin of the dogs had a significant effect on the average lifespan. Giant breeds reached with 9,0 years the lowest mean age compared to the other bodyweight categories. The mean life expectancy of brachycephalic dogs was 9,8 years, i.e., 2,1 and 1,7 years less than mesocephalic and dolichocephalic dogs, respectively. Brachycephalic dogs and dogs imported from abroad showed increased mortality at a young age.
Tackling the mechanisms underlying ageing is desirable to help to extend the duration and improve the quality of life. Life extension has been achieved in animal models by suppressing the growth hormone-insulin-like growth factor 1 (IGF-1) axis and also via dietary restriction. Metformin has become the focus of increased interest as a possible anti-ageing drug. There is some overlap in the postulated mechanisms of how these three approaches could produce anti-ageing effects, with convergence on common downstream pathways. In this Review, we draw on evidence from both animal models and human studies to assess the effects of suppression of the growth hormone-IGF-1 axis, dietary restriction, and metformin on ageing.
Die Dank der steigenden Lebenserwartung zunehmende Zahl alternder Männer rückt die endokrine Situation dieser Altersgruppe mehr und mehr in den Fokus der Medizin. Bei Männern gibt es zwar kein Klimakterium, aber einen allmählichen Abfall des Testosterons, wobei die Werte durchaus im Normbereich jüngerer Männer bleiben können. Bei einigen Männern fallen die Werte jedoch unter die Normalgrenze. Wenn dies in Verbindung mit charakteristischen Symptomen auftritt, kann es sich um einen genuinen Altershypogondismus (LOH = late onset hypogonadism) oder um einen funktionellen Hypogonadismus handeln. In diesen Fällen kann eine Testosteronsubstitution erwogen werden, die streng überwacht werden muss.
Anterior pituitary growth hormone (GH) exerts myriad growth-promoting and metabolic functions. Although primarily responsible for determining skeletal growth and height, GH also is active in adults, functioning to maintain body composition, as well as muscle, liver, metabolic, and epithelial homeostasis. The hormone binds to peripheral GH receptors, initiating several intracellular signaling pathways resulting in the generation of insulin-like growth factor (IGF)-1, cytoskeletal changes, alterations in glucose metabolism, and modulation of cell proliferation genes. IGF-1, synthesized primarily in the liver, mediates most of the growth-promoting actions of GH. Metabolic actions of GH also affect carbohydrate, protein, and lipid metabolism and alter body composition. GH and IGF-1 influence body composition, cardiovascular function, muscle strength, and exercise performance. Clinical evaluation of GH excess or deficiency requires estimation of GH responses to inhibitory or stimulatory factors during provocative testing. GH replacement therapy has beneficial effects in GH-deficient children with short stature and in adults with GH deficiency. Short- and long-term actions of GH have been evaluated for potential beneficial effects in the aging population and for enhanced athletic performance by athletes, with lack of proven efficacy.
In the late 19th century, José Dantas de Souza Leite, a physician born in Sergipe, published the first detailed clinical description of acromegaly under the guidance of the French neurologist Pierre Marie. In 2014, the Brazilian Society of Endocrinology and Metabolism created the “José Dantas de Souza Leite Award”, which is granted every two years to a Brazilian researcher who has contributed to the development of endocrinology. In 2022, the award was given to another physician from Sergipe, Manuel Hermínio de Aguiar Oliveira, from the Federal University of Sergipe for the description of “Itabaianinha syndrome” in a cohort of individuals with isolated GH deficiency due to a homozygous inactivating mutation in the GH-releasing hormone receptor gene. This research, which was carried out over almost 30 years, was performed in partnership with Roberto Salvatori from Johns Hopkins University and in collaboration with other researchers around the world. This review article tells the story of Souza Leite, some milestones in the history of GH, and summarizes the description of Itabaianinha syndrome.
Keywords
GH; GHRH receptor; IGF1; acromegaly; growth hormone deficiency
Aging is a natural physiological process, but aging can increase the prevalence and mortality of chronic diseases in the elderly. It involves multiple organs and systems, and an essential aspect of aging is immunosenescence. With the increase of age, the immune system has undergone a series of changes and disorders. These changes have led to a decline in the resistance of the elderly to infection, reduced immunity to vaccines, increased incidence of cancer and autoimmune diseases, and an increased structural prevalence of low-grade inflammation. Moreover, affecting the aging process to a certain extent. This review introduces the changes in the immune system during aging and discusses the consequences and effects of these changes. And its effect on the aging process and the methods and ways of anti-aging were discussed.
Type 1 diabetes (T1D) is autoimmune destruction of the beta cells of pancreatic islets. Due to complexity of that disease, the mechanisms leading to the tolerance breakdown are still not fully understood. Previous hypothesis of imbalance in the Th1 and Th2 cells as the main contributing factor has been recently changed towards role of other lymphocytes – regulatory (Treg) and IL-17A-producing (Th17). Our study aims to assess changes within Treg and Th17 cells in newly diagnosed T1D pediatric patients and their association with disease remission. Flow cytometry implementation allowed for Treg and Th17 analysis in studied groups and further combination with clinical and laboratory data. In addition, expression of diabetes-related genes was tested and evaluated in context of their association with studied lymphocytes. Initial results revealed that Treg and ratio Treg/Th17 are significantly higher in T1D than in healthy controls. Moreover, patients with lower HbA1c and daily insulin requirements demonstrated higher levels of Tregs. Similar tendency for insulin intake was also observed in reference to Th17 cells, together with high levels of these cells in patients demonstrating higher values for c-peptide after 2 years. In low-level Treg patients, that subset correlates with the c-peptide in the admission stage. In addition, higher levels of IL-10 were associated with its correlation with HbA1c and insulin dosage. In the context of gene expression, moderate associations were demonstrated in T1D subjects inter alia between CTLA4 and Treg or ratio Treg/Th17. Cumulatively, our data indicate a possible novel role of Treg and Th17 in mechanism of type 1 diabetes. Moreover, potential prognostic value of these populations has been shown in reference to diabetes remission.
The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel‐like factor 1 (KLF1/EKLF), the SUMOylation‐deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age‐related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild‐type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age‐related diseases thus extending the healthspan as well as lifespan. The quest for prolonged lifespan has been ongoing for decades with the hope of unlocking the mystery of the key substance(s) in longevity. This study presents a longevity mouse model that significantly improves geriatric disorders and lifespan in a hematopoietic manner. This animal model is invaluable for exploring new approaches for antiaging and offers a contribution to advancing geroscience.
The aging process in semelparous and iteroparous species is different, but how different? Death in semelparous organisms (e.g., Pacific salmon) results from suicidal reproductive effort (reproductive death). Aging (senescence) in iteroparous organisms such as humans is often viewed as a quite different process. Recent findings suggest that the nematode Caenorhabditis elegans , widely used to study aging, undergoes reproductive death. In post-reproductive C. elegans hermaphrodites, intestinal biomass is repurposed to produce yolk which when vented serves as a milk to support larval growth. This apparent benefit of lactation comes at the cost of intestinal atrophy in the mother. Germline removal and inhibition of insulin/IGF-1 signaling (IIS) suppress C. elegans reproductive pathology and greatly increase lifespan. Blocking sexual maturity, e.g., by gonadectomy, suppresses reproductive death thereby strongly increasing lifespan in semelparous organisms, but typically has little effect on lifespan in iteroparous ones. Similarly, reduced IIS causes relatively modest increases in lifespan in iteroparous organisms. We argue that the more regulated and plastic mechanisms of senescence in semelparous organisms, involving costly resource reallocation under endocrine control, exist as one extreme of an etiological continuum with mechanisms operative in iteroparous organisms. We suggest that reproductive death evolved by exaggeration of mechanisms operative in iteroparous species, where other mechanisms also promote senescence. Thus, knowledge of C. elegans senescence can guide understanding of mechanisms contributing to human aging.
Objective
To understand the growth of teeth and mandibular and maxillary bones in subjects with isolated growth hormone deficiency (IGHD).
Material and methods
Mesiodistal tooth width of 28 maxillary and mandibular dental models of 14 adult IGHD subjects (9 men) were digitalized and compared to 40 models of 20 normal-statured controls (11 men). The mean SDS of the maxillary and mandibular teeth were compared with height, cephalic perimeter, total anterior facial height, total maxillary and mandibular length, and maxillary and mandibular arches.
Results
All average mesiodistal dimensions in absolute values of the 14 dental pairs were reduced in the IGHD group. Eight of 28 (28.6%) mesiodistal dimensions in IGHD subjects of both sexes had an average SDS below −2, thirteen of them (46.4%) had mean SDS between −1 and − 2, and seven of them (25.0%) had SDS above −1. The highest SDS values were the upper lateral incisor (−0.32 in women), and the upper canine (−0.91 in men). The lowest SDS values were the 2nd upper molar (−3.51 in men), and the 2nd upper premolar (−2.64 in women). The ascending order of the mean SDS was height, total maxillary length, total mandibular length, total anterior height of the face, cephalic perimeter, the maxillary arches width, the mesiodistal width of the mandibular teeth, the mesiodistal width of the maxillary teeth and the mandibular arches width.
Conclusions
Reduction in mesiodistal width is present in untreated IGHD adults with magnitude of tooth size reduction being lower than height, cephalic perimeter, total anterior facial height, and most jaw measurements. IGHD abolishes the sexual dimorphism in mesiodistal dental measures.
Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and musculoskeletal effects, GH is closely associated with aging, with levels declining as individuals age but GH action negatively correlating with lifespan. GH’s effects have been studied in human conditions of GH alteration, such as acromegaly and Laron syndrome, and GH therapies have been suggested to combat aging-related musculoskeletal diseases, in part, because of the decline in GH levels with advanced age. While clinical data are inconclusive, animal models have been indispensable in understanding the underlying molecular mechanisms of GH action. This review will provide a brief overview of the musculoskeletal effects of GH, focusing on clinical and animal models.
Normal growth pattern variations [i.e., constitutional advancement and constitutional delay of growth and puberty (CAGP and CDGP)] are the mirror image of each other and are associated with early puberty (EP) and delayed puberty (DP), respectively. Differences between CAGP and CDGP relate not only to auxological characteristics (height, weight) but also to insulin-like growth factor-1 (IGF-1). IGF-1 levels in CAGP are above average whereas in CDGP they are below average, suggesting a role for IGF-1 in the induction of these growth patterns. Herein, we provide data suggesting that early activation of the growth hormone (GH)/IGF-1 axis induces the growth pattern of CAGP. Moreover, we suggest that IGF-1 is a decisive factor for the release of the gonadotropin-releasing hormone (GnRH) inhibition brake that occurs in prepuberty. It is therefore crucial for puberty onset.
This chapter reviews the pertinent changes in the pituitary gland that occur with ageing and the diseases that affect this gland that are relevant to the care of the older individual. The pituitary gland is the master endocrine gland as it detects and integrates multiple sources of information to regulate physiologic functions. The blood supply to the anterior pituitary is through a rich vascular network. Hypopituitarism and hyperprolactinaemia are usually present in varying degrees. Nonfunctioning microadenomas have a benign natural history and can be followed with annual visual acuity and visual field testing and neuroimaging in the asymptomatic patient. The predominant cause of acromegaly is growth hormone (GH)‐producing tumours and the effects of GH are mediated by insulin growth factor‐1. Gamma‐knife radiosurgery is a recent option for the management of pituitary tumours. There is no consensus on the effects of ageing on prolactin secretion. In mice, a GH‐releasing hormone antagonist improved memory and increased lifespan.
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.
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.
Equation 3 of the original published version of this article was incorrect. Correct presentation is given below.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.