Growth Hormone Receptor Gene Disruption in Mature-Adult Mice Improves Glucose Metabolism and Lifespan in Females

Abstract Growth hormone (GH) serves an important role in early and adult life. Reduction of GH action has been shown to increase life span in many species of animals. In fact, mice bearing a congenital disruption of GH receptor (GHR) gene (GHRKO) hold the record for the longest-lived laboratory mice. In addition to extended life span, these mice show improved health with lower rates of cancer, increased insulin sensitivity, and resistance to age-associated cognitive decline. Furthermore, humans with decreased GH action due to inactivating mutations in the GHR (Laron Syndrome patients) are resistant to cancer and diabetes. Even though the beneficial effects of congenital Ghr gene disruption are well studied, the consequences of postnatal disruption of GH action were unknown. Previously our laboratory generated a mouse line with disrupted GH action at 1.5 months of age (1.5mGHRKO mice). Results showed that these mice had improved insulin sensitivity and increased maximal lifespan only in females, yet growth retardation was still present. To consider decreased GH action as a possible therapeutic to extend healthy lifespan, it was imperative to elucidate the effects of disrupting Ghr gene at a mature-adult age, well after the developmental and growth period of the mice. To this end, we hypothesized that removal of GH action in adult life would convey some of the same health and life span benefits seen in the GHRKO mice without the reduced body length. To test this hypothesis, we used the cre-lox system to generate mice with a disrupted Ghr gene at a mature-adult age (6 months), referred as 6mGHRKO mice. We then performed a phenotypic and lifespan characterization, and tested for molecular mechanisms known to be associated with extended longevity, namely oxidative stress resistance and mTOR modulation. We found that similar to GHRKO and 1.5mGHRKO mice, disruption of GHR at 6 months of age resulted in mice with increased adipose tissue mass, decreased lean mass, high circulating GH, but decreased insulin growth factor-1 levels compared to control mice. Furthermore, the 6mGHRKO mice displayed significantly improved insulin sensitivity in males, with no changes in glucose tolerance. Also, serum levels of inflammatory markers and liver triglycerides were unchanged in these mice. Experiments to evaluate the status of oxidative damage and mTOR activation in liver, skeletal muscle and subcutaneous adipose tissue of male and female 6mGHRKO mice showed a tissue-specificity and sexual dimorphism in these results. Importantly, male and female 6mGHRKO mice showed no change in body length, but mean, median and maximal lifespan were significantly extended in females. In conclusion, disruption of GH action well past sexual maturation produces beneficial effects on insulin sensitivity and aging in mice. Acknowledgements: This work is supported by the State of Ohio’s Eminent Scholar Program, by NIH grant AG059779 and by the AMVETS.

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Growth hormone receptor gene disruption in mature‐adult mice improves male insulin sensitivity and extends female lifespan

Aging Cell ◽

10.1111/acel.13506 ◽

2021 ◽

Author(s):

Silvana Duran‐Ortiz ◽

Edward O. List ◽

Yuji Ikeno ◽

Jonathan Young ◽

Reetobrata Basu ◽

...

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Gene Disruption ◽

Growth Hormone Receptor ◽

Receptor Gene ◽

Mature Adult ◽

Adult Mice ◽

Growth Hormone Receptor Gene ◽

Female Lifespan ◽

Hormone Receptor Gene

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Effects of Childhood Multidisciplinary Care and Growth Hormone Treatment on Health Problems in Adults with Prader-Willi Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10153250 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3250

Author(s):

Karlijn Pellikaan ◽

Anna G. W. Rosenberg ◽

Kirsten Davidse ◽

Anja A. Kattentidt-Mouravieva ◽

Rogier Kersseboom ◽

...

Keyword(s):

Growth Hormone ◽

Growth Hormone Treatment ◽

Multidisciplinary Care ◽

Hormone Treatment ◽

Health Problems ◽

Pituitary Hormone ◽

Childhood And Adolescence ◽

Prader Willi Syndrome ◽

Adult Age ◽

Beneficial Effects

Prader-Willi syndrome (PWS) is a complex hypothalamic disorder. Features of PWS include hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. The combination of growth hormone treatment and multidisciplinary care (GHMDc) has greatly improved the health of children with PWS. Little is known about the effects of childhood GHMDc on health outcomes in adulthood. We retrospectively collected clinical data of 109 adults with PWS. Thirty-nine had received GHMDc during childhood and adolescence (GHMDc+ group) and sixty-three had never received growth hormone treatment (GHt) nor multidisciplinary care (GHMDc− group). Our systematic screening revealed fewer undetected health problems in the GHMDc+ group (10%) than in the GHMDc− group (84%). All health problems revealed in the GHMDc+ group had developed between the last visit to the paediatric and the first visit to the adult clinic and/or did not require treatment. Mean BMI and the prevalence of diabetes mellitus type 2 were significantly lower in the GHMDc+ group compared to the GHMDc− group. As all patients who received GHt were treated in a multidisciplinary setting, it is unknown which effects are the result of GHt and which are the result of multidisciplinary care. However, our data clearly show that the combination of both has beneficial effects. Therefore, we recommend continuing GHMDc after patients with PWS have reached adult age.

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Temporal patterns of gene expression in the antenna of the adult Drosophila melanogaster.

Genetics ◽

10.1093/genetics/140.2.549 ◽

1995 ◽

Vol 140 (2) ◽

pp. 549-555 ◽

Cited By ~ 1

Author(s):

S L Helfand ◽

K J Blake ◽

B Rogina ◽

M D Stracks ◽

A Centurion ◽

...

Keyword(s):

Gene Expression ◽

Life Span ◽

Time Course ◽

Adult Life ◽

Temporal Patterns ◽

Fruit Fly ◽

Reporter Protein ◽

Adult Age ◽

Biological Time ◽

Adult Drosophila

Abstract The time course of gene expression in the adult fruit fly has been partially characterized by using enhancer trap and reporter gene constructs that mark 49 different genes. The relative intensity of the reporter protein in individual cells of the antennae was measured as a function of adult age. Most genes showed a graduated expression, and the intensity of expression had a reproducible and characteristic time course. Different genes displayed different temporal patterns of expression and more often than not the pattern of expression was complex. We found a number of genes having patterns that scaled with life span. In these cases the intensity of gene expression was found to be invariant with respect to biological time, when expressed as a fraction of the life span of the line. The scaling was observed even when life span was varied as much as threefold. Such scaling serves to (1) further demonstrate that deterministic mechanisms such as gene regulation act to generate the temporal patterns of expression seen during adult life, (2) indicate that control of these regulatory mechanisms is linked to life span, and (3) suggest mechanisms by which this control is accomplished. We have concluded that gene expression in the adult fly is often regulated in a fashion that allows for graduated expression over time, and that the regulation itself is changing throughout adult life according to some prescribed program or algorithm.

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Measurement Invariance of the UPPS-P Impulsive Behavior Scale Across Age and Sex Across the Adult Life Span

Assessment ◽

10.1177/1073191119832660 ◽

2019 ◽

Vol 27 (3) ◽

pp. 432-453 ◽

Cited By ~ 4

Author(s):

Evangelia Argyriou ◽

Miji Um ◽

Wei Wu ◽

Melissa A. Cyders

Keyword(s):

Life Span ◽

Sensation Seeking ◽

Adult Life ◽

Impulsive Behavior ◽

Adult Life Span ◽

Adult Age ◽

Item Functioning ◽

Behavior Scale ◽

Mean Differences ◽

Age And Sex

Impulsive personality is a widely used construct for the prediction of multiple clinical problems; however, research has often disregarded important differences in its conceptualization and measurement across age and sex. The goals of this article are to test the invariance of, to compare mean differences in, and to examine the differential validity of the Urgency (negative), Premeditation (lack of), Perseverance (lack of), Sensation Seeking, with added subscale of Positive Urgency (UPPS-P) Impulsive Behavior Scale across adult age and sex. The data for this study were obtained from 799 participants in the Nathan Kline Institute’s Rockland Sample. Multigroup invariance analysis indicated full invariance of the UPPS-P Impulsive Behavior Scale across age and sex. However, invariance analysis as a function of age using Multiple-Indicators Multiple-Causes modeling identified three items with differential item functioning. Sensation Seeking was higher in males and lower as age increased. In general, age and sex did not moderate the relationships between UPPS-P traits and risk-taking behaviors, with the exception of cannabis use. Overall, the results of this study support that the UPPS-P scale can be validly used to assess and compare impulsive personality across the adult life span and sex. We suggest the removal of Items 5, 28, and 51 when using the UPPS-P with older adults to be overly cautious to age invariance effects.

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Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis

Biological Chemistry ◽

10.1515/bc.2010.124 ◽

2010 ◽

Vol 391 (10) ◽

Cited By ~ 21

Author(s):

Ravneet K. Boparai ◽

Oge Arum ◽

Romesh Khardori ◽

Andrzej Bartke

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Glucose Homeostasis ◽

Endocrine Control ◽

Cross Sectional ◽

Systematic Assessment ◽

Beneficial Effects ◽

Glucose Stimulated Insulin Secretion ◽

The Impact

Abstract In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

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Beneficial effects of two Ayurvedic formulations, Saraswata Ghrita and Kalyanaka Ghrita on survival and on toxic aggregates in Drosophila models of Huntington’s and Alzheimer’s disease

10.1101/2021.10.06.463232 ◽

2021 ◽

Author(s):

Swati Sharma ◽

Girish Singh ◽

Kishor Patwardhan ◽

Subhash C. Lakhotia

Keyword(s):

Life Span ◽

Adult Life ◽

Larval Survival ◽

Human Populations ◽

Wild Type ◽

Adult Life Span ◽

Beneficial Effects ◽

Model Study ◽

Study Results

AbstractIn order to understand the health promotive, rejuvenative and disease preventive approach of the Ayurvedic system of medicine in the light of current principles, we examined two Rasayana formulations, viz., Kalayanaka Ghrita (KG) and Saraswata Ghrita (SG) for their effects in Alzheimer’s (AD) and Huntington’s (HD) neurodegenerative disease models of Drosophila. Initial experiments involving feeding of wild type flies on food supplemented with 0.05%, 0.25% and 0.5% (w/v) KG or SG revealed 0.05% to be without any adverse effect while higher concentrations caused dose-dependent reduction in pupation frequency and adult life span in wild type flies. Rearing GMR-GAL4>127Q (HD model) and ey-GAL4>Aβ42 (AD model) larvae and adults on 0.05% or 0.25% SG or KG supplemented food enhanced the otherwise significantly reduced larval lethality and enhanced their median life span, with the 0.25% SG or KG concentrations being less effective than the 0.05%. In parallel with the better larval survival and enhanced adult life span, feeding the HD and AD model larvae on either of the Ghrita supplemented food (0.05% and 0.25%) substantially reduced the polyQ aggregates or amyloid plaques, respectively, in the larval eye discs. The present first in vivo organismic model study results have clinical implications for the increasing burden of age-associated dementia and neurodegenerative diseases like AD and HD in human populations.

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