Minireview: Role of the Growth Hormone/Insulin-Like Growth Factor System in Mammalian Aging

Abstract The important role of IGF and insulin-related signaling pathways in the control of longevity of worms and insects is very well documented. In the mouse, several spontaneous or experimentally induced mutations that interfere with GH biosynthesis, GH actions, or sensitivity to IGF-I lead to extended longevity. Increases in the average life span in these mutants range from approximately 20–70% depending on the nature of the endocrine defect, gender, diet, and/or genetic background. Extended longevity of hypopituitary and GH-resistant mice appears to be due to multiple mechanisms including reduced insulin levels, enhanced insulin sensitivity, alterations in carbohydrate and lipid metabolism, reduced generation of reactive oxygen species, enhanced resistance to stress, reduced oxidative damage, and delayed onset of age-related disease. There is considerable evidence to suggest that the genetic and endocrine mechanisms that influence aging and longevity in mice may play a similar role in other mammalian species, including the human.

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The role of polymorphisms in the IGF-I gene in aging and age-related diseases

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2004-832867 ◽

2004 ◽

Vol 112 (08) ◽

Author(s):

JAMJL Janssen

Keyword(s):

Age Related ◽

Igf I ◽

I Gene

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Changes in sleep EEG with aging in humans and rodents

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-021-02545-y ◽

2021 ◽

Author(s):

Diana Campos-Beltrán ◽

Lisa Marshall

Keyword(s):

Mammalian Species ◽

Electric Activity ◽

Age Related ◽

Laboratory Rodents ◽

Integrative View ◽

Level Scale ◽

Meta Analyses ◽

Global Systems ◽

Common Laboratory

AbstractSleep is one of the most ubiquitous but also complex animal behaviors. It is regulated at the global, systems level scale by circadian and homeostatic processes. Across the 24-h day, distribution of sleep/wake activity differs between species, with global sleep states characterized by defined patterns of brain electric activity and electromyography. Sleep patterns have been most intensely investigated in mammalian species. The present review begins with a brief overview on current understandings on the regulation of sleep, and its interaction with aging. An overview on age-related variations in the sleep states and associated electrophysiology and oscillatory events in humans as well as in the most common laboratory rodents follows. We present findings observed in different studies and meta-analyses, indicating links to putative physiological changes in the aged brain. Concepts requiring a more integrative view on the role of circadian and homeostatic sleep regulatory mechanisms to explain aging in sleep are emerging.

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Inactivation of the IGF-I receptor gene in primary Sertoli cells highlights the autocrine effects of IGF-I

Journal of Endocrinology ◽

10.1677/joe-07-0258 ◽

2007 ◽

Vol 194 (3) ◽

pp. 557-568 ◽

Cited By ~ 31

Author(s):

P Froment ◽

M Vigier ◽

D Nègre ◽

I Fontaine ◽

J Beghelli ◽

...

Keyword(s):

Sertoli Cell ◽

Sertoli Cells ◽

Function Analysis ◽

Receptor Gene ◽

Mammalian Species ◽

Cell Physiology ◽

Loss Of Function ◽

Igf I

IGF-I regulates pituitaryand gonadal functions, and is pivotal for sexual development and fertility in mammalian species. To better understand the function of autocrine IGF-I in Sertoli cell physiology, we established a system for Cre-mediated conditional inactivation of the IGF-I receptor (IGF-IR) in cultured Sertoli cells. We show here that loss of IGF-IR decreased the number of viable Sertoli cells as a consequence of diminished Sertoli cell proliferation and increased Sertoli cell death. Furthermore, the lack of IGF-IR altered the morphology of cultured Sertoli cells and decreased lactate and transferrin secretions. Collectively, our data indicate that autocrine IGF-I contributes significantly to Sertoli cell homeostasis. The described in vitro system for loss-of-function analysis of the IGF-IR can be readily transposed to study the role of other intratesticular growth factors involved in spermatogenesis.

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Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and Longevity

Physiological Reviews ◽

10.1152/physrev.00006.2012 ◽

2013 ◽

Vol 93 (2) ◽

pp. 571-598 ◽

Cited By ~ 169

Author(s):

Andrzej Bartke ◽

Liou Y. Sun ◽

Valter Longo

Keyword(s):

Insulin Signaling ◽

Single Gene ◽

Postnatal Growth ◽

Related Disease ◽

Experimental Systems ◽

Trade Offs ◽

Age Related ◽

Evolutionarily Conserved ◽

Extended Longevity

Growth hormone (GH) is a key determinant of postnatal growth and plays an important role in the control of metabolism and body composition. Surprisingly, deficiency in GH signaling delays aging and remarkably extends longevity in laboratory mice. In GH-deficient and GH-resistant animals, the “healthspan” is also extended with delays in cognitive decline and in the onset of age-related disease. The role of hormones homologous to insulin-like growth factor (IGF, an important mediator of GH actions) in the control of aging and lifespan is evolutionarily conserved from worms to mammals with some homologies extending to unicellular yeast. The combination of reduced GH, IGF-I, and insulin signaling likely contributes to extended longevity in GH or GH receptor-deficient organisms. Diminutive body size and reduced fecundity of GH-deficient and GH-resistant mice can be viewed as trade-offs for extended longevity. Mechanisms responsible for delayed aging of GH-related mutants include enhanced stress resistance and xenobiotic metabolism, reduced inflammation, improved insulin signaling, and various metabolic adjustments. Pathological excess of GH reduces life expectancy in men as well as in mice, and GH resistance or deficiency provides protection from major age-related diseases, including diabetes and cancer, in both species. However, there is yet no evidence of increased longevity in GH-resistant or GH-deficient humans, possibly due to non-age-related deaths. Results obtained in GH-related mutant mice provide striking examples of mutations of a single gene delaying aging, reducing age-related disease, and extending lifespan in a mammal and providing novel experimental systems for the study of mechanisms of aging.

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Age-Related Loss of Muscle Mass and Strength

Journal of Aging Research ◽

10.1155/2012/158279 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 28

Author(s):

Geoffrey Goldspink

Keyword(s):

Muscle Wasting ◽

Mechanical Strain ◽

Special Role ◽

Medical Problems ◽

Musculoskeletal Tissues ◽

Age Related ◽

Igf I ◽

Satellite Stem Cells

Age-related muscle wasting and increased frailty are major socioeconomic as well as medical problems. In the quest to extend quality of life it is important to increase the strength of elderly people sufficiently so they can carry out everyday tasks and to prevent them falling and breaking bones that are brittle due to osteoporosis. Muscles generate the mechanical strain that contributes to the maintenance of other musculoskeletal tissues, and a vicious circle is established as muscle loss results in bone loss and weakening of tendons. Molecular and proteomic approaches now provide strategies for preventing age-related muscle wasting. Here, attention is paid to the role of the GH/IGF-1 axis and the special role of the IGFI-Ec (mechano growth factor/MGF) which is derived from the IGF-I gene by alternative splicing. During aging MGF levels decline but when administered MGF activates the muscle satellite (stem) cells that “kick start” local muscle repair and induces hypertrophy.

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Sonneradon A Extends Lifespan of Caenorhabditis elegans by Modulating Mitochondrial and IIS Signaling Pathways

Marine Drugs ◽

10.3390/md20010059 ◽

2022 ◽

Vol 20 (1) ◽

pp. 59

Author(s):

Shu Jiang ◽

Cui-Ping Jiang ◽

Pei Cao ◽

Yong-Hong Liu ◽

Cheng-Hai Gao ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Innate Immune ◽

C Elegans ◽

Enhanced Resistance ◽

Age Related ◽

Increased Risk ◽

Pseudomonas Aeruginosa Infection ◽

New Evidence ◽

Overall Functioning

Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Sonneradon A (SDA), a new compound first extracted from the edible fruits of mangrove Sonneratia apetala, showed remarkable antiaging activity. However, the role of SDA in antiaging remains unclear. In this article, we studied the function of SDA in antiaging by using the animal model Caenorhabditis elegans. Results showed that SDA inhibited production of reactive oxygen species (ROS) by 53%, and reduced the accumulation of aging markers such as lipids and lipofuscins. Moreover, SDA also enhanced the innate immune response to Pseudomonas aeruginosa infection. Genetic analysis of a series of mutants showed that SDA extended the lifespan of the mutants of eat-2 and glp-1. Together, this effect may be related to the enhanced resistance to oxidative stress via mitochondrial and insulin/insulin-like growth factor-1 signaling (IIS) pathways. The results of this study provided new evidence for an antiaging effect of SDA in C. elegans, as well as insights into the implication of antiaging activity of SDA in higher organisms.

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Analysis of the role of tryptophan-kynurenine pathway in the life span control in Drosophila melanogaster

Faktori eksperimental'noi evolucii organizmiv ◽

10.7124/feeo.v25.1135 ◽

2019 ◽

Vol 25 ◽

pp. 32-37

Author(s):

O. V. Gorenskaya ◽

V. V. Navrotskaya

Keyword(s):

Drosophila Melanogaster ◽

Life Span ◽

Kynurenine Pathway ◽

Tryptophan Metabolism ◽

Wild Type ◽

Survival Curves ◽

Average Life ◽

Average Life Span ◽

Kynurenine Metabolism

Aim. To analyze life span in mutant Drosophila stocks with impaired tryptophan-kynurenine metabolism. Methods. Wild type stocks Canton-S and Oregon, stocks with mutations of the locus white: white, whiteapricot, whitesatsuma, and stocks with the mutation vermilion have been used. The average life span of imago has been determined, survival curves have been analyzed. Results. It has been shown that the average life span of Drosophila females with mutant alleles of the white gene does not differ from the wild-type stock; in males of the w(C-S) and wa(C-S) stocks the index is increased. The presence of the mutantion vermilion in the genotype also increases the average life span of imago of both sexes, but in males the extension is more pronounced. Conclusions. The results suggest that aging is associated with the regulation of tryptophan-kynurenine metabolism. Keywords: Drosophila melanogaster, life span, kynurenine pathway of tryptophan metabolism.

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Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00236.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. E1140-E1152 ◽

Cited By ~ 20

Author(s):

Miriam García-San Frutos ◽

Lucinda Cacicedo ◽

Carolina Fernández ◽

David Vicent ◽

Beatriz Velasco ◽

...

Keyword(s):

Growth Hormone ◽

Median Eminence ◽

Pituitary Cells ◽

Mrna Levels ◽

Gh Secretion ◽

Age Related ◽

Igf I ◽

Hypothalamic Cells ◽

Old Rats

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased ( P < 0.01 and P < 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P < 0.001) and SS mRNA ( P < 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA ( P < 0.01 and P < 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment.

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