Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and 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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PHYSICAL ACTIVITY AS HEALTHY INTERVENTION AGAINST SEVERE OXIDATIVE STRESS IN ELDERLY POPULATION

Journal of Frailty & Aging ◽

10.14283/jfa.2013.20 ◽

2013 ◽

pp. 1-9

Author(s):

C. TOMAS-ZAPICO ◽

E. IGLESIAS-GUTIERREZ ◽

B. FERNANDEZ-GARCIA ◽

D. DE GONZALO-CALVO

Keyword(s):

Oxidative Stress ◽

Physical Activity ◽

Elderly Population ◽

Physiological Basis ◽

Related Disease ◽

Age Related ◽

Wide Range ◽

Health Related ◽

Relevant Risk Factor

Severe oxidative stress is a relevant risk factor for major deleterious health-related events in olderpeople and is thought to be an important contributor to age-related disease. Literature has suggested oxidativestress as a therapeutic target for mitigating the biological decline and attenuating the occurrence of adverseclinical events in aged individuals. However, definitive treatments are not known. Regular and moderate physicalactivity has been proposed as possible intervention for slowing age-related decline. This healthy strategy presentsa wide range of beneficial aspects for elderly, from the reduction of morbidity, disability, frailty and mortalityrates to treatment of many age-related disorders. Importantly, the global benefits on health are not shared by anyother strategies. Nevertheless, the physiological basis by which exercise produces its benefits to the organism isnot fully understood. This review summarizes the evidence for the role of physical activity as potential healthyintervention for mitigating the negative aspects of aging through the modulation of the oxidative mechanisms.

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

Endocrinology ◽

10.1210/en.2005-0411 ◽

2005 ◽

Vol 146 (9) ◽

pp. 3718-3723 ◽

Cited By ~ 199

Author(s):

Andrzej Bartke

Keyword(s):

Mammalian Species ◽

Induced Mutations ◽

Average Life ◽

Average Life Span ◽

Enhanced Resistance ◽

Age Related ◽

Igf I ◽

Extended Longevity ◽

Resistance To Stress

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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Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

10.1101/659128 ◽

2019 ◽

Author(s):

Kerui Huang ◽

Ting Miao ◽

Kai Chang ◽

Ping Kang ◽

Qiuhan Jiang ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Inflammatory Cytokine ◽

Cytokine Signaling ◽

Over Expression ◽

Autonomous Regulation ◽

Age Related ◽

Evolutionarily Conserved ◽

Age Dependent ◽

Import Receptor

AbstractAge is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

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The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

Aging Cell ◽

10.1111/acel.13048 ◽

2019 ◽

Vol 18 (6) ◽

Cited By ~ 22

Author(s):

Adiv A. Johnson ◽

Alexandra Stolzing

Keyword(s):

Lipid Metabolism ◽

Related Disease ◽

Age Related ◽

Lifespan Regulation

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The Role of Macromolecular Damage in Aging and Age-related Disease

The Journals of Gerontology Series A ◽

10.1093/gerona/glu056 ◽

2014 ◽

Vol 69 (Suppl 1) ◽

pp. S28-S32 ◽

Cited By ~ 26

Author(s):

A. G. Richardson ◽

E. E. Schadt

Keyword(s):

Related Disease ◽

Age Related ◽

Macromolecular Damage

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Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

Cells ◽

10.3390/cells10030694 ◽

2021 ◽

Vol 10 (3) ◽

pp. 694

Author(s):

Georgios Konstantinidis ◽

Nektarios Tavernarakis

Keyword(s):

Caenorhabditis Elegans ◽

Degradation Process ◽

Pathogen Invasion ◽

Age Related ◽

Distinct Cell ◽

Evolutionarily Conserved ◽

Subsequent Degradation ◽

Membrane Organelle ◽

Neuronal Autophagy

Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode Caenorhabditis elegans.

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The Aging Stress Response and Its Implication for AMD Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21228840 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8840

Author(s):

Janusz Blasiak ◽

Elzbieta Pawlowska ◽

Anna Sobczuk ◽

Joanna Szczepanska ◽

Kai Kaarniranta

Keyword(s):

Stress Response ◽

Vision Loss ◽

The Elderly ◽

Cellular Level ◽

Age Related Macular Degeneration ◽

Age Related ◽

Evolutionarily Conserved ◽

Nutrient Signaling ◽

Amp Activated Protein Kinase

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

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IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

10.1101/737262 ◽

2019 ◽

Author(s):

Alexei Arnaoutov ◽

Hangnoh Lee ◽

Karen Plevock Haase ◽

Vasilisa Aksenova ◽

Michal Jarnik ◽

...

Keyword(s):

Cell Types ◽

Intestinal Stem Cells ◽

Intestinal Tissue ◽

Tissue Integrity ◽

Regulatory Circuit ◽

Age Related ◽

Evolutionarily Conserved ◽

Gut Homeostasis ◽

Epithelium Cells

SummaryThe maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells is essential for their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a rapid, premature loss of intestinal tissue integrity as flies age. This age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate an unexpected and novel role of the IRBIT-RNR pathway in gut homeostasis.

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