Signaling Networks Determining Life Span

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Abstract

The health of an organism is orchestrated by a multitude of molecular and biochemical networks responsible for ensuring homeostasis within cells and tissues. However, upon aging, a progressive failure in the maintenance of this homeostatic balance occurs in response to a variety of endogenous and environmental stresses, allowing the accumulation of damage, the physiological decline of individual tissues, and susceptibility to diseases. What are the molecular and cellular signaling events that control the aging process and how can this knowledge help design therapeutic strategies to combat age-associated diseases? Here we provide a comprehensive overview of the evolutionarily conserved biological processes that alter the rate of aging and discuss their link to disease prevention and the extension of healthy life span.

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Most cited references 94

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AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

Sibylle Jager, Christoph Handschin, Julie St-Pierre … (2007)

Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.

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Telomere dysfunction induces metabolic and mitochondrial compromise.

Ergun Sahin, Simona Colla, Marc Liesa … (2011)

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

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Regulation of aging and age-related disease by DAF-16 and heat-shock factor.

A.-L. Hsu (2003)

The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2-insulin/IGF-1 receptor mutations to extend life-span. Our findings suggest this is because HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.

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Author and article information

Journal

Title: Annual Review of Biochemistry

Abbreviated Title: Annu. Rev. Biochem.

Publisher: Annual Reviews

ISSN (Print): 0066-4154

ISSN (Electronic): 1545-4509

Publication date Created: June 02 2016

Publication date (Print): June 02 2016

Volume: 85

Issue: 1

Pages: 35-64

Affiliations

[1 ]Department of Molecular and Cell Biology, University of California, Berkeley, California 94720; email:

[2 ]Howard Hughes Medical Institute, Chevy Chase, Maryland 20815

[3 ]Glenn Center for Research on Aging, University of California, Berkeley, California 94720

[4 ]The Salk Institute for Biological Studies, La Jolla, California 92037

Article

DOI: 10.1146/annurev-biochem-060815-014451

PubMed ID: 27294438

SO-VID: 4ebc778b-9f8c-430c-a7e9-b880fed55d09

History

ScienceOpen disciplines: Geriatric medicine,Medicine,Neurology,Anatomy & Physiology,Health & Social care,Public health

Data availability:

ScienceOpen disciplines: Geriatric medicine, Medicine, Neurology, Anatomy & Physiology, Health & Social care, Public health

Signaling Networks Determining Life Span

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Most cited references 94

AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

Telomere dysfunction induces metabolic and mitochondrial compromise.

Regulation of aging and age-related disease by DAF-16 and heat-shock factor.

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Affiliations

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