Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

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Abstract

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored. Here, we review some of the mitochondrial signaling pathways that participate in establishing cellular senescence. We discuss the role of mitochondrial reactive oxygen species (ROS), mitochondrial dynamics (fission and fusion), the electron transport chain (ETC), bioenergetic balance, redox state, metabolic signature, and calcium homeostasis in controlling cellular growth arrest. We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence. Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.

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Aging, Cellular Senescence, and Cancer

Judith Campisi (2013)

For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

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Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

Francis Rodier, Jean-Philippe Coppe, Christopher K Patil … (2009)

Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.

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Mammalian sirtuins: biological insights and disease relevance.

Marcia Haigis, David A Sinclair (2010)

Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.

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Author and article information

Journal

Journal ID (nlm-ta): Aging Cell

Journal ID (iso-abbrev): Aging Cell

Journal ID (publisher-id): acel

Title: Aging Cell

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 1474-9718

ISSN (Electronic): 1474-9726

Publication date (Print): February 2015

Publication date (Electronic): 14 November 2014

Volume: 14

Issue: 1

Pages: 1-7

Affiliations

[1 ]Département de Biologie, Ecole Normale Supérieure de Lyon 46 allée d'Italie, Lyon, 69007, France

[2 ]Buck Institute for Research on Aging 8001 Redwood Blvd., Novato, CA, 94945, USA

Author notes

Correspondence, Michael C. Velarde, Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA. Tel.: + 1-415-209-2000 (ext. 6716); fax: +1-415-209-9920; e-mail : mvelarde@ 123456buckinstitute.org

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DOI: 10.1111/acel.12287

PMC ID: 4310776

PubMed ID: 25399755

SO-VID: 1669b5f3-1812-4987-8a39-3dc2d1c27d00

License:

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

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Abstract

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Stress signalling in stem cells

Most cited references 66

Aging, Cellular Senescence, and Cancer

Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

Mammalian sirtuins: biological insights and disease relevance.

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