Stem cell aging: mechanisms, regulators and therapeutic opportunities.

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Abstract

Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.

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The senescence-associated secretory phenotype: the dark side of tumor suppression.

Jean-Philippe Coppe, Pierre-Yves Desprez, Ana Krtolica … (2010)

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

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mTOR signaling in growth control and disease.

Mathieu Laplante, David M. Sabatini (2012)

The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.

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Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

Darren J. Baker, Tobias Wijshake, Tamar Tchkonia … (2012)

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

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Author and article information

Journal

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

Publisher: Springer Nature

ISSN (Electronic): 1546-170X

ISSN (Print): 1078-8956

Publication date (Electronic): Aug 2014

Volume: 20

Issue: 8

Affiliations

[1 ] 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Joslin Diabetes Center, Boston, Massachusetts, USA.

[2 ] 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Joslin Diabetes Center, Boston, Massachusetts, USA. [3] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

[3 ] 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Joslin Diabetes Center, Boston, Massachusetts, USA. [3] Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.

Article

Publisher Item ID: nm.3651 Mid ID: NIHMS624043

DOI: 10.1038/nm.3651

PMC ID: 4160113

PubMed ID: 25100532

SO-VID: 8d29a349-5f10-4fd8-9c5e-70f9cae77b3d

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Stem cell aging: mechanisms, regulators and therapeutic opportunities.

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cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 189

The senescence-associated secretory phenotype: the dark side of tumor suppression.

mTOR signaling in growth control and disease.

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

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