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Review Series

Aging

Series edited by Christopher B. Newgard and Norman E. Sharpless

Aging is an inevitable facet of life. However, research into the molecular mechanisms of aging suggests potential targets that could be therapeutically modified to slow the aging process and increase the span of healthy living. The articles in this series explore selected cellular mechanisms of aging and their link to age-related clinical conditions. These mechanisms include short telomeres, the induction of the senescence-associated secretory phenotype (SASP) in systemic aging, sirtuin regulation of metabolism and aging-associated diseases, mitochondrial metabolism in aging, the mTOR signaling pathway and longevity, aging and immune system function, and aging-associated changes in pancreatic β-cells.

Articles in series

Coming of age: molecular drivers of aging and therapeutic opportunities
Christopher B. Newgard, Norman E. Sharpless
Christopher B. Newgard, Norman E. Sharpless
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):946-950. https://doi.org/10.1172/JCI68833.
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Coming of age: molecular drivers of aging and therapeutic opportunities

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Abstract

Aging is like the weather: everyone talks about it, but no one seems to do anything about it. We believe this may soon change, as an improved understanding of the molecular and genetic pathways underlying aging suggests it is possible to therapeutically target the aging process and increase health span. This Review series focuses on fundamental cellular mechanisms of aging and their relationship to human disease. These pathways include telomere dysfunction in cellular senescence and induction of the senescence-associated secretory phenotype (SASP) in systemic aging, sirtuin family regulation of metabolism and aging-associated diseases, mitochondrial metabolism in aging, the mechanistic target of rapamycin (mTOR) signaling pathway and the use of mTOR inhibitors to increase longevity, the progressive decline of the immune system with age, and aging-associated changes to pancreatic islet β cells that may contribute to diabetes. Together, these articles explore pathways affecting aging and possible interventional targets to slow or delay the onset of age-related pathologies.

Authors

Christopher B. Newgard, Norman E. Sharpless

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The role of mitochondria in aging
Ana Bratic, Nils-Göran Larsson
Ana Bratic, Nils-Göran Larsson
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):951-957. https://doi.org/10.1172/JCI64125.
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The role of mitochondria in aging

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Abstract

Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.

Authors

Ana Bratic, Nils-Göran Larsson

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Causes, consequences, and reversal of immune system aging
Encarnacion Montecino-Rodriguez, … , Beata Berent-Maoz, Kenneth Dorshkind
Encarnacion Montecino-Rodriguez, … , Beata Berent-Maoz, Kenneth Dorshkind
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):958-965. https://doi.org/10.1172/JCI64096.
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Causes, consequences, and reversal of immune system aging

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Abstract

The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.

Authors

Encarnacion Montecino-Rodriguez, Beata Berent-Maoz, Kenneth Dorshkind

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Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tamara Tchkonia, … , Judith Campisi, James L. Kirkland
Tamara Tchkonia, … , Judith Campisi, James L. Kirkland
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):966-972. https://doi.org/10.1172/JCI64098.
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Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

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Abstract

Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions.

Authors

Tamara Tchkonia, Yi Zhu, Jan van Deursen, Judith Campisi, James L. Kirkland

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The sirtuin family’s role in aging and age-associated pathologies
Jessica A. Hall, … , Yoonjin Lee, Pere Puigserver
Jessica A. Hall, … , Yoonjin Lee, Pere Puigserver
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):973-979. https://doi.org/10.1172/JCI64094.
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The sirtuin family’s role in aging and age-associated pathologies

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Abstract

The 7 mammalian sirtuin proteins compose a protective cavalry of enzymes that can be invoked by cells to aid in the defense against a vast array of stressors. The pathologies associated with aging, such as metabolic syndrome, neurodegeneration, and cancer, are either caused by or exacerbated by a lifetime of chronic stress. As such, the activation of sirtuin proteins could provide a therapeutic approach to buffer against chronic stress and ameliorate age-related decline. Here we review experimental evidence both for and against this proposal, as well as the implications that isoform-specific sirtuin activation may have for healthy aging in humans.

Authors

Jessica A. Hall, John E. Dominy, Yoonjin Lee, Pere Puigserver

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Rapalogs and mTOR inhibitors as anti-aging therapeutics
Dudley W. Lamming, … , David M. Sabatini, Joseph A. Baur
Dudley W. Lamming, … , David M. Sabatini, Joseph A. Baur
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):980-989. https://doi.org/10.1172/JCI64099.
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Rapalogs and mTOR inhibitors as anti-aging therapeutics

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Abstract

Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.

Authors

Dudley W. Lamming, Lan Ye, David M. Sabatini, Joseph A. Baur

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The role of aging upon β cell turnover
Jake A. Kushner
Jake A. Kushner
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):990-995. https://doi.org/10.1172/JCI64095.
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The role of aging upon β cell turnover

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Abstract

Preservation and regeneration of β cell endocrine function is a long-sought goal in diabetes research. Defective insulin secretion from β cells underlies both type 1 and type 2 diabetes, thus fueling considerable interest in molecules capable of rebuilding β cell secretion capacity. Though early work in rodents suggested that regeneration might be possible, recent studies have revealed that aging powerfully restricts cell cycle entry of β cells, which may limit regeneration capacity. Consequently, aging has emerged as an enigmatic challenge that might limit β cell regeneration therapies. This Review summarizes recent data regarding the role of aging in β cell regeneration and proposes models explaining these phenomena.

Authors

Jake A. Kushner

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Telomeres and age-related disease: how telomere biology informs clinical paradigms
Mary Armanios
Mary Armanios
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):996-1002. https://doi.org/10.1172/JCI66370.
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Telomeres and age-related disease: how telomere biology informs clinical paradigms

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Abstract

Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies.

Authors

Mary Armanios

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