Cellular Senescence: A Translational Perspective.

doi:10.1016/J.EBIOM.2017.04.013

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Cellular Senescence: A Translational Perspective.

Journal Article•DOI•

Cellular Senescence: A Translational Perspective.

James L. Kirkland¹, Tamara Tchkonia¹•Institutions (1)

Mayo Clinic¹

01 Jul 2017-EBioMedicine (Elsevier)-Vol. 21, pp 21-28

TL;DR: This work used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-APoptotic microenvironment.

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About: This article is published in EBioMedicine.The article was published on 2017-07-01 and is currently open access. It has received 622 citations till now. The article focuses on the topics: Senolytic.

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Journal Article•DOI•

Ageing as a risk factor for neurodegenerative disease.

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Yujun Hou¹, Xiuli Dan¹, Mansi Babbar¹, Yong Wei¹, Steen G. Hasselbalch², Deborah L. Croteau¹, Vilhelm A. Bohr², Vilhelm A. Bohr¹ - Show less +4 more•Institutions (2)

National Institutes of Health¹, University of Copenhagen²

09 Sep 2019-Nature Reviews Neurology

TL;DR: Hallmarks of ageing — genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication — correlate with susceptibility to neurodegenerative disease.

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Abstract: Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

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1,223 citations

Journal Article•DOI•

Senolytics improve physical function and increase lifespan in old age

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Ming Xu¹, Ming Xu², Tamar Pirtskhalava¹, Joshua N. Farr¹, Bettina M. Weigand³, Bettina M. Weigand¹, Allyson K. Palmer¹, Megan M. Weivoda¹, Christina L. Inman¹, Mikolaj Ogrodnik¹, Mikolaj Ogrodnik³, Christine M Hachfeld¹, Daniel G. Fraser¹, Jennifer L Onken¹, Kurt O. Johnson¹, Grace C Verzosa¹, Larissa G.P. Langhi¹, Moritz Weigl¹, Nino Giorgadze¹, Nathan K. LeBrasseur¹, Jordan D. Miller¹, Diana Jurk³, Ravinder J. Singh¹, David B. Allison⁴, David B. Allison⁵, Keisuke Ejima⁵, Keisuke Ejima⁴, Gene B. Hubbard⁶, Yuji Ikeno⁶, Yuji Ikeno⁷, Hajrunisa Cubro¹, Vesna D. Garovic¹, Xiaonan Hou¹, S. John Weroha¹, Paul D. Robbins⁸, Laura J. Niedernhofer⁸, Sundeep Khosla¹, Tamara Tchkonia¹, James L. Kirkland¹ - Show less +35 more•Institutions (8)

Mayo Clinic¹, University of Connecticut², Newcastle University³, Indiana University⁴, University of Alabama at Birmingham⁵, University of Texas Health Science Center at San Antonio⁶, Veterans Health Administration⁷, Scripps Research Institute⁸

09 Jul 2018-Nature Medicine

TL;DR: It is demonstrated that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.

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Abstract: Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

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1,201 citations

Journal Article•DOI•

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

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Jamie N. Justice¹, Anoop M. Nambiar², Tamar Tchkonia³, Nathan K. LeBrasseur³, Rodolfo M. Pascual¹, Shahrukh K. Hashmi³, Larissa G.P. Langhi Prata³, Michal M. Masternak⁴, Stephen B. Kritchevsky¹, Nicolas Musi², James L. Kirkland³ - Show less +7 more•Institutions (4)

Wake Forest University¹, University of Texas at Austin², Mayo Clinic³, University of Central Florida⁴

01 Feb 2019-EBioMedicine

TL;DR: The authors' first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases.

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644 citations

Cites background or methods from "Cellular Senescence: A Translationa..."

...If fisetin proves to be safe and effective in mouse IPF models, it would be a strong candidate to advance into clinical trials, as may be other next-generation senolytics [8,42]....
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...We used intermittent DQ here because: 1) D and Q have been used extensively for other indications in humans and their safety profiles are understood, 2) DQ was effective in improving function in a mouse model of IPF [5], 3) DQ has been shown to be senolytic in human tissues [24], 4) DQ targets a broader range of senescent cells than some other senolytic regimens [8,42], and 5) DQalleviates physical dysfunction, delays or treats multiple age-related disorders, and extends lifespan in oldmice [5,8,11,18,20–25]....
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...However, senescent cell clearance by senolytics can occur within 18h of a brief exposure, and senolytics do not need to be present continuously to occupy a receptor or affect an enzyme [5,8,42]....
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...Cellular senescence is a nonproliferative cell state that can entail a senescence-associated secretory phenotype (SASP) comprising cytokines, chemokines, pro-fibrotic factors, matrix metalloproteases (MMPs), factors causing stem/progenitor cell dysfunction, and growth factors that impose detrimental effects on the local and systemic environment [8,9]....
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Journal Article•DOI•

Sarcopenia: Aging-Related Loss of Muscle Mass and Function.

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Lars Larsson¹, Hans Degens¹, Meishan Li², Leonardo Salviati³, Youngil Lee⁴, Wesley J. Thompson⁵, James L. Kirkland, Marco Sandri⁶ - Show less +4 more•Institutions (6)

Karolinska Institutet¹, Pennsylvania State University², Metropolitan University³, Lithuanian Sports University⁴, University of Padua⁵, Texas A&M University⁶

01 Jan 2019-Physiological Reviews

TL;DR: This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the α-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates.

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Abstract: Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and ex...

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630 citations

Journal Article•DOI•

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.

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La Tonya J. Hickson¹, Larissa G.P. Langhi Prata¹, Shane A. Bobart¹, Tamara K. Evans¹, Nino Giorgadze¹, Shahrukh K. Hashmi¹, Sandra M. Herrmann¹, Michael D. Jensen¹, Qingyi Jia¹, Kyra L. Jordan¹, Todd A. Kellogg¹, Sundeep Khosla¹, Daniel M. Koerber¹, Anthony B. Lagnado¹, Donna K. Lawson², Nathan K. LeBrasseur¹, Lilach O. Lerman¹, Kathleen M. McDonald¹, Travis J. McKenzie¹, João F. Passos¹, Robert J. Pignolo, Tamar Pirtskhalava¹, Ishran M. Saadiq¹, Kalli K. Schaefer¹, Stephen C. Textor¹, Stella Victorelli¹, Tammie L Volkman¹, Ailing Xue¹, Mark A. Wentworth¹, Erin O. Wissler Gerdes¹, Yi Zhu¹, Tamara Tchkonia¹, James L. Kirkland - Show less +29 more•Institutions (2)

Mayo Clinic¹, Society of Hospital Medicine²

01 Sep 2019-EBioMedicine

TL;DR: “Hit-and-run” treatment with senolytics, which in the case of D’+ Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans.

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603 citations

Cites background from "Cellular Senescence: A Translationa..."

...Insults such as serial passaging, DNA damage, exposure to the damage-associated molecular pattern molecules that accumulate in injured or chronically-diseased tissues, and metabolic insults can cause cells to become senescent [2]....
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References

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Journal Article•DOI•

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

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David E. Harrison, Randy Strong¹, Zelton D Sharp¹, James F. Nelson¹, Clinton M. Astle, Kevin Flurkey, Nancy L. Nadon², J. Erby Wilkinson³, Krystyna Frenkel⁴, Christy S. Carter⁵, Christy S. Carter⁶, Marco Pahor⁶, Marco Pahor⁵, Martin A. Javors¹, Elizabeth Fernandez¹, Richard A. Miller³ - Show less +12 more•Institutions (6)

University of Texas Health Science Center at San Antonio¹, National Institutes of Health², University of Michigan³, New York University⁴, University of Florida⁵, Wake Forest University⁶

16 Jul 2009-Nature

TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.

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Abstract: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

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3,216 citations

"Cellular Senescence: A Translationa..." refers background in this paper

...…impairment, and immune dysfunction in mouse models, and enhance antibody response to influenza vaccination in elderly humans, among other effects (Harrison et al., 2009; Li et al., 2014; Majumder et al., 2012; Wilkinson et al., 2012, Zhang et al., 2014, Mannick et al., 2014; Bitto et al., 2016)....
[...]
...An increase in maximum lifespan, as opposed to median lifespan, is perhaps the best indication that an aging mechanism has been targeted (Harrison et al., 2009)....
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...Rapamycin and related agents increase lifespan in mice, delay age-related adipose tissue loss, alleviate frailty in old mice, decrease heart failure, cancers, cognitive impairment, and immune dysfunction in mouse models, and enhance antibody response to influenza vaccination in elderly humans, among other effects (Harrison et al., 2009; Li et al., 2014; Majumder et al., 2012; Wilkinson et al., 2012, Zhang et al., 2014, Mannick et al., 2014; Bitto et al., 2016)....
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Journal Article•DOI•

Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders

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Darren J. Baker¹, Tobias Wijshake¹, Tamar Tchkonia¹, Nathan K. LeBrasseur¹, Bennett G. Childs¹, Bart van de Sluis, James L. Kirkland¹, Jan M. van Deursen¹ - Show less +4 more•Institutions (1)

Mayo Clinic¹

10 Nov 2011-Nature

TL;DR: 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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Abstract: 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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2,738 citations

"Cellular Senescence: A Translationa..." refers background in this paper

...In a later study, an increase in median lifespan was suggested in INKATTAC mice in which p16Ink4a+ cells had been targeted by repeated intraperitoneal (ip) injections of AP20187 beginning in mid-adulthood at the equivalent of 40 years of human age, compared to vehicle-treated controls (Baker et al., 2016)....
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...AP20187 might clear non-senescent cells that have high p16Ink4a levels and therefore increased ATTAC, such as activated macrophages (Hall et al., 2016)....
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...Reasons for this include: 1) not all senescent cells necessarily have increased p16Ink4a expression and consequent susceptibility to clearance by AP20187....
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...…that clearing senescent cells has any effects on phenotypes in naturally-aged animals, as opposed to the progeroid INK-ATTAC;BubR1H/H mice from which p16Ink4a+ senescent cells had been reduced by AP20187 (Baker et al., 2011), was reported in 24 month old mice treated with D + Q (Zhu et al., 2015b)....
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...Senescent cells can be eliminated from transgenic INK-ATTAC mice by administering a drug, AP20187, that does not affect normal cells....
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Journal Article•DOI•

Naturally occurring p16 Ink4a -positive cells shorten healthy lifespan

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Darren J. Baker¹, Bennett G. Childs¹, Matej Durik¹, Melinde Wijers¹, Cynthia J. Sieben¹, Jian Zhong¹, Rachel A. Saltness¹, Karthik B. Jeganathan¹, Grace C Verzosa¹, Abdulmohammad Pezeshki¹, Khashayarsha Khazaie¹, Jordan D. Miller¹, Jan M. van Deursen¹ - Show less +9 more•Institutions (1)

Mayo Clinic¹

11 Feb 2016-Nature

TL;DR: It is shown that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds and the clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects.

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Abstract: Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

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1,882 citations

"Cellular Senescence: A Translationa..." refers background in this paper

...…study, an increase in median lifespan was suggested in INKATTAC mice in which p16Ink4a+ cells had been targeted by repeated intraperitoneal (ip) injections of AP20187 beginning in mid-adulthood at the equivalent of 40 years of human age, compared to vehicle-treated controls (Baker et al., 2016)....
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Journal Article•DOI•

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

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Yi-Yi Zhu¹, Tamara Tchkonia¹, Tamar Pirtskhalava¹, Adam C. Gower², Husheng Ding¹, Nino Giorgadze¹, Allyson K. Palmer¹, Yuji Ikeno³, Yuji Ikeno⁴, Gene B. Hubbard³, Gene B. Hubbard⁴, Marc E. Lenburg², Steven P. O'Hara¹, Nicholas F. LaRusso¹, Jordan D. Miller¹, Carolyn M Roos¹, Grace C Verzosa¹, Nathan K. LeBrasseur¹, Jonathan D. Wren⁵, Joshua N. Farr¹, Sundeep Khosla¹, Michael B. Stout¹, Sara J. McGowan⁶, Heike Fuhrmann-Stroissnigg⁶, Aditi U. Gurkar⁶, Jing-jing Zhao⁶, Debora Colangelo⁶, Akaitz Dorronsoro⁶, Yuan Yuan Ling⁶, Amira S. Barghouthy⁶, Diana C. Navarro⁶, Tokio Sano⁶, Paul D. Robbins⁶, Laura J. Niedernhofer⁶, James L. Kirkland¹ - Show less +31 more•Institutions (6)

Mayo Clinic¹, Boston University², Murphy Oil³, University of Texas Health Science Center at San Antonio⁴, Oklahoma Medical Research Foundation⁵, Scripps Research Institute⁶

01 Aug 2015-Aging Cell

TL;DR: The results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

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Abstract: The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

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1,417 citations

Journal Article•DOI•

Ink4a/Arf expression is a biomarker of aging

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Janakiraman Krishnamurthy¹, Chad Torrice¹, Matthew R. Ramsey¹, Grigoriy I. Kovalev¹, Khalid A. Al-Regaiey², Lishan Su, Norman E. Sharpless - Show less +3 more•Institutions (2)

University of North Carolina at Chapel Hill¹, Southern Illinois University Carbondale²

01 Nov 2004-Journal of Clinical Investigation

TL;DR: In this article, the authors examined the links between senescence and aging in vivo, and showed that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of related cell cycle inhibitors.

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Abstract: The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.

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1,369 citations

"Cellular Senescence: A Translationa..." refers background in this paper

...In a key study, caloric restriction, an invention that increases maximum lifespan in mice, was associated with decreased p16 and SA-βgal cell abundance in mice (Krishnamurthy et al., 2004)....
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...In a key study, caloric restriction, an invention that increases maximum lifespan in mice, was associated with decreased p16Ink4a+ and SA-βgal+ cell abundance in mice (Krishnamurthy et al., 2004)....
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...In that and another study, single genemutations that increase maximum lifespan in mice were associated with decreased senescent cell burden (Krishnamurthy et al., 2004; Stout et al., 2014)....
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