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

Zhu, Yiyi; Tchkonia, Tamar; Pirtskhalava, Tamar; Gower, Adam C.; Ding, Husheng; Giorgadze, Nino; Palmer, Allyson K.; Ikeno, Yuji; Hubbard, Gene B.; Lenburg, Marc E.; O’Hara, Steven P.; LaRusso, Nicholas F.; Miller, Jordan D.; Roos, Carolyn M; Verzosa, Grace C; LeBrasseur, Nathan K.; Wren, Jonathan D.; Farr, Joshua N.; Khosla, Sundeep; Stout, Michael B.; McGowan, Sara J.; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U.; Jin, Zhao; Colangelo, Debora; Dorronsoro, Akaitz; Ling, Yuan Yuan; Barghouthy, Amira S.; Navarro, Diana C.; Sano, Tokio; Robbins, Paul D.; Niedernhofer, Laura J.; Kirkland, James L.

doi:10.1111/acel.12344

Cited by 1,802 publications

(2,040 citation statements)

References 67 publications

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“…Among other possibilities, this could be related to intimal plaque penetrance by D+Q. Effects of newer senolytics, such as navitoclax (Zhu et al ., 2015a,b), remain to be determined. We did, however, find that intimal plaque calcification was significantly reduced in D+Q‐ vs .…”

Section: Can Chronic Senolytic Treatment Improve Hypercholesterolemiamentioning

confidence: 99%

“…Recent work suggests senescent cell burden can be dramatically increased by chronological aging or in models of progeria (Lecka‐Czernik et al ., 1997; Baker et al ., 2004; Varela et al ., 2005), high‐fat feeding (Shi et al ., 2007), diabetes (Verzola et al ., 2008), tobacco exposure (Nyunoya et al ., 2006), or atherosclerosis (Wang & Bennett, 2012), and short‐term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging‐related phenotypes (Zhu et al ., 2015a,b). However, effects of long‐term senescent cell clearance on vascular reactivity and structure with aging or chronic hypercholesterolemia remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

et al. 2016

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SummaryWhile reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF + cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

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Section: Can Chronic Senolytic Treatment Improve Hypercholesterolemiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

et al. 2016

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“…This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age‐related diseases and disorders in both progeroid and naturally aged mice (Baker et al., 2011, 2016). Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti‐aging strategy and a new treatment for chemotherapy‐ and radiotherapy‐induced side effects (Baar et al., 2017; Chang et al., 2016; Childs et al., 2016; Demaria et al., 2017; Jeon et al., 2017; Ogrodnik et al., 2017; Pan et al., 2017; Schafer et al., 2017; Yosef et al., 2016; Zhu et al., 2015). …”

Section: Introductionmentioning

confidence: 99%

“…Since the first senolytic was published (Zhu et al., 2015), twelve molecular targets have been identified (Childs et al., 2017), including the prosurvival Bcl‐2 family proteins (Chang et al., 2016; Yosef et al., 2016; Zhu et al., 2016) and forkhead Box O4 (FOXO4) (Baar et al., 2017). These findings led to the discovery of a few senolytic agents, including ABT‐263 and ABT‐737, two Bcl‐2/xl/w inhibitors, and FOXO4‐DRI, a peptide molecule that interferes with the interaction of FOXO4 and p53.…”

Section: Introductionmentioning

confidence: 99%

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Oxidation resistance 1 is a novel senolytic target

et al. 2018

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SummaryThe selective depletion of senescent cells (SCs) by small molecules, termed senolytic agents, is a promising therapeutic approach for treating age‐related diseases and chemotherapy‐ and radiotherapy‐induced side effects. Piperlongumine (PL) was recently identified as a novel senolytic agent. However, its mechanism of action and molecular targets in SCs was unknown and thus was investigated. Specifically, we used a PL‐based chemical probe to pull‐down PL‐binding proteins from live cells and then mass spectrometry‐based proteomic analysis to identify potential molecular targets of PL in SCs. One prominent target was oxidation resistance 1 (OXR1), an important antioxidant protein that regulates the expression of a variety of antioxidant enzymes. We found that OXR1 was upregulated in senescent human WI38 fibroblasts. PL bound to OXR1 directly and induced its degradation through the ubiquitin‐proteasome system in an SC‐specific manner. The knockdown of OXR1 expression by RNA interference significantly increased the production of reactive oxygen species in SCs in conjunction with the downregulation of antioxidant enzymes such as heme oxygenase 1, glutathione peroxidase 2, and catalase, but these effects were much less significant when OXR1 was knocked down in non‐SCs. More importantly, knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide. These findings provide new insights into the mechanism by which SCs are highly resistant to oxidative stress and suggest that OXR1 is a novel senolytic target that can be further exploited for the development of new senolytic agents.

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Aging, Cell Senescence, and Chronic Disease

Tchkonia

Kirkland

2018

JAMA

253

172

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Age is the leading predictive factor for most of the chronic diseases that account for the majority of morbidity, hospitalizations, health costs, and mortality worldwide. These diseases include Alzheimer disease and other neurodegenerative diseases, cardiovascular disease, and most cancers. Chronological age is also the main risk factor for the geriatric syndromes, including frailty and immobility as well as decreased physical resilience, which is manifested by delayed or incomplete recovery from stressors, such as surgery, hip fracture, and pneumonia. The prevalence of these problems not only increases with age, but these conditions tend to cluster within older individuals, leading to multimorbidity. Therefore, if any single major age-related disease were cured, it would only be supplanted by others, adding little to quality or length of life and limiting the effectiveness of treating age-related chronic diseases one at a time.The fundamental aging processes that contribute to phenotypes characteristic of advanced old age, such as muscle weakness and loss of subcutaneous fat, also appear to underlie the major chronic diseases, geriatric syndromes, and loss of physical resilience. These aging processes can be broadly classified as follows: (1) chronic, low-grade inflammation that is "sterile" (occurring in the absence of known pathogens), together with fibrosis; (2) macromolecular and cell organelle dysfunction (such as DNA damage, dysfunctional telomeres, protein aggregation and misfolding, decreased removal of damaged proteins, or mitochondrial dysfunction); (3) changes in stem cells and progenitors that lead to reduced capacity to repair or replace tissues; and (4) cellular senescence. These aging processes are frequently evident at etiologic sites of chronic diseases, for example, in the brain of patients with Alzheimer disease or in the adipose tissue of patients with type 2 diabetes. Activation of any single fundamental aging process tends to influence the others. In laboratory animals, genetic or other interventions that target a particular aging process often also target others. Thus, fundamental aging processes are an attractive target for developing interventions to delay, prevent, or alleviate age-related disorders as a group.

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

Cited by 1,802 publications

References 67 publications

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

Oxidation resistance 1 is a novel senolytic target

Aging, Cell Senescence, and Chronic Disease

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