Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

Song, Shuling; Tchkonia, Tamara; Jiang, Jing; Kirkland, James L.; Sun, Yu

doi:10.1002/advs.202002611

Cited by 91 publications

(90 citation statements)

References 166 publications

(232 reference statements)

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“…To this end, we focused on the senomorphics – a class of drugs proved to reduce SASP secretion without affecting viability of senescent cells (Borghesan et al, 2020). We chose two compounds rapamycin and metformin, whose senomorphic activity is well established for various cell types and different models of senescence (Borghesan et al, 2020; Song et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Today the role of cellular senescence is extensively studied with regard to various pathologies (He & Sharpless, 2017; Borghesan et al, 2020; Karin & Alon, 2021). Promising results in treating diseases of different etiologies have been already obtained based on the senolytics or senomorphics applications, leading either to targeted killing of senescent cells or to reduction of SASP secretion (Song et al, 2020). However, from this point of view, endometrium and female infertility still remain poorly studied, probably, due to several obstacles, which will be discussed below.…”

Section: Introductionmentioning

confidence: 99%

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Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

Deryabin

Ivanova

Borodkina

2021

Preprint

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Successful implantation requires two-sided interaction between genetically normal embryo and properly prepared endometrium. At the cellular level the latter means hormone-regulated differentiation of endometrial stromal cells (ESCs) into decidual ones that create appropriate microenvironment for invading embryo. Impaired decidualization is proved to mediate implantation failures. Here we elicited ESCs’ senescence as the cause for disturbed decidualization of endometrial stroma and impaired blastocyst implantation. Ability to decidualize and to accept modeled blastocysts inversely correlated with senescence in patients’ ESCs lines. Reduced hormonal responsiveness of senescent ESCs led to inappropriate decidualization dynamics resulting in altered receptivity, disturbed ligand-receptor interaction with trophoblasts and modified architecture of extracellular matrix what hindered blastocysts’ invasion. Furthermore, senescent ESCs caused ‘bystander’ quenching of decidual reaction in adjacent cells reinforcing dysfunction of stromal compartment. Implementation of senomorphics reducing senescence phenotype diminished adverse effects of senescent ESCs on decidualization and implantation using both in vitro models and patients’ lines, what suggests a promising strategy to increase in vitro fertilization efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

Deryabin

Ivanova

Borodkina

2021

Preprint

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“…Cellular senescence often triggers an immune response in the tumor microenvironment (Song et al, 2020), and immune cell infiltration into the tumor microenvironment promotes tumor growth (Sarode et al, 2020). However, the modulation of immune cells by ARGs is relatively unclear in LUAD.…”

Section: Discussionmentioning

confidence: 99%

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Lung Adenocarcinoma

Chen

2021

Front. Cell Dev. Biol.

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Aging is an inevitable time-dependent process associated with a gradual decline in many physiological functions. Importantly, some studies have supported that aging may be involved in the development of lung adenocarcinoma (LUAD). However, no studies have described an aging-related gene (ARG)-based prognosis signature for LUAD. Accordingly, in this study, we analyzed ARG expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). After LASSO and Cox regression analyses, a six ARG-based signature (APOC3, EPOR, H2AFX, MXD1, PLCG2, and YWHAZ) was constructed using TCGA dataset that significantly stratified cases into high- and low-risk groups in terms of overall survival (OS). Cox regression analysis indicated that the ARG signature was an independent prognostic factor in LUAD. A nomogram based on the ARG signature and clinicopathological factors was developed in TCGA cohort and validated in the GEO dataset. Moreover, to visualize the prediction results, we established a web-based calculator yurong.shinyapps.io/ARGs_LUAD/. Calibration plots showed good consistency between the prediction of the nomogram and actual observations. Receiver operating characteristic curve and decision curve analyses indicated that the ARG nomogram had better OS prediction and clinical net benefit than the staging system. Taken together, these results established a genetic signature for LUAD based on ARGs, which may promote individualized treatment and provide promising novel molecular markers for immunotherapy.

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“…It is expected that rapamycin-like effect may be responsible for the therapeutic effects of senolytics in disease. Some senolytics are investigated for treatment of diseases such as idiopathic pulmonary fibrosis [ 10 , 45 , 149 , 174 ]. Although the treatment of specific diseases is very important, it is a different story entirely.…”

Section: Discussionmentioning

confidence: 99%

Anti-aging: senolytics or gerostatics (unconventional view)

Blagosklonny

2021

Oncotarget

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Senolytics are basically anti-cancer drugs, repurposed to kill senescent cells selectively. It is even more difficult to selectively kill senescent cells than to kill cancer cells. Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways. Unlike senolytics, gerostatics do not kill cells but slow down cellular geroconversion to senescence. Numerous studies demonstrated that inhibition of the mTOR pathways by any means (genetic, pharmacological and dietary) extends lifespan. Currently, only two studies demonstrated that senolytics (fisetin and a combination Dasatinib plus Quercetin) extend lifespan in mice. These senolytics slightly inhibit the mTOR pathway. Thus, life extension by these senolytics can be explained by their slight rapamycin-like (gerostatic) effects.

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Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

Cited by 91 publications

References 166 publications

Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Lung Adenocarcinoma

Anti-aging: senolytics or gerostatics (unconventional view)

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