Fisetin is a senotherapeutic that extends health and lifespan

Yousefzadeh, Matthew J.; Zhu, Yi; McGowan, Sara J.; Angelini, Luise; Fuhrmann-Stroissnigg, Heike; Xu, Ming; Ling, Yuan Yuan; Melos, Kendra I.; Pirtskhalava, Tamar; Inman, Christina L.; McGuckian, Collin A.; Wade, Erin A.; Kato, Jonathon I.; Grassi, Diego; Wentworth, Mark; Burd, Christin E.; Arriaga, Edgar A.; Ladiges, Warren; Tchkonia, Tamara; Kirkland, James L.; Robbins, Paul D.; Niedernhofer, Laura J.

doi:10.1016/j.ebiom.2018.09.015

Cited by 703 publications

(592 citation statements)

References 85 publications

Supporting

Mentioning

541

Contrasting

Unclassified

Order By: Relevance

“…After reaching adulthood, the senescence and SASP markers were significantly increased in multiple tissues and by multiple measures, and continued to rise as the animals aged (Figures and ). This correlates with the onset and progression of age‐related pathologies in multiple tissues of the Ercc1 − /∆ model (Dolle et al, ; Gregg et al, ; Gurkar & Niedernhofer, ; Harkema et al, ; Yousefzadeh et al, ; Yousefzadeh, Zhu, et al, ), providing further evidence that senescent cells play a causal role in numerous age‐related pathologies (Baker et al, ).…”

Section: Discussionmentioning

confidence: 78%

“…Likewise, senescence marker expression was elevated in the skin of both aged wild‐type and progeroid mice. Peripheral T cells and skin, which are readily accessible organs, or the aorta, with its large dynamic range of senescence marker expression, may prove useful for measuring the response to senolytic interventions in mice (Yousefzadeh, Zhu, et al, ). We did not detect increased expression of p16 Ink4a and p21 Cip1 in skeletal muscle or the heart of aged WT or young adult Ercc1 − /∆ mice (Figure b–c).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.

show abstract

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The use of p16‐3MR mice to perform longitudinal tracking and elimination of p16‐high cells provided evidence for the beneficial role of senescence in wound healing (14) and demonstrated that clearance of senescent cells could ameliorate age‐related diseases such as atherosclerosis (40) and OA (9). The knock‐in p16 LUC allele has been used to assess the senescence burden after senolytic treatment (41), and the p16 tdTom allele extends the analysis capabilities through the isolation of p16‐high and p16‐low cells with flow cytometry cell sorting.…”

Section: Discussionmentioning

confidence: 99%

Controlled induction and targeted elimination of p16^INK4a‐expressing chondrocytes in cartilage explant culture

Sessions¹,

Copp

Liu

et al. 2019

The FASEB Journal

View full text Add to dashboard Cite

Cellular senescence is a phenotypic state that contributes to age‐related diseases through the secretion of matrix‐degrading and inflammatory molecules. An emerging therapeutic strategy for osteoarthritis (OA) is to selectively eliminate senescent cells by initiating apoptosis. This study establishes a cartilage explant model of senescence induction and senolytic clearance using p16Ink4a expression as a biomarker of senescence. Growth‐factor stimulation of explants increased the expression of p16Ink4a at both the mRNA and protein levels. Applying this culture system to cartilage from p16tdTom reporter mice (a knockin allele with tdTomato fluorescent protein regulated by the endogenous p16Ink4a promoter) demonstrated the emergence of a p16‐high population that was quantified using flow cytometry for tdTomato. Cell sorting was used to separate chondrocytes based on tdTomato fluorescence and p16‐high cells showed higher senescence‐associated β‐galactosidase activity and increased gene expression of the senescence‐associated secretory phenotype as compared with p16‐low cells. The potential for effective senolysis within the cartilage extracellular matrix was assessed using navitoclax (ABT‐263). Navitoclax treatment reduced the percentage of p16‐high cells from 17.9 to 6.1% (mean of 13 matched pairs; P < 0.001) and increased cleaved caspase‐3 confirmed apoptotic activity. Together, these findings establish a physiologically relevant cartilage explant model for testing the induction and elimination of senescent chondrocytes, which will support investigations of senolytic therapy for OA.—Sessions, G. A., Copp, M. E., Liu, J.‐Y., Sinkler, M. A., D'Costa, S., Diekman, B. O. Controlled induction and targeted elimination of p16INK4a‐expressing chondrocytes in cartilage explant culture. FASEB J. 33, 12364–12373 (2019). http://www.fasebj.org

show abstract

“…Of note, a panel of flavonoid polyphenols distinct from quercetin has been screened for senolytic activity. Fisetin reduced senescence markers in multiple tissues in progeroid and naturally aged mice (Yousefzadeh et al , ), and administration of fisetin in normally aged mice restored tissue homeostasis, reduced age‐related dysfunction and extended lifespan. Future therapeutic outcomes will be required for initial proof of principle of combination therapies.…”

Section: Introductionmentioning

confidence: 99%

Targeting senescent cells in translational medicine

et al. 2019

View full text Add to dashboard Cite

Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age‐related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.

show abstract

Fisetin is a senotherapeutic that extends health and lifespan

Cited by 703 publications

References 85 publications

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Controlled induction and targeted elimination of p16^INK4a‐expressing chondrocytes in cartilage explant culture

Targeting senescent cells in translational medicine

Contact Info

Product

Resources

About