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

By Yi Zhu, T. Tchkonia, T. Pirtskhalava, A. Gower, H. Ding, N. Giorgadze, Allyson K. Palmer, Y. Ikeno, G. Hubbard, M. Lenburg and 23 more. Aging Cell, 2015

2,184 citations recorded by the source corpus.

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.

Subfields: Endocrine and Autonomic Systems, Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/b28ac1f15c7c5abd50d4c55a9d475faad778f3dc

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Citations in the corpus

Cellular senescence mediates fibrotic pulmonary disease (2017, positive): “An alternative approach to transgenic senescent cell clearance is senolytics 21,22 , which may be a tractable treatment option for humans.”
Cellular senescence drives age-dependent hepatic steatosis (2017, positive): “Recent studies have demonstrated that selectively eliminating senescent cells can attenuate several age-dependent disorders 10–12 .”
JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age (2015, background): “We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan (21, 22).”
Inflammation and aging: signaling pathways and intervention therapies (2023, background): “Dasatinib removes senescent human adipocyte progenitor cells, while Quercetin is more potent in killing senescent human endothelial cells and bone marrow stem cells in mice.(341) The most potent removal of senescent cells was achieved when these two compounds were combined.”
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL (2016, positive): “Overall, these ﬁndings suggest that the clearance of senescent cells can lead to tissue renewal and improved ﬁtness, a possibility consistent with the recent ﬁnding that elimination of senescent cells via transgenic techniques and combinatorial treatments improves aging-associated phenotypes 14,43 .”
Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors (2016, methodology): “Also, similar to D and Q (Zhu et al., 2015), N is not a cell typeindependent senolytic agent.”
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study (2019, methodology): “consistent with preclinical findings of marked improvements in treadmill endurance and frailty following the selective ablation of senescent cells in progeroid, naturally aged, and lung-injured murine models [5,11,24,26].”
Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease (2019, methodology): “These included age-related declines in cardiac regenerative capacity, frailty, muscle weakness, reduced daily activity, decreased running endurance on a treadmill, and osteoporosis [3,5,9,28,32].”
LINE-1 derepression in senescent cells triggers interferon and inflammaging (2019, neutral): “Hence, NRTIs can be categorized as “senostatic” agents, to contrast them from “senolytic” treatments that remove senescent cells from tissues 21,22 .”
Hallmarks of Cellular Senescence. (2018, positive): “Secretory phenotype: cytokines (e.g., IL-1a, IL-6,and IL-8), chemokines (e.g., CCL2) and metalloproteinases (e.g., MMP-1 and MMP-3) are used as markers [3,51].”
Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice (2016, background): “…(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).”