Author: Marengo, Marita ; Lundgren, Torbjörn ; Ward, Liam ; Steinmetz-Späh, Julia ; Arefin, Samsul ; Ebert, Thomas ; Kublickiene, Karolina ; Bruno, Stefania ; Hobson, Sam ; Witasp, Anna ; Hernandez, Leah ; Wennberg, Lars ; Mudrovcic, Neja ; Thorell, Anders ; Larsson, Karin ; Pietrocola, Federico ; Stenvinkel, Peter ; Cantaluppi, Vincenzo

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular mortality and morbidity. We hypothesized that a senescent phenotype instigated by uremic toxins could account for early vascular aging (EVA) and vascular dysfunctions of microvasculature in end stage kidney disease (ESKD) patients which ultimately lead to increased cardiovascular complication. To test this hypothesis, we utilized both in vivo, and ex vivo approaches to study endothelial and smooth muscle function and structure, and characterized markers related to EVA in 82 ESKD patients (eGFR <15 ml/min) and 70 non-CKD controls. In vivo measurement revealed no major difference in endothelial function between ESKD and control group, aside from higher stiffness detected in the microcirculation of ESKD participants. In contrast, ex vivo measurements revealed a notable change in the contribution of endothelium-derived factors and increased stiffness in ESKD patients vs. controls. In support, we demonstrated that ex vivo exposure of arteries to uremic toxins such as Trimethylamine N-oxide, Phenylacetyl glutamine, or extracellular vesicles from CKD patients impaired endothelial function via diminishing the contribution of endothelium-derived relaxing factors such as nitric oxide and endothelium derived hyperpolarizing factor. Uremic arteries displayed elevated expression of senescence markers (p21CIP1, p16INK4a, and SA-β-gal), calcification marker (RUNX2), and reduced expression of Ki67, sirtuin1, Nrf2, and MHY11 markers, indicating the accumulation of senescent cells and EVA phenotype. Correspondingly, treating uremic vessel rings ex vivo with senolytic agents (Dasatinib + Quercetin) effectively reduced the senescence-associated secretory phenotype and changed the origin of extracellular vesicles. Notably, sex differences exist for certain abnormalities suggesting the importance of biological sex in the pathogenesis of vascular complications. In conclusion, the uremic microvasculature is characterized by a "senescence signature", which may contribute to EVA and cardiovascular complications in ESKD patients and could be alleviated by treatment with senolytic agents.

01 Nov 2024·Life Sciences

Effect of senolytic drugs in young female mice chemically induced to estropause

Article

Author: da Cruz, Pedro H ; Vaucher, Rodrigo A. ; Ávila, Bianca M. ; Masternak, Michal M ; Zanini, Bianka M. ; Schneider, Augusto ; Zanini, Bianka M ; Oliveira, Thais L ; Prosczek, Juliane ; Oliveira, Thais L. ; Mason, Jeffrey B. ; Hense, Jéssica D ; Luduvico, Karina P ; Garcia, Driele N ; Stefanello, Francielle M. ; Garcia, Driele N. ; Mason, Jeffrey B ; Luduvico, Karina P. ; Giongo, Janice L. ; Ávila, Bianca M ; Hense, Jéssica D. ; Giongo, Janice L ; Vaucher, Rodrigo A ; da Cruz, Pedro H. ; Masternak, Michal M. ; Stefanello, Francieli M

AIMSThis study aimed to assess metabolic responses and senescent cell burden in young female mice induced to estropause and treated with senolytic drugs.MAIN METHODSEstropause was induced by 4-vinylcyclohexene diepoxide (VCD) injection in two-month-old mice. The senolytics dasatinib and quercetin (D + Q) or fisetin were given by oral gavage once a month from five to 11 months of age.KEY FINDINGSVCD-induced estropause led to increased body mass and reduced albumin concentrations compared to untreated cyclic mice, without affecting insulin sensitivity, lipid profile, liver enzymes, or total proteins. Estropause decreased catalase activity in adipose tissue but had no significant effect on other redox parameters in adipose and hepatic tissues. Fisetin treatment reduced ROS levels in the hepatic tissue of estropause mice. Estropause did not influence senescence-associated beta-galactosidase activity in adipose and hepatic tissues but increased senescent cell markers and fibrosis in ovaries. Senolytic treatment did not decrease ovarian cellular senescence induced by estropause.SIGNIFICANCEOverall, the findings suggest that estropause leads to minor metabolic changes in young females, and the senolytics D + Q and fisetin had no protective effects despite increased ovarian senescence.

01 Nov 2024·Journal of Orthopaedic Translation

The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells

Article

Author: Dong, Zhan ; Goltzman, David ; Qiao, Wanxin ; Yang, Cuicui ; Miao, Dengshun ; Xue, Qi

Background/ObjectiveActive vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells.MethodsBone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)₂D-insufficient (Cyp27b1^+/-) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups.ResultsABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)₂D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)₂D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)₂D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)₂D insufficiency by reducing the expression of senescence and SASP-related genes and proteins.ConclusionABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency.The translational potential of this articleThis study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

100 Deals associated with Senolytic (Entos/Oisin)

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Indication	Highest Phase	Country/Location	Organization	Date
disorder of aging	Preclinical	CA	Entos Pharmaceuticals, Inc.Startup	26 Jul 2024
disorder of aging	Preclinical	US	Oisin Biotechnologies, Inc.Startup	26 Jul 2024

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