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https://www.readbyqxmd.com/read/27913811/discovery-of-piperlongumine-as-a-potential-novel-lead-for-the-development-of-senolytic-agents
#1
Yingying Wang, Jianhui Chang, Xingui Liu, Xuan Zhang, Suping Zhang, Xin Zhang, Daohong Zhou, Guangrong Zheng
Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a "senolytic agent", a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL)...
November 19, 2016: Aging
https://www.readbyqxmd.com/read/27789842/senescent-intimal-foam-cells-are-deleterious-at-all-stages-of-atherosclerosis
#2
Bennett G Childs, Darren J Baker, Tobias Wijshake, Cheryl A Conover, Judith Campisi, Jan M van Deursen
Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines...
October 28, 2016: Science
https://www.readbyqxmd.com/read/27721062/molecular-pathology-endpoints-useful-for-aging-studies
#3
L J Niedernhofer, J L Kirkland, W Ladiges
The first clinical trial aimed at targeting fundamental processes of aging will soon be launched (TAME: Targeting Aging with Metformin). In its wake is a robust pipeline of therapeutic interventions that have been demonstrated to extend lifespan or healthspan of preclinical models, including rapalogs, antioxidants, anti-inflammatory agents, and senolytics. This ensures that if the TAME trial is successful, numerous additional clinical trials are apt to follow. But a significant impediment to these trials remains the question of what endpoints should be measured? The design of the TAME trial very cleverly skirts around this based on the fact that there are decades of data on metformin in humans, providing unequaled clarity of what endpoints are most likely to yield a positive outcome...
October 6, 2016: Ageing Research Reviews
https://www.readbyqxmd.com/read/27524412/anti-aging-pharmacology-promises-and-pitfalls
#4
REVIEW
Alexander M Vaiserman, Oleh V Lushchak, Alexander K Koliada
Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness...
November 2016: Ageing Research Reviews
https://www.readbyqxmd.com/read/27380967/aging-clonality-and-rejuvenation-of-hematopoietic-stem-cells
#5
REVIEW
Shailaja Akunuru, Hartmut Geiger
Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and the increased production of reactive oxygen species (ROS) have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts, such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as the clonal selection of HSCs upon aging, provide new insights into HSC aging mechanisms...
August 2016: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27260561/energetic-interventions-for-healthspan-and-resiliency-with-aging
#6
Derek M Huffman, Marissa J Schafer, Nathan K LeBrasseur
Several behavioral and pharmacological strategies improve longevity, which is indicative of delayed organismal aging, with the most effective interventions extending both life- and healthspan. In free living creatures, maintaining health and function into old age requires resilience against a multitude of stressors. Conversely, in experimental settings, conventional housing of rodents limits exposure to such challenges, thereby obscuring an accurate assessment of resilience. Caloric restriction (CR) and exercise, as well as pharmacologic strategies (resveratrol, rapamycin, metformin, senolytics), are well established to improve indices of health and aging, but some paradoxical effects have been observed on resilience...
May 31, 2016: Experimental Gerontology
https://www.readbyqxmd.com/read/27000748/rejuvenating-muscle-stem-cell-function-restoring-quiescence-and-overcoming-senescence
#7
Andrew R Mendelsohn, James W Larrick
Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle satellite (or stem) cells (SMSCs) and progenitor cells. Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a presenescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion...
April 2016: Rejuvenation Research
https://www.readbyqxmd.com/read/26864908/chronic-senolytic-treatment-alleviates-established-vasomotor-dysfunction-in-aged-or-atherosclerotic-mice
#8
Carolyn M Roos, Bin Zhang, Allyson K Palmer, Mikolaj B Ogrodnik, Tamar Pirtskhalava, Nassir M Thalji, Michael Hagler, Diana Jurk, Leslie A Smith, Grace Casaclang-Verzosa, Yi Zhu, Marissa J Schafer, Tamara Tchkonia, James L Kirkland, Jordan D Miller
While 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...
October 2016: Aging Cell
https://www.readbyqxmd.com/read/26711051/identification-of-a-novel-senolytic-agent-navitoclax-targeting-the-bcl-2-family-of-anti-apoptotic-factors
#9
Yi Zhu, Tamara Tchkonia, Heike Fuhrmann-Stroissnigg, Haiming M Dai, Yuanyuan Y Ling, Michael B Stout, Tamar Pirtskhalava, Nino Giorgadze, Kurt O Johnson, Cory B Giles, Jonathan D Wren, Laura J Niedernhofer, Paul D Robbins, James L Kirkland
Clearing senescent cells extends healthspan in mice. Using a hypothesis-driven bioinformatics-based approach, we recently identified pro-survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro-survival regulators identified was Bcl-xl. Here, we tested whether the Bcl-2 family inhibitors, navitoclax (N) and TW-37 (T), are senolytic...
June 2016: Aging Cell
https://www.readbyqxmd.com/read/26657143/clearance-of-senescent-cells-by-abt263-rejuvenates-aged-hematopoietic-stem-cells-in-mice
#10
Jianhui Chang, Yingying Wang, Lijian Shao, Remi-Martin Laberge, Marco Demaria, Judith Campisi, Krishnamurthy Janakiraman, Norman E Sharpless, Sheng Ding, Wei Feng, Yi Luo, Xiaoyan Wang, Nukhet Aykin-Burns, Kimberly Krager, Usha Ponnappan, Martin Hauer-Jensen, Aimin Meng, Daohong Zhou
Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug...
January 2016: Nature Medicine
https://www.readbyqxmd.com/read/26343116/pleiotropic-effects-of-tocotrienols-and-quercetin-on-cellular-senescence-introducing-the-perspective-of-senolytic-effects-of-phytochemicals
#11
REVIEW
Marco Malavolta, Elisa Pierpaoli, Robertina Giacconi, Laura Costarelli, Francesco Piacenza, Andrea Basso, Maurizio Cardelli, Mauro Provinciali
The possibility to target cellular senescence with natural bioactive substances open interesting therapeutic perspective in cancer and aging. Engaging senescence response is suggested as a key component for therapeutic intervention in the eradication of cancer. At the same time, delaying senescence or even promote death of accumulating apoptosis-resistant senescent cells is proposed as a strategy to prevent age related diseases. Although these two desired outcome present an intrinsic dichotomy, there are examples of promising natural compounds that appear to satisfy all the requirements to develop senescence- targeted health promoting nutraceuticals...
2016: Current Drug Targets
https://www.readbyqxmd.com/read/25754370/the-achilles-heel-of-senescent-cells-from-transcriptome-to-senolytic-drugs
#12
Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava, Adam C Gower, Husheng Ding, Nino Giorgadze, Allyson K Palmer, Yuji Ikeno, Gene B Hubbard, Marc Lenburg, Steven P O'Hara, Nicholas F LaRusso, Jordan D Miller, Carolyn M Roos, Grace C Verzosa, Nathan K LeBrasseur, Jonathan D Wren, Joshua N Farr, Sundeep Khosla, Michael B Stout, Sara J McGowan, Heike Fuhrmann-Stroissnigg, Aditi U Gurkar, Jing Zhao, Debora Colangelo, Akaitz Dorronsoro, Yuan Yuan Ling, Amira S Barghouthy, Diana C Navarro, Tokio Sano, Paul D Robbins, Laura J Niedernhofer, James L Kirkland
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...
August 2015: Aging Cell
https://www.readbyqxmd.com/read/25446976/clinical-strategies-and-animal-models-for-developing-senolytic-agents
#13
James L Kirkland, Tamara Tchkonia
Aging is associated with increasing predisposition to multiple chronic diseases. One fundamental aging process that is often operative at sites of the pathology underlying chronic age-related diseases is cellular senescence. Small molecule senolytic agents are being developed. For successful drug development: 1) appropriate animal models of human age-related diseases need to be devised. 2) Models have to be made in which it can be proven that beneficial phenotypic effects are actually caused through clearing senescent cells by putative senolytic agents, as opposed to "off-target" effects of these agents on non-senescent cells...
August 2015: Experimental Gerontology
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