Cell Metabolism, Год журнала: 2019, Номер 30(1), С. 129 - 142.e4
Опубликована: Май 30, 2019
Язык: Английский
Nature Reviews Cardiology, Год журнала: 2018, Номер 15(9), С. 505 - 522
Опубликована: Июль 31, 2018
Язык: Английский
Процитировано
2477
Cell, Год журнала: 2019, Номер 179(4), С. 813 - 827
Опубликована: Окт. 1, 2019
Язык: Английский
Процитировано
2256
Nature Medicine, Год журнала: 2018, Номер 24(8), С. 1246 - 1256
Опубликована: Июль 6, 2018
Язык: Английский
Процитировано
1784
Nature, Год журнала: 2019, Номер 571(7764), С. 183 - 192
Опубликована: Июль 10, 2019
Язык: Английский
Процитировано
1085
The Journal of Cell Biology, Год журнала: 2017, Номер 217(1), С. 65 - 77
Опубликована: Ноя. 7, 2017
Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding biological basis of aging, research suggests that targeting aging process itself could ameliorate many age-related pathologies. Senescence a cellular response characterized by stable growth arrest other phenotypic alterations include proinflammatory secretome. plays roles in normal development, maintains tissue homeostasis, limits tumor progression. However, senescence has also been implicated as cause disease. In this regard, recent experimental evidence shown genetic or pharmacological ablation senescent cells extends life span improves health span. Here, review molecular links between discuss novel therapeutic avenues connection opens.
Язык: Английский
Процитировано
1029
EBioMedicine, Год журнала: 2019, Номер 47, С. 446 - 456
Опубликована: Сен. 1, 2019
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing at etiological sites in multiple chronic diseases. Senolytics, including combination of Dasatinib Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks defend them against their own apoptotic environment. In first clinical trial senolytics, D Q improved physical function patients idiopathic pulmonary fibrosis (IPF), a fatal disease, but to date, no peer-reviewed study has directly demonstrated senolytics decrease humans.In an open label Phase 1 pilot study, we administered 3 days oral 100 mg 1000 subjects diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 2·3 kg/m2; eGFR:27·0 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, blood were collected before 11 after completing senolytic treatment. cell macrophage/Langerhans markers circulating SASP assayed.D reduced adipose tissue burden within days, decreases p16INK4A-and p21CIP1-expressing β-galactosidase activity, adipocyte progenitors limited replicative potential. macrophages, are attracted, anchored, activated crown-like structures decreased. Skin epidermal p16INK4A+ p21CIP1+ reduced, as factors, IL-1α, IL-6, MMPs-9 -12."Hit-and-run" treatment case have elimination half-lives <11 h, significantly humans. FUND: NIH Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, Mesenchymal Stem Cell Functionality Chronic Kidney Disease: Effect Senolytic Agents.
Язык: Английский
Процитировано
972
EBioMedicine, Год журнала: 2019, Номер 40, С. 554 - 563
Опубликована: Янв. 5, 2019
BackgroundCellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction bleomycin-administered mice.MethodsA two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 three-days/week over three-weeks) was conducted participants with IPF (n = 14) evaluate feasibility implementing senolytic intervention. The primary endpoints were retention rates and completion for planned clinical assessments. Secondary safety change functional reported health measures. Associations the secretory phenotype (SASP) explored.FindingsFourteen patients stable recruited. rate 100% no discontinuation; assessments complete 13/14 participants. One serious adverse event reported. Non-serious events primarily mild-moderate, respiratory symptoms 16 total events), skin irritation/bruising 14), gastrointestinal discomfort 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, chair-stands time significantly clinically-meaningfully improved (p < .05). Pulmonary function, chemistries, frailty index (FI-LAB), unchanged. effects on circulat.ing SASP factors inconclusive, correlations observed between SASP-related matrix-remodeling proteins, microRNAs, pro-inflammatory cytokines (23/48 markers r ≥ 0.50).InterpretationOur first-in-humans pilot supports provides initial evidence senolytics may alleviate physical IPF, warranting evaluation larger randomized controlled trials senescence-related diseases.ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).
Язык: Английский
Процитировано
938
Journal of Internal Medicine, Год журнала: 2020, Номер 288(5), С. 518 - 536
Опубликована: Июль 20, 2020
Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using hypothesis-driven approach. SC accumulate with ageing at causal sites multiple chronic disorders, including diseases accounting for the bulk morbidity, mortality health expenditures. most deleterious resistant to apoptosis have up-regulation anti-apoptotic pathways which defend against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them survive, despite killing neighbouring cells. transiently disable these SCAPs, causing those tissue-destructive SASP. Because take weeks reaccumulate, senolytics can be administered intermittently - 'hit-and-run' In preclinical models, delay, prevent or alleviate frailty, cancers cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic skin disorders as well complications organ transplantation, radiation cancer treatment. As anticipated agents targeting fundamental mechanisms 'root cause' contributors potential uses protean, potentially alleviating over 40 conditions in studies, opening new route treating age-related dysfunction diseases. Early pilot trials suggest they decrease cells, reduce inflammation frailty humans. Clinical diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, COVID-19, osteoarthritis, osteoporosis, eye bone marrow transplant childhood survivors underway beginning. Until such studies done, it is too early used outside clinical trials.
Язык: Английский
Процитировано
789
EBioMedicine, Год журнала: 2018, Номер 36, С. 18 - 28
Опубликована: Сен. 29, 2018
Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent have been demonstrated play causal role driving aging and age-related diseases using genetic pharmacologic approaches. We previously that the combination dasatinib flavonoid quercetin potent senolytic improving numerous conditions including frailty, osteoporosis cardiovascular disease. The goal this study was identify flavonoids with more activity.
Язык: Английский
Процитировано
766
Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)
Опубликована: Дек. 16, 2022
Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.
Язык: Английский
Процитировано
700