Ageing as a risk factor for neurodegenerative disease

Nature Reviews Neurology, Год журнала: 2019, Номер 15(10), С. 565 - 581

Опубликована: Сен. 9, 2019

Язык: Английский

---

Cellular senescence in ageing: from mechanisms to therapeutic opportunities

Nature Reviews Molecular Cell Biology, Год журнала: 2020, Номер 22(2), С. 75 - 95

Опубликована: Дек. 16, 2020

Язык: Английский

---

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

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

---

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

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

---

Synergy between amyloid-β and tau in Alzheimer’s disease

Nature Neuroscience, Год журнала: 2020, Номер 23(10), С. 1183 - 1193

Опубликована: Авг. 10, 2020

Язык: Английский

---

Senolytic drugs: from discovery to translation

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

---

Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model

Nature Neuroscience, Год журнала: 2019, Номер 22(5), С. 719 - 728

Опубликована: Апрель 1, 2019

Язык: Английский

---

Cellular senescence and senolytics: the path to the clinic

Nature Medicine, Год журнала: 2022, Номер 28(8), С. 1556 - 1568

Опубликована: Авг. 1, 2022

Язык: Английский

---

Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

Aging Cell, Год журнала: 2019, Номер 18(3)

Опубликована: Март 25, 2019

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance diabetes, but mechanisms underlying this relationship unclear. Although senescent cells accumulate in adipose of obese humans rodents, a direct pathogenic role for these the development diabetes remains to be demonstrated. Here, we show that reducing cell burden mice, either by activating drug-inducible "suicide" genes driven p16

Язык: Английский

---

Tau protein aggregation is associated with cellular senescence in the brain

Aging Cell, Год журнала: 2018, Номер 17(6)

Опубликована: Авг. 20, 2018

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic injury (TBI), and over twenty others. Tau-containing neurofibrillary tangle (NFT) closest correlate with cognitive decline cell loss (Arriagada, Growdon, Hedley-Whyte, & Hyman, ), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires-Jones, Pitstick, Carlson, 2009), which suggests that secondary driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD revealed an expression profile consistent cellular senescence. This complex stress response induces aberrant cycle activity, adaptations to maintain survival, remodeling, metabolic dysfunction. Using four transgenic mouse models, we found NFTs, but Aβ plaques, display a senescence-like phenotype. Cdkn2a transcript level, hallmark measure senescence, directly correlated atrophy burden in mice. relationship extended tissue humans PSP indicate phenomenon mice late-stage were treated senolytics remove senescent cells. Despite advanced age progression, MRI imaging histopathological indicated reduction total density, neuron loss, ventricular enlargement. Collectively, these findings strong association between presence NFTs senescence brain, contributes neurodegeneration. Given prevalence deposition neurodegenerative have broad implications for understanding, potentially treating, dozens diseases.

Язык: Английский

---