Senolytics reduce coronavirus-related mortality in old mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Camell CD
PROVIDER: S-EPMC8607935 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:With aging, skeletal muscle plasticity is attenuated in response to exercise. Here, we report that senescent cells, identified using senescence markers senescence-associated β-Galactosidase (SA β-Gal) and p21 are very infrequent in resting muscle but emerge approximately two-weeks after a bout of resistance exercise in humans. We hypothesized that these cells contribute to blunted hypertrophic potential in old age. Using synergist ablation-induced mechanical overload of the plantaris muscle to model resistance training in adult (5-6 month) and old (23-24 month) male C57BL/6J mice, we found increased senescent cells in both age groups during hypertrophy. Consistent with the human data, there were negligible senescent cells in adult and old sham controls, but old mice had significantly more senescent cells 7- and 14-days following overload relative to young. Old mice had blunted whole muscle hypertrophy when compared to adult mice, along with smaller muscle fibers, specifically glycolytic Type 2x+2b fibers. To ablate senescent cells using a hit-and-run approach, old mice were treated with vehicle or a senolytic cocktail consisting of 5 mg/kg dasatinib and 50 mg/kg quercetin (D+Q) on day 7 and 10 during 14-days of overload; control mice underwent sham surgery with or without senolytic treatment. Old mice given D+Q had larger muscles and muscle fibers after 14 days of overload, fewer senescent cells when compared to vehicle-treated old mice, and changes in the expression of genes (i.e., Igf1, Ddit4, Mmp14) that are associated with hypertrophic growth . Our data collectively show that senescent cells emerge in human and mouse skeletal muscle following a hypertrophic stimulus, and that D+Q improves muscle growth in old mice.
2022-05-29 | GSE195707 | GEO
Project description:Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
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Project description:Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.
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Project description:Aging is one of the major risk factors for degenerative joint disorders, including those involving the temporomandibular joint (TMJ). TMJ degeneration occurs primarily in the population over 65, significantly increasing the risk of joint discomfort, restricted joint mobility, and reduced quality of life. Unfortunately, there is currently no effective mechanism-based treatment available in the clinic to alleviate TMJ degeneration with aging. We now demonstrate that intermittent administration of senolytics, drugs which can selectively clear senescent cells, preserved mandibular condylar cartilage thickness, improved subchondral bone volume and turnover, and reduced Osteoarthritis Research Society International (OARSI) histopathological score in both 23- to 24-month-old male and female mice. Senolytics had little effect on 4 months old young mice, indicating age-specific benefits. Our study provides proof-of-concept evidence that age-related TMJ degeneration can be alleviated by pharmaceutical intervention targeting cellular senescence. Since the senolytics used in this study have been proven relatively safe in recent human studies, our findings may help justify future clinical trials addressing TMJ degeneration in old age.
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Project description:We report RNA-seq of skeletal muscle (quadriceps) of young (6-month), old (24-month), and senolytic (Dasatinib + quercetin) treated mice
2022-05-20 | GSE184348 | GEO
Project description:Senolytics rescue blunted muscle hypertrophy in old mice
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Project description:OBJECTIVE:To replicate and analyse the information available to UK policymakers when the lockdown decision was taken in March 2020 in the United Kingdom. DESIGN:Independent calculations using the CovidSim code, which implements Imperial College London's individual based model, with data available in March 2020 applied to the coronavirus disease 2019 (covid-19) epidemic. SETTING:Simulations considering the spread of covid-19 in Great Britain and Northern Ireland. POPULATION:About 70 million simulated people matched as closely as possible to actual UK demographics, geography, and social behaviours. MAIN OUTCOME MEASURES:Replication of summary data on the covid-19 epidemic reported to the UK government Scientific Advisory Group for Emergencies (SAGE), and a detailed study of unpublished results, especially the effect of school closures. RESULTS:The CovidSim model would have produced a good forecast of the subsequent data if initialised with a reproduction number of about 3.5 for covid-19. The model predicted that school closures and isolation of younger people would increase the total number of deaths, albeit postponed to a second and subsequent waves. The findings of this study suggest that prompt interventions were shown to be highly effective at reducing peak demand for intensive care unit (ICU) beds but also prolong the epidemic, in some cases resulting in more deaths long term. This happens because covid-19 related mortality is highly skewed towards older age groups. In the absence of an effective vaccination programme, none of the proposed mitigation strategies in the UK would reduce the predicted total number of deaths below 200?000. CONCLUSIONS:It was predicted in March 2020 that in response to covid-19 a broad lockdown, as opposed to a focus on shielding the most vulnerable members of society, would reduce immediate demand for ICU beds at the cost of more deaths long term. The optimal strategy for saving lives in a covid-19 epidemic is different from that anticipated for an influenza epidemic with a different mortality age profile.
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Project description:Pneumonia-related mortality is expected to increase in aging societies. This prospective cohort study examined whether daily walking (1?hour/day) could reduce pneumonia-related mortality among older people who lacked other exercise habits. We analysed data from Japanese Specific Health Checkup across 82 municipalities in 7 prefectures among participants aged ?65 years who participated in daily walking but did not regularly engage in other forms of exercise (n?=?132,448). Information on walking habits and health-related indicators was assessed at a baseline survey conducted between 2008 and 2014. Pneumonia-related and all-cause mortality were followed for a median of 3.4 years. We performed a competing risk model with propensity score matching to evaluate the association between daily walking habits and pneumonia-related mortality. Our propensity-matched analysis revealed a significant association between daily walking and pneumonia-related mortality among older people who lacked other exercise habits, such that the sub-hazard ratio and 95% confidence intervals were 0.58 (0.39, 0.86). This study extends the findings of previous research on the effects of exercise on pneumonia by demonstrating that daily walking alone is sufficient to reduce pneumonia-related mortality among older people who do not regularly engage in other exercise habits.
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Project description:ImportanceThe US opioid epidemic is complex and dynamic, yet relatively little is known regarding its likely future impact and the potential mitigating impact of interventions to address it.ObjectiveTo estimate the future burden of the opioid epidemic and the potential of interventions to address the burden.Design, setting, and participantsA decision analytic dynamic Markov model was calibrated using 2010-2018 data from the National Survey on Drug Use and Health, Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey, the US Census, and National Epidemiologic Survey on Alcohol and Related Conditions-III. Data on individuals 12 years or older from the US general population or with prescription opioid medical use; prescription opioid nonmedical use; heroin use; prescription, heroin, or combined prescription and heroin opioid use disorder (OUD); 1 of 7 treatment categories; or nonfatal or fatal overdose were examined. The model was designed to project fatal opioid overdoses between 2020 and 2029.ExposuresThe model projected prescribing reductions (5% annually), naloxone distribution (assumed 5% reduction in case-fatality), and treatment expansion (assumed 35% increase in uptake annually for 4 years and 50% relapse reduction), with each compared vs status quo.Main outcomes and measuresProjected 10-year overdose deaths and prevalence of OUD.ResultsUnder status quo, 484 429 (95% confidence band, 390 543-576 631) individuals were projected to experience fatal opioid overdose between 2020 and 2029. Projected decreases in deaths were 0.3% with prescribing reductions, 15.4% with naloxone distribution, and 25.3% with treatment expansion; when combined, these interventions were associated with 179 151 fewer overdose deaths (37.0%) over 10 years. Interventions had a smaller association with the prevalence of OUD; for example, the combined intervention was estimated to reduce OUD prevalence by 27.5%, from 2.47 million in 2019 to 1.79 million in 2029. Model projections were most sensitive to assumptions regarding future rates of fatal and nonfatal overdose.Conclusions and relevanceThe findings of this study suggest that the opioid epidemic is likely to continue to cause tens of thousands of deaths annually over the next decade. Aggressive deployment of evidence-based interventions may reduce deaths by at least a third but will likely have less impact for the number of people with OUD.
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Project description:The osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) declines dramatically with aging. By using a calvarial defect model, we showed that a senolytic cocktail (dasatinib+quercetin; D + Q) improved osteogenic capacity of aged BMSC both in vitro and in vivo. The study presented a model to assess strategies to improve bone-forming potential on aged BMSCs. D + Q might hold promise for improving BMSC function in aged populations.
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