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1.
Nat Rev Immunol ; 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-2050403

ABSTRACT

The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a 'cytokine storm', tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.

2.
Ann N Y Acad Sci ; 1507(1): 70-83, 2022 01.
Article in English | MEDLINE | ID: covidwho-1673249

ABSTRACT

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.


Subject(s)
Aging/genetics , Aging/metabolism , Congresses as Topic/trends , Longevity/physiology , Research Report , Autophagy/physiology , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/therapy , Humans , Metabolomics/methods , Metabolomics/trends , Nervous System Diseases/genetics , Nervous System Diseases/metabolism , Nervous System Diseases/therapy , Stem Cell Transplantation/methods , Stem Cell Transplantation/trends
3.
Aging (Albany NY) ; 13(18): 21838-21854, 2021 09 16.
Article in English | MEDLINE | ID: covidwho-1417382

ABSTRACT

Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse ß-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3). TLR-3, which senses viral RNA, was increased in human senescent compared to non-senescent cells. Notably, genetically or pharmacologically inhibiting TLR-3 prevented senescence induction and SASP amplification by SARS-CoV-2 or Spike pseudotyped virus. While an artificial TLR-3 agonist alone was not sufficient to induce senescence, it amplified the SASP in senescent human cells. Consistent with these findings, lung p16INK4a+ senescent cell burden was higher in patients who died from acute SARS-CoV-2 infection than other causes. Our results suggest that induction of cellular senescence and SASP amplification through TLR-3 contribute to SARS-CoV-2 morbidity, indicating that clinical trials of senolytics and/or SASP/TLR-3 inhibitors for alleviating acute and long-term SARS-CoV-2 sequelae are warranted.


Subject(s)
COVID-19/virology , Cellular Senescence , SARS-CoV-2/pathogenicity , Toll-Like Receptor 3/metabolism , Aging , Animals , Apoptosis , COVID-19/drug therapy , COVID-19/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Humans , Inflammation , Lung/metabolism , Mice , Phenotype , Viral Proteins
4.
J Am Geriatr Soc ; 69(11): 3023-3033, 2021 11.
Article in English | MEDLINE | ID: covidwho-1367342

ABSTRACT

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.


Subject(s)
COVID-19/drug therapy , Cellular Senescence/drug effects , Flavonols/therapeutic use , Skilled Nursing Facilities , Aged , COVID-19/prevention & control , Clinical Trials as Topic , Drug Monitoring , Humans
5.
Science ; 373(6552)2021 07 16.
Article in English | MEDLINE | ID: covidwho-1262378

ABSTRACT

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse ß-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.


Subject(s)
Aging , Cellular Senescence/drug effects , Coronavirus Infections/mortality , Flavonols/therapeutic use , Pathogen-Associated Molecular Pattern Molecules/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/drug therapy , COVID-19/immunology , COVID-19/mortality , Cell Line , Coronavirus Infections/immunology , Dasatinib/pharmacology , Dasatinib/therapeutic use , Female , Flavonols/pharmacology , Gene Expression Regulation , Humans , Lipopolysaccharides , Male , Mice , Mice, Inbred C57BL , Murine hepatitis virus/immunology , Quercetin/pharmacology , Quercetin/therapeutic use , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , Specific Pathogen-Free Organisms
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