Reducing burden and building goodwill for practice-embedded trials: Results of rapid qualitative methods in the preimplementation phase of a community paramedic trial to reduce hospitalizations.

Pragmatic trials aim to generate timely evidence while ensuring feasibility, minimizing practice burden, and maintaining real-world conditions. We conducted rapid-cycle qualitative research in the preimplementation period of a trial evaluating a community paramedic program to shorten and prevent hospitalizations. Between December 2021 and March 2022, interviews (n = 30) and presentations/discussions (n = 17) were conducted with clinical and administrative stakeholders. Two investigators analyzed interview and presentation data to identify potential trial challenges, and team reflections were used to develop responsive strategies. Solutions were implemented prior to the commencement of trial enrollment and were aimed at bolstering feasibility and building ongoing practice feedback loops.

Role of senescence in the chronic health consequences of COVID-19.

While the full impact of COVID-19 is not yet clear, early studies have indicated that upwards of 10% of patients experience COVID-19 symptoms longer than 3 weeks, known as Long-Hauler's Syndrome or PACS (postacute sequelae of SARS-CoV-2 infection). There is little known about risk factors or predictors of susceptibility for Long-Hauler's Syndrome, but older adults are at greater risk for severe outcomes and mortality from COVID-19. The pillars of aging (including cellular senescence, telomere dysfunction, impaired proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, genomic instability, progenitor cell exhaustion, altered intercellular communication, and epigenetic alterations) that contribute to age-related dysfunction and chronic diseases (the "Geroscience Hypothesis") may interfere with defenses against viral infection and consequences of these infections. Heightening of the low-grade inflammation that is associated with aging may generate an exaggerated response to an acute COVID-19 infection. Innate immune system dysfunction that leads to decreased senescent cell removal and/or increased senescent cell formation could contribute to accumulation of senescent cells with both aging and viral infections. These processes may contribute to increased risk for long-term COVID-19 sequelae in older or chronically ill patients. Hence, senolytics and other geroscience interventions that may prolong healthspan and alleviate chronic diseases and multimorbidity linked to fundamental aging processes might be an option for delaying, preventing, or alleviating Long-Hauler's Syndrome.

Strategies for late phase preclinical and early clinical trials of senolytics.

Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.

Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era.

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.

Discovery, development, and future application of senolytics: theories and predictions.

Senescent cells accumulate with aging and at etiological sites of multiple diseases, including those accounting for most morbidity, mortality, and health costs. Senescent cells do not replicate, can release factors that cause tissue dysfunction, and yet remain viable. The discovery of senolytic drugs, agents that selectively eliminate senescent cells, created a new route for alleviating age-related dysfunction and diseases. As anticipated for agents targeting fundamental aging mechanisms that are 'root cause' contributors to multiple disorders, potential applications of senolytics are protean. We review the discovery of senolytics, strategies for translation into clinical application, and promising early signals from clinical trials.

Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases.

Aging is the major predictor for developing multiple neurodegenerative diseases, including Alzheimer's disease (AD) other dementias, and Parkinson's disease (PD). Senescent cells, which can drive aging phenotypes, accumulate at etiological sites of many age-related chronic diseases. These cells are resistant to apoptosis and can cause local and systemic dysfunction. Decreasing senescent cell abundance using senolytic drugs, agents that selectively target these cells, alleviates neurodegenerative diseases in preclinical models. In this review, we consider roles of senescent cells in neurodegenerative diseases and potential implications of senolytic agents as an innovative treatment.

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

BACKGROUND: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. METHODS: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ±â€¯3·1 years old; 2 female; BMI:33·9 ±â€¯2·3 kg/m2; eGFR:27·0 ±â€¯2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. FINDINGS: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ß-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. INTERPRETATION: "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.