Past and Future Directions for Research on Cellular Senescence.

Cellular senescence was initially described in the early 1960s by Hayflick and Moorehead. They noted sustained cell-cycle arrest after repeated subculturing of human primary cells. Over half a century later, cellular senescence has become recognized as one of the fundamental pillars of aging. Developing senotherapeutics, interventions that selectively eliminate or target senescent cells, has emerged as a key focus in health research. In this article, we note major milestones in cellular senescence research, discuss current challenges, and point to future directions for this rapidly growing field.

Incidence of Respiratory Syncytial Virus Infection in Older Adults Before and During the COVID-19 Pandemic.

Importance: Little is known about the burden and outcomes of respiratory syncytial virus (RSV)-positive acute respiratory infection (ARI) in community-dwelling older adults. Objective: To assess the incidence of RSV-positive ARI before and during the COVID-19 pandemic, and to assess outcomes for RSV-positive ARI in older adults. Design, Setting, and Participants: This was a community-based cohort study of adults residing in southeast Minnesota that followed up with 2325 adults aged 50 years or older for 2 RSV seasons (2019-2021) to assess the incidence of RSV-positive ARI. The study assessed outcomes at 2 to 4 weeks, 6 to 7 months, and 12 to 13 months after RSV-positive ARI. Exposure: RSV-positive and -negative ARI. Main Outcomes and Measures: RSV status was the main study outcome. Incidence and attack rates of RSV-positive ARI were calculated during each RSV season, including before (October 2019 to April 2020) and during (October 2020 to April 2021) COVID-19 pandemic, and further calculated during non-RSV season (May to September 2021) for assessing impact of COVID-19. The self-reported quality of life (QOL) by Short-Form Health Survey-36 (SF-36) and physical functional measures (eg, 6-minute walk and spirometry) at each time point was assessed. Results: In this study of 2325 participants, the median (range) age of study participants was 67 (50-98) years, 1380 (59%) were female, and 2240 (96%) were non-Hispanic White individuals. The prepandemic incidence rate of RSV-positive ARI was 48.6 (95% CI, 36.9-62.9) per 1000 person-years with a 2.50% (95% CI, 1.90%-3.21%) attack rate. No RSV-positive ARI case was identified during the COVID-19 pandemic RSV season. Incidence of 10.2 (95% CI, 4.1-21.1) per 1000 person-years and attack rate of 0.42%; (95% CI, 0.17%-0.86%) were observed during the summer of 2021. Based on prepandemic RSV season results, participants with RSV-positive ARI (vs matched RSV-negative ARI) reported significantly lower QOL adjusted mean difference (limitations due to physical health, -16.7 [95% CI, -31.8 to -1.8]; fatigue, -8.4 [95% CI, -14.3 to -2.4]; and difficulty in social functioning, -11.9 [95% CI, -19.8 to -4.0] within 2 to 4 weeks after RSV-positive ARI [ie, short-term outcome]). Compared with participants with RSV-negative ARI, those with RSV-positive ARI also had lower QOL (fatigue: -4.0 [95% CI, -8.5 to -1.3]; difficulty in social functioning, -5.8 [95% CI, -10.3 to -1.3]; and limitation due to emotional problem, -7.0 [95% CI, -12.7 to -1.3] at 6 to 7 months after RSV-positive ARI [intermediate-term outcome]; fatigue, -4.4 [95% CI, -7.3 to -1.5]; difficulty in social functioning, -5.2 [95% CI, -8.7 to -1.7] and limitation due to emotional problem, -5.7 [95% CI, -10.7 to -0.6] at 12-13 months after RSV-positive ARI [ie, long-term outcomes]) independent of age, sex, race and/or ethnicity, socioeconomic status, and high-risk comorbidities. Conclusions and Relevance: In this cohort study, the burden of RSV-positive ARI in older adults during the pre-COVID-19 period was substantial. After a reduction of RSV-positive ARI incidence from October 2020 to April 2021, RSV-positive ARI re-emerged during the summer of 2021. RSV-positive ARI was associated with significant long-term lower QOL beyond the short-term lower QOL in older adults.

Adherence to Public Health Measures Mitigates the Risk of COVID-19 Infection in Older Adults: A Community-Based Study.

OBJECTIVE: To assess the prevalence and characteristics of coronavirus disease 2019 (COVID-19) cases during the reopening period in older adults, given that little is known about the prevalence of COVID-19 after the stay-at-home order was lifted in the United States, nor the actual effects of adherence to recommended public health measures (RPHM) on the risk of COVID-19. PATIENTS AND METHODS: This was a cross-sectional study nested in a parent prospective cohort study, which followed a population-based sample of 2325 adults 50 years and older residing in southeast Minnesota to assess the incidence of viral infections. Participants were instructed to self-collect both nasal and oropharyngeal swabs, which were tested by reverse transcription polymerase chain reaction-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assay between May 8, 2020, and June, 30, 2020. We assessed the prevalence of COVID-19 cases and characteristics of study subjects. RESULTS: A total of 1505 eligible subjects participated in the study whose mean age was 68 years, with 885 (59%) women, 32 (2%) racial/ethnic minorities, and 906 (60%) with high-risk conditions for influenza. The prevalence of other Coronaviridae (human coronavirus [HCoV]-229E, HCoV-NL63, and HCoV-OC43) during the 2019 to 2020 flu season was 109 (7%), and none tested positive for SARS-CoV-2. Almost all participants reported adhering to the RPHM (1,488 [99%] for social distancing, 1,438 [96%] for wearing mask in a public space, 1,476 [98%] for hand hygiene, and 1,441 (96%) for staying home mostly). Eighty-six percent of participants resided in a single-family home. CONCLUSION: We did not identify SARS-COV-2 infection in our study cohort. The combination of participants' behavior in following the RPHM and their living environment may considerably mitigate the risk of COVID-19.

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.

Effect of time to titration to maximum dose of statins on cardiovascular outcomes: a retrospective analysis in high-risk patients.

BACKGROUND: Recent trials have shown that high-dose HMG-CoA reductase inhibitor (statin) therapy reduces cardiovascular events in high-risk subjects within weeks of initiating therapy. We investigated the effect of time to titration to maximum dose of statin therapy on cardiovascular events. METHODS: From a list of all patients actively taking simvastatin 80 mg/day as of April 2003 at our hospital, two clinical pharmacists reviewed 213 electronic medical records including pharmacy records from November 1992 to April 2003. Data on cardiovascular risk factors, laboratory results, titration schedules, and outcomes were extracted from the electronic database. RESULTS: Titration period time frames were compared between patient groups using a Student t-test and multiple-variable logistic regression to account for other risk factors. Titration schedules and time frames to attain a regimen of simvastatin 80 mg/day were available for 154 (73%) subjects. Titrations ranged from 1 to 8 and averaged 2.3 +/- 1.3 titrations per patient (median titrations = 2) over 1 month to 8.4 years. On follow-up, 47 patients experienced 80 cardiovascular-related outcomes. The average time to titration to maximum dose of statin therapy was longer for patients who experienced a cardiac event than for those who did not (3.5 +/- 2.2 vs 2.1 +/- 1.8 years; p = 0.0004). After accounting for other risk factors, the titration period was still significantly related to the presence of a cardiac event (p = 0.0060, odds ratio per month increase in the titration period 1.3, 95% CI 1.08, 1.58). CONCLUSIONS: Despite potential limitations, the results of our study show that an excessive delay in titrating statin therapy to the optimal dose may lead to an increased risk of atherosclerosis-related events in high-risk patients.

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.

Effect of 80 mg/day simvastatin therapy on cardiovascular outcomes in adults with versus without metabolic syndrome.

It is not known whether high-dose statins can reduce the excess burden (and consequent adverse cardiovascular outcomes) of coronary artery disease in patients with metabolic syndrome compared with those without metabolic syndrome. The results of our study suggest that high-dose simvastatin may be required to reduce excess events in very high-risk cohorts with metabolic syndrome.

A review of the management of heart failure in long-term care residents.

OBJECTIVE: The objective of this study was to describe the characteristics of long-term care residents with heart failure (HF), to evaluate the management of HF, and to compare their management with nationally published American College of Cardiology/American Heart Association guidelines. DESIGN/SETTING: Residents in long-term care facilities were identified by diagnosis of HF within their electronic medical record. PARTICIPANTS: Data were collected on 302 residents in 19 long-term care facilities. The average age of the study population was 83.2 +/- 11.1 years and comprised 68.5% females. RESULTS: Diabetes, obesity, hypertension, coronary artery disease, dementia, and hypothyroidism were identified in greater than 30% of residents. A diuretic was prescribed in 76.8% of residents. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers were prescribed to 40.7% and 38.4% of residents, respectively; 16.2% of residents received both agents. Residents with diabetes or hypertension were not prescribed ACE inhibitors more often than residents without these comorbidities. Digoxin was prescribed more frequently in residents with atrial fibrillation (P = 0.028). Hospital admissions related to HF were documented in 30 (9.9%) residents within the past 12 months. CONCLUSIONS: According to guidelines, most patients with HF should be routinely managed with a combination of four types of drugs: a diuretic, an ACE inhibitor, a betablocker, and, often, digoxin. Improvement in HF outcomes resulting in reduced morbidity and mortality may be achieved through greater adherence to nationally recognized guidelines. Opportunities exist for health care professionals to improve the management of residents with HF through appropriate drug therapy management.

The Challenge of Managing Psoriasis: Unmet Medical Needs and Stakeholder Perspectives.

BACKGROUND: Psoriasis is a debilitating chronic inflammatory autoimmune disease affecting approximately 7.4 million adults in the United States. Plaque psoriasis is the most common form, affecting 80% to 90% of patients. OBJECTIVES: To describe the impact and challenges that psoriasis presents for various stakeholders, and to provide nondermatologist healthcare decision makers with information to enhance their contributions to drug and pharmacy benefit design discussions. DISCUSSION: Psoriasis carries an increased risk for early mortality and an increased prevalence of comorbidities, including psoriatic arthritis, cardiovascular disease, and diabetes. It is also associated with anxiety, depression, and social isolation, and can negatively impact patients' relationships, productivity, and careers. The physical, psychologic, social, and economic impact of psoriasis, plus the associated stigma, result in cumulative impairment over a patient's lifetime. The current treatments for moderate-to-severe psoriasis include topical therapy, phototherapy, and systemic drugs (nonbiologic and biologic); however, patient satisfaction remains low, combination therapy and treatment switching are common, and many patients remain untreated or undertreated. Clinicians should consider the patient holistically, and should select treatment based on a range of factors, including disease severity (with physical and psychosocial manifestations), susceptibility to cumulative life-course impairment (considering personality, behavior, and cognition), comorbidities, concomitant medication, and patient preference. It is estimated that the total annual direct cost of treating psoriasis in the United States in 2015 exceeded $12.2 billion. CONCLUSION: Psoriasis is a complex disease, and appropriate management is correspondingly complex. Newer psoriasis treatments provide improved efficacy and safety versus traditional treatments, but challenges remain in ensuring patients access to these medications. An improved understanding of the barriers to appropriate treatment is needed, as well as clear and accessible information for payers and clinicians on current treatment options, to ensure that decision makers can control costs while providing patients with optimal care.

Medication adherence trends with statins.

Lipid-lowering medication can significantly reduce the risk for cardiac events in patients with dyslipidemia. Despite well-publicized guidelines and the availability of potentially effective therapies, many patients do not achieve their lipid goals and remain at high risk for cardiac events because of poor adherence. To assess adherence to statin therapy based on an analysis of pharmacy records, the records of 562 patients were screened. A washout rule, designed to ensure that only new medication starts were analyzed, resulted in the inclusion of 140 records in this study. Dates of prescription fillings, drug name and strength, quantity dispensed, and the number of days supplied were recorded. Length of therapy, persistence, medication possession ratio (MPR), and median gap between prescriptions were calculated. Overall persistence declined from 56% at 9 months to 35% at 12 months. Persistence at the study end point was 34% for men, 18% for women, 19% for patients younger than 65 years, and 41% for patients aged 65 years and older. The median number of gap days between prescription refills was 6.83 for all patients and was approximately 7 days longer for women than for men. The number of gap days differed only slightly for patients younger than 65 years compared with patients aged 65 years or older (6.44 vs 7.41, respectively). MPRs ranged from 0.64 to 0.56, with no substantive between-group differences. Among the statins used most often in this study, persistence was highest with atorvastatin (36%) compared with simvastatin (26%) and pravastatin (5%). Adherence to statin therapy can result in significant improvement. In patients with dyslipidemia, personal interventions by healthcare providers can improve compliance with potentially effective therapy.

An assessment of the diagnosis and management of dementia in nursing homes.

OBJECTIVES: The purpose of this study was to evaluate the diagnosis and management of dementia in the nursing home setting through use of the Mini-Mental State Examination (MMSE) and monitoring of acetylcholinesterase-inhibitor (ACHEI) therapy. DESIGN: Longitudinal cross-sectional study. SETTING: Long-term care facilities in Indiana. PATIENTS: Residents in long-term care facilities were included. MAIN OUTCOME MEASURES: The number of residents with MMSE scores indicative of dementia, the presence of a dementia diagnosis, and receipt of ACHEI therapy. RESULTS: Data were collected on 782 residents. An MMSE score was available within the past 12 months in 456 (58.3%) of residents. The median MMSE score was 17 and ranged from 0 to 30 points. Out of the total population, ACHEI therapy was prescribed in 165 (21.1%) residents. Seventy-five (29.2%) of the residents with mild-moderate dementia (MMSE = 10-26) were prescribed ACHEI therapy. The most frequently prescribed ACHEI was donepezil 10 mg/day prescribed in 98 (59.4%) of the residents receiving ACHEI therapy. Average length of ACHEI therapy was 9.0 months. CONCLUSION: MMSE scores were not available in a large proportion of this nursing home population (41.7%). Of those residents with an available MMSE score, a significant number of them had scores indicative of dementia. Despite having scores indicative of dementia, 182 (70.8%) residents were not receiving AChEI therapy. An assessment to determine why residents were not receiving therapy is needed. Opportunities exist to improve the screening, diagnosis, and treatment of dementia in the nursing home setting.

Developing a clinical trial unit to advance research in an academic institution.

Research, clinical care, and education are the three cornerstones of academic health centers in the United States. The research climate has always been riddled with ebbs and flows, depending on funding availability. During a time of reduced funding, the number and scope of research studies have been reduced, and in some instances, a field of study has been eliminated. Recent reductions in the research funding landscape have led institutions to explore new ways to continue supporting research. Mayo Clinic in Rochester, MN has developed a clinical trial unit within the Department of Medicine, which provides shared resources for many researchers and serves as a solution for training and mentoring new investigators and study teams. By building on existing infrastructure and providing supplemental resources to existing research, the Department of Medicine clinical trial unit has evolved into an effective mechanism for conducting research. This article discusses the creation of a central unit to provide research support in clinical trials and presents the advantages, disadvantages, and required building blocks for such a unit.

Evaluating the response of patients undergoing both allergy skin testing and in vitro allergy testing with the ImmunoCAP Technology System.

PURPOSE: To evaluate the response of patients who underwent both skin and in vitro allergy testing, both of which are accepted methods. DATA SOURCES: Retrospective review of the case notes of 100 patients evaluated by both testing methods for allergic disease. CONCLUSIONS: A total of 62 patients (62%) tested positive to at least one of the tested allergens via the in vitro method. A total of 65 patients (65%) tested positive to at least one allergen via the skin-testing method. The most frequently elicited allergic response from the in vitro method was to white oak. Indoor mold and dust most frequently elicited response via skin testing. IMPLICATIONS FOR PRACTICE: Both in vitro and in vivo allergy testing have limitations. Practitioners should be aware of these when establishing a treatment plan based on the results of differing allergy testing methods. Due to differing responses to skin and in vitro testing methods, it may be prudent to perform both tests to obtain a definitive diagnosis for the allergic patient.

Gastrointestinal-related complications in a long-term care population taking NSAIDs versus COX-2 inhibitor therapy.

OBJECTIVES: To determine the following in a long-term care population taking traditional nonsteroidal anti-inflammatory drug (NSAID) or cyclo-oxygenase-2 (COX-2) inhibitor therapy: (1) incidence of gastrointestinal (GI) adverse events and GI-related hospitalizations, (2) prevalence of GI-protective medication use, and (3) prevalence of GI risk factors as defined by Indiana Medicaid prior-authorization criteria. DESIGN: Longitudinal cross-sectional study. SETTING: Long-term care facilities in Indiana. PATIENTS: Residents in long-term care and assisted-living facilities were included if they were receiving either traditional NSAID or COX-2 inhibitor therapy. MAIN OUTCOME MEASURES: The number of residents experiencing GI intolerance or complications or GI-related hospitalizations associated with NSAID or COX-2 inhibitor use. RESULTS: Over this 14-month evaluation period, 1,198 long-term care and assisted living residents were identified as receiving NSAID or COX-2 inhibitor therapy. Celecoxib was the most frequently prescribed medication used in this population. Age >70 years and concomitant aspirin use were the most frequently noted risk factors for GI disease. Significantly fewer GI complications were observed in COX-2 recipients (4.0%) compared with NSAID users (8.4%) (P = 0.002). GI-related hospitalizations occurred significantly less with COX-2 use (2.0%) compared with traditional NSAID use (4.5%) (P = 0.014). A relatively low incidence of GI-related events also was associated with ibuprofen use. CONCLUSION: Individuals residing in assisted living or long-term care settings had lower rates of GI complications and hospitalizations related to COX-2 inhibitors compared with traditional NSAIDs.

The use of medications with known or potential anticholinergic activity in patients with dementia receiving cholinesterase inhibitors.

OBJECTIVES: To assess the prevalence of prescribed medications with anticholinergic activity given concurrently with acetylcholinesterase-inhibitor therapy in long-term care residents with dementia and to recommend dose adjustment or discontinuation of these medications with anticholinergic activity. DESIGN: Prospective case series. SETTING: Long-term care facilities in Indiana. PATIENTS: Geriatric residents in long-term care facilities were included if they were receiving both an agent with anticholinergic activity as determined by radioreceptor assay and an acetylcholinesterase inhibitor. INTERVENTIONS: Recommendations were made to the resident's physician suggesting substitution, dose reduction, or discontinuation of the agent with anticholinergic activity. MAIN OUTCOME MEASURES: The number of residents with a recommended change in their anticholinergic medication regimen as a result of the consultant pharmacist's recommendation. RESULTS: Of the 2,021 long-term care residents evaluated, 498 (25%) were receiving an acetylcholinesterase inhibitor. Of the 498 residents receiving acetylcholinesterase inhibitor therapy, 103 (20.7%) were receiving concurrent medications with anticholinergic activity. The most commonly prescribed medication with anticholinergic activity was furosemide, an agent with "possible" or low anticholinergic effects. One hundred forty-six medications with anticholinergic activity were used in these 103 residents. Overall, adjustments to the agents with anticholinergic activity were completed in 24 (16.4%) cases. The majority of medications prescribed had "possible" anticholinergic activity (62.3%) compared with those prescribed with "definite" anticholinergic activity (37.7%). No medication dose adjustments or discontinuations were frequent, regardless of whether the medication was deemed to have "definite" (29.1%) or "possible" (31.9%) anticholinergic activity. Medication changes or discontinuations occurred in 13 (23.6%) agents with "definite" and 11 (12.1%) agents with "possible" anticholinergic activity. CONCLUSIONS: Medications with anticholinergic activity may interfere with the beneficial effects of acetylcholinesterase inhibitors. Attention should be placed, however, on agents with moderate or strong anticholinergic activity or the use of multiple medications with anticholinergic activity. Health care providers should consider the risk versus benefit of using agents with anticholinergic activity in someone with cognitive impairment receiving an acetylcholinesterase inhibitor.