Search

Age is among the main risk factors for cancer and any cancer study in adults is faced with an aging tissue and organism. Yet, pre-clinical studies are carried out using young mice and are not able address the impact of aging and associated comorbidities on disease biology and treatment outcomes. Here, we discuss the limitations of current mouse cancer models and suggest strategies for developing novel models to address these major gaps in knowledge and experimental approaches.

Volume hyposensitivity resulting from impaired sympathetic detrusor relaxation during bladder filling contributes to detrusor underactivity (DU) associated with aging. Detrusor tension regulation provides an adaptive sensory input of bladder volume to the brainstem and is challenged by physiological stressors superimposed upon biological aging. We recently showed that HCN channels have a stabilizing role in detrusor sympathetic relaxation. While mature mice maintain homeostasis in the face of stressors, old mice are not always capable. In old mice, there is a dichotomous phenotype, in which resilient mice adapt and maintain homeostasis, while non-resilient mice fail to maintain physiologic homeostasis. In this DU model, we used cystometry as a stressor to categorize mice as old-responders (old-R, develop a filling/voiding cycle) or old-non-responders (old-NR, fail to develop a filling/voiding cycle; fluctuating high pressures and continuous leaking), while also assessing functional and molecular differences. Lamotrigine (HCN activator)-induced bladder relaxation is diminished in old-NR mice following HCN-blockade. Relaxation responses to NS 1619 were reduced in old-NR mice, with the effect lost following HCN-blockade. However, RNA-sequencing revealed no differences in HCN gene expression and electrophysiology studies showed similar percentage of detrusor myocytes expressing HCN (I(h)) current between old-R and old-NR mice. Our murine model of DU further defines a role for HCN, with failure of adaptive recalibration of HCN participation and intensity of HCN-mediated stabilization, while genomic studies show upregulated myofibroblast and fibrosis pathways and downregulated neurotransmitter-degradation pathways in old-NR mice. Thus, the DU phenotype is multifactorial and represents the accumulation of age-associated loss in homeostatic mechanisms.

Senescent cells are highly associated with aging and pathological conditions and could be targeted to slow the aging process. One commonly used marker to examine senescent cells in vivo is p16, which has led to important discoveries. Recent studies have also described new senescence markers beyond p16 and have highlighted the importance of investigating senescence heterogeneity in cell types and tissues. With the development of high-throughput technologies, such as single-cell RNA-seq and single-nucleus RNA-seq, we can examine senescent cells at the single-cell level and potentially uncover new markers. This review emphasizes that there is an urgent need to investigate senescence heterogeneity and discuss how this could be accomplished by using advanced technologies and sequencing datasets.

Background and ObjectivesDNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults.MethodsWe tested 3 “generations” of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia.ResultsIn ADNI (N = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08–0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = −0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = −0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort (N = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07–1.49]).DiscussionThird-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.

The endocannabinoid system (ECS) participates in regulating whole body energy balance. Overactivation of the ECS has been associated with the negative consequence of obesity and type 2 diabetes. Since activators of the ECS rely on lipid-derived ligands, an investigation was conducted to determine whether dietary PUFA could influence the ECS to affect glucose clearance by measuring metabolites of macronutrient metabolism. C57/blk6 mice were fed a control or DHA-enriched semi-purified diet for a period of 112 d. Plasma, skeletal muscle, and liver were collected after 56 d and 112 d of feeding the diets for metabolomics analysis. Key findings characterized a shift in glucose metabolism and greater catabolism of fatty acids in mice fed the DHA diet. Glucose use and promotion of fatty acids as substrate were found based on levels of metabolic pathway intermediates and altered metabolic changes related to pathway flux with DHA feeding. Greater levels of DHA-derived glycerol lipids were found subsequently leading to the decrease of arachidonate-derived endocannabinoids (eCB). Levels of 1- and 2-arachidonylglcerol eCB in muscle and liver were lower in the DHA diet group compared to controls. These findings demonstrate that DHA feeding in mice alters macronutrient metabolism and may restore ECS tone by lowering arachidonic acid derived eCB.

Pneumococcal infections cause serious illness and death among older adults. A capsular polysaccharide vaccine PPSV23 (Pneumovax®) and a conjugated polysaccharide vaccine PCV13 (Prevnar®) are used to prevent these infections, yet underlying responses, and baseline predictors remain unknown. We recruited and vaccinated 39 older adults (>60 years) with PPSV23 or PCV13. Both vaccines induced strong antibody responses at day 28 and similar plasmablast transcriptional signatures at day 10, however, their baseline predictors were distinct. Analyses of baseline flow cytometry and RNA-seq data (bulk and single cell) revealed a novel baseline phenotype that is specifically associated with weaker PCV13 responses, characterized by i) increased expression of cytotoxicity-associated genes and increased CD16+NK frequency; ii) increased Th17 and decreased Th1 cell frequency. Men were more likely to display this cytotoxic phenotype and mounted weaker responses to PCV13 than women. Baseline expression levels of a distinct gene set was predictive of PPSV23 responses. This first precision vaccinology study for pneumococcal vaccine responses of older adults uncovered novel and distinct baseline predictors that might transform vaccination strategies and initiate novel interventions.

Objective To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus. Methods This retrospective cohort study included enterprise-wide Mayo Clinic patients using Informatics for Integrating Biology at the Bedside from January 1994 through December 2019. The antidiabetic outcomes (change in hemoglobin A1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n=32). Results Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P=.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply by 0.0555) and required 28.8 fewer total daily insulin units (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P=.045). Linear regression analysis suggests that the relative difference in weight accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P=.05) reduction in hemoglobin A1c and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P=.06). Conclusion Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments and may be considered for use as a novel diabetic therapy. Future studies are needed to determine whether these results are translatable to patients with type 2 diabetes mellitus without underlying malignant diseases and to determine whether the antidiabetic effects of dasatinib are due to its senolytic properties.

The role of senescent cells has been implicated in various tissue dysfunctions associated with aging, obesity and other pathological conditions. Currently, most transgenic mouse models target only p16Ink4a-highly expressing (p16high) cells. In the present technical report, we generated a p21-Cre mouse model, containing a p21 promoter-driving inducible Cre, enabling us to examine p21Cip1-highly expressing (p21high) cells, a previously unexplored cell population exhibiting several characteristics typical of senescent cells. By crossing p21-Cre mice with different floxed mice, we managed to monitor, sort, image, eliminate or modulate p21high cells in vivo. We showed that p21high cells can be induced by various conditions, and percentages of p21high cells varied from 1.5% to 10% across different tissues in 23-month-old mice. Intermittent clearance of p21high cells improved physical function in 23-month-old mice. Our report demonstrates that the p21-Cre mouse model is a valuable and powerful tool for studying p21high cells to further understand the biology of senescent cells. Wang et al. report a mouse model for targeting of cells with high p21 expression. Using this model, they are able to monitor, sort, image, eliminate or modulate these cells in vivo, which could be a valuable tool to study senescent cells.

Older adults represent a vulnerable population with elevated risk for numerous morbidities. To explore the association of the microbiome with aging and age-related susceptibilities including frailty and infectious disease risk, we conducted a longitudinal study of the skin, oral, and gut microbiota in 47 community- or skilled nursing facility-dwelling older adults vs. younger adults. We found that microbiome changes were not associated with chronological age so much as frailty: we identified prominent changes in microbiome features associated with susceptibility to pathogen colonization and disease risk, including diversity, stability, heterogeneity, and biogeographic determinism, which were moreover associated with a loss of Cutibacterium (C.) acnes in the skin microbiome. Strikingly, the skin microbiota were also the primary reservoir for antimicrobial resistance, clinically important pathobionts, and nosocomial strains, suggesting a potential role particularly for the skin microbiome in disease risk and dissemination of multidrug resistant pathogens.

Evidence has begun to emerge indicating that cancer survivors experience accelerated aging. This study examines this phenomenon by evaluating trajectories of functional decline in older adults with a history of a cancer diagnosis relative to those without a history of cancer.Community dwelling healthy volunteers in the Baltimore Longitudinal Study of Aging were evaluated in the Clinical Research Unit of the National Institute on Aging Intramural Research Program. Between 2006 and 2019, 1728 men and women (aged 22-100) underwent clinical evaluation of functional status; 359 reported having a history of cancer. Longitudinal associations between self-reported cancer history and measures of functional decline were examined using generalized estimating equations. Additionally, time-to-event and Cox proportional hazards models were used to examine trajectories of decline. Where appropriate, age-stratified associations were examined, and models were adjusted for sex, body mass index, race, smoking status, education, and number of comorbid conditions.Among all participants, a history of cancer was associated with 1.42 (95% CI 1.11-1.81) greater odds of weak grip strength. Among older participants (65 years of age), those with a history of cancer had 1.61 (95% CI 1.28, 2.02) greater odds of slow gait speed and a 0.11 unit (95% CI 0.19-0.03) lower physical performance score than those with no cancer history. Time-to-event analysis showed that older individuals with a history of cancer experienced steeper decline in grip strength and gait speed than older adults with no history of cancer (p 0.01).Cancer survivors, especially older individuals, demonstrate greater odds of and accelerated functional decline, suggesting that cancer and/or its treatment may alter aging trajectories. Observational and intervention studies are needed for prevention, mitigation, and/or reversal of aging-related effects of cancer and its treatment.

Among older women, the clinical presentation of urinary incontinence (UI) is heterogeneous; presenting as a pelvic floor condition or geriatric syndrome. We aimed to characterize the geriatric incontinence syndrome (GIS) to establish its foundation in clinical practice.Prospective study.Geriatric Clinical Research Unit.Sixty-one community-dwelling women aged 70 and older with bothersome UI symptoms.UI symptom type and severity were determined by 3-day bladder diary. UI severity was defined; moderate UI defined as2 UI episodes/day and severe UI defined as ≥2 UI episodes/day. Subjective assessment of physical performance was determined using the Short Physical Performance Battery (SPPB) score. Total SPPB scores9 define normal physical performance and scores ≤9 defined impaired physical performance.The average age was 77.1 ± 5.8 (mean ± SD) years; 69% of women had severe UI and 31% had moderate UI. Demographic characteristics were similar between groups. Daytime voiding frequency was 7.1 ± 2.9 and nocturia was present equally between groups. The majority of women (59%) with severe UI had SPPB ≤9 compared with 26% among women with moderate UI (p = 0.02); featuring significantly slower chair stand scores (2.3 ± 1.4 vs 3.3 ± 0.9, p = 0.007) and gait speed (0.08 ± 0.2 m/s compared with 1.0 ± 0.2 in women with moderate UI).A multifactorial GIS may be present in older women evidenced by the co-existence of severe UI, physical disability, slower chair stand pace, and gait speed. Prospective studies are needed to understand how these clinical features may impact the clinical care of older incontinent women.

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.

Urinary incontinence is a prevalent pelvic floor disorder among women of all ages. However, in many older women, especially those who have multiple chronic conditions it may be a geriatric syndrome because of its shared characteristics of physical function impairments, cognitive decline, and mobility disability. The geriatric incontinence syndrome may represent a poorly characterized phenotype of UI among older women which in many ways reflects unhealthy aging. In this article, we explore the evidence behind these concepts together with potentiel impact on the diagnosis and management of UI in this group.

Background: In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence, but risks for other cancers in male and female homozygotes are unclear. Methods: 451,143 UK Biobank European ancestry participants (aged 40–70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than nonmelanoma and liver cancer) and common incident cancers [bladder, blood (with subanalyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, esophageal, ovarian, pancreatic, prostate and stomach] in those with p.C282Y and p.H63D genotypes, compared with participants without HFE mutations. Results: Male p.C282Y homozygotes (n = 2,890, 12.1% with baseline diagnosed hereditary hemochromatosis) had increased incidence of prostate cancer [6.8% vs. 5.4% without mutations; HR = 1.32; 95% confidence interval (CI), 1.07–1.63; P = 0.01; Bonferroni adjusted P = 0.17] during follow-up. In life table estimates from ages 40 to 75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%; 95% CI, 1.3–6.8). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex. Conclusions: In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (nonliver) cancers. Impact: Replication of results in other large community genotyped cohorts are needed to confirm if clinical monitoring for prostate cancer is necessary in p.C282Y homozygous males.

ImportanceTelomere attribution is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD).ObjectiveTo assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes.Design, Setting, and ParticipantsData from European-ancestry participants in the UK Biobank (n=435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n=43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology.ExposuresRelative mean leukocyte TL at baseline was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction technique by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S).Main Outcomes and MeasuresAD/ADRD was confirmed by mapping multi-source data to 3-charcter ICD codes (G30; F00; F01; F03; G31), excluding other-cause dementias (F02).ResultsLonger TL was associated with a lower risk of incident AD/ADRD (adjusted HR [aHR] per SD=0.93, 95% CI 0.90 to 0.96, P=3.37×10−7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume (adjusted standardized β [aβ] per SD=0.012, 95% CI 0.003 to 0.021, P=0.012), lower total volume of white matter hyperintensities (aβ per SD= -0.015, 95% CI -0.024 to -0.006, P=0.002), and higher fractional anisotropy (FA; aβ per SD=0.018, 95% CI 0.009 to 0.027, P=9.44×10−5) and lower mean diffusivity (MD; aβ per SD=0.045, 95% CI 0.035 to 0.056, P=1.07×10−17) in the fornix.Conclusions and RelevanceLonger TL is a protective factor against AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. A better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults.Key PointsQuestionIs leukocyte telomere length (TL) associated with Alzheimer’s disease (AD) and AD related dementias (AD/ADRD) and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging phenotypes?FindingsLonger TL was associated with a lower risk of incident AD/ADRD, larger hippocampus volume, lower total volume of white matter hyperintensities, higher fractional anisotropy and lower mean diffusivity in the fornix.MeaningLonger TL in midlife may play a protective role against AD/ADRD, and a better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults.

Geriatricians and others must embrace the emerging field of geroscience. Until recently geroscience research was pursued in laboratory animals, but now this field requires specialized expertise in the care of vulnerable older patients with multiple chronic diseases and geriatric syndromes, the population likely to benefit the most from emerging therapies. While chronological aging measures the inevitable passage of clock time that occurs equally for everyone, biological aging varies among individuals, and importantly, it is modifiable. Advances in our understanding of biological aging, the discovery of strategies for modifying its rate, and an appreciation of aging as a shared risk factor for chronic diseases have jointly led to the Geroscience Hypothesis. This hypothesis states that interventions modifying aging biology can slow its progression-resulting in the delay or prevention of the onset of multiple diseases and disorders. Here we wish to report on the Third Geroscience Summit held at National Institutes of Health on November 4-5, 2019, which highlighted the importance of engaging other disciplines including clinicians. Involvement by scientists with expertise in clinical trials, health outcomes research, behavioral and social sciences, health policy, and economics is urgently needed to translate geroscience discoveries from the bench to clinical care and health policy. Adding to the urgency of broadening this geroscience coalition is the emergence of biological aging as one the most important modifiable factors of COVID-19, combined with the inability of our society to once again recognize and confront aging as a priority and opportunity when facing these types of public health emergencies.

Introduction During the COVID-19 pandemic, pre-existing dementia was associated with a 3x increase in risk of hospitalisation and (25.6%) of COVID-19 related deaths had dementia. However, it is unclear whether people living with dementia are at higher risk of COVID-19 due to dementia or whether there may be a biologically plausible link between dementia and COVID-19. The ApoE e4 allele is highly associated with dementia. We aimed to test the COVID-19 risk associated with dementia and the association between ApoE e4e4 allele and COVID-19 with the aim of clarifying biological vulnerability. Methods UK Biobank (England) participants baseline (2006 to 2010), plus secondary care data to 2017. Separate analysis tested dementia and ApoE genotype association with COVID-19 status (16th March-31st May 2020) or mortality (to March 31, 2020, plus incomplete deaths from April, 2020) in logistic models, adjusted for demographics and technical covariates. Results In 269,070 participants aged 65+, including 507(0.2%) hospitalized COVID-19 patients, those with pre-existing dementia were at increased risk of being hospitalized for COVID-19 (OR = 3.50 95% CI 1.93 to 6.34) and also for COVID-19 and death (OR = 7.30 95% CI 3.28–16.21). In 375,689 European-ancestry UKB participants, ApoE e4e4 homozygotes were more likely to be COVID-19 test positives (reaching genome-wide significance: OR = 2.24, 95% CI:1.72–2.93, p = 3.24 × 10–9) and of mortality with test-confirmed COVID-19 (OR = 4.29, 95% CI: 2.38–7.72, p = 1.22 × 10–6), compared to e3e3s homozygotes. The associations were little changed in subsets of participants who were free of diseases associated with ApoE e4 and COVID-19 severity. Conclusion Dementia was found to be disproportionally common in older adults who develop severe COVID-19. We have shown a plausible genetic pathway of increased COVID-19 risk with dementia, therefore suggesting that the positive association between dementia and COVID-19 is not just the result of high cases of COVID-19 in care homes.

Control of urinary continence is predicated on sensory signaling about bladder volume. Bladder sensory nerve activity is dependent on tension, implicating autonomic control over detrusor myocyte activity during bladder filling. Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are known contributors to bladder control, but their mechanism of action is not well understood. The lack of a definitive identification of cell type(s) expressing HCN in the bladder presents a significant knowledge gap. We recently reported a complete transcriptomic atlas of the C57BL/6 mouse bladder showing the dominant HCN paralog in mouse bladder, Hcn1, is limited to a subpopulation of detrusor smooth myocytes (DSMs). Here, we report details of these findings, along with results of patch-clamp experiments, immunohistochemistry, and functional myobath/tension experiments in bladder strips. With the use of a transgenic mouse expressing fluorescence-tagged α-smooth muscle actin, our data confirmed location and function of DSM HCN channels. Despite previous associations of HCN with postulated bladder interstitial cells, neither evidence of specific interstitial cell types nor an association of nonmyocytes with HCN was discovered. We confirm that HCN activation participates in reducing sustained (tonic) detrusor tension via cAMP, with no effect on intermittent (phasic) detrusor activity. In contrast, blockade of HCN increases phasic activity induced by a protein kinase A (PKA) blocker or a large-conductance Ca2+-activated K+ (BK) channel opener. Our findings, therefore, suggest a central role for detrusor myocyte HCN in regulating and constraining detrusor myocyte activity during bladder filling.

While most Alzheimer's disease (AD) research emphasizes cognitive and behavioral abnormalities, lower urinary tract symptoms (LUTS) are observed in a third of AD patients, contributing to morbidity, poor quality of life, and need for institutionalization. Alzheimer's disease-associated urinary dysfunction (ADUD) has been assumed to be due to cognitive decline alone. While mouse studies have suggested that bladder innervation and voiding behavior may be altered in AD models, technical challenges precluded voiding reflex assessments. This study seeks to establish a mouse model of ADUD, and it seeks to characterize the noncognitive sequelae involved in AD-pathology associated alterations in the voiding reflex.Having developed techniques permitting the assessment of bladder volume, pressure, and flow in mice, we now provide evidence of alterations in involuntary bladder control and increased response heterogeneity in a transgenic amyloidosis mouse model of AD using cystometry and tissue pharmacomyography. Tg-APP/PS1DE9 (PA) mice and their wild-type (WT) littermates (n = 6-8 per group) were used before plaque onset in the PA mice (4-6 months) and after plaque accumulation in the PA mice (8-10 months) in comparison to their WT control littermates.Novel findings include data suggestive of sphincteric discoordination, with pharmacological evidence of altered adrenergic mechanisms.Together, these data highlight the importance of addressing noncognitive sequelae of AD and offer novel translational insights into the debilitating impact of AD on LUTS and incontinence.

Dementia, depression, and delirium alone or in combination (3Ds) can threaten independence among older adults, and polypharmacy may further accelerate decline. Clinical pharmacists can play an important role on multidisciplinary home-based care teams by identifying medication therapy problems (MTPs) involving cognition. Within a larger ongoing clinical trial, this paper describes cognition-related MTPs and pharmacist recommendations among older adults with 3Ds followed by a home-based care team. We conducted a retrospective analysis of medication data among Medicare Advantage members aged ≥ 65 years living at home in Connecticut with International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes related to 3Ds; analyses include the first 105 subjects randomized to the home-based care team from March 2017 to January 2019. Advanced practice registered nurses conducted in-home medication reconciliations along with medical and cognitive assessments. Clinical pharmacists then conducted medication reviews centered on agents treating or exacerbating 3Ds. After review by the study advanced practice registered nurse, geriatrician, and psychiatrist, salient recommendations were forwarded to primary care providers for consideration. Medication therapy problems related to cognition were retrospectively abstracted and classified as: (1) indication: underuse or overuse; (2) effectiveness: ineffective agent or low dose (mainly for antidepressants); and (3) safety: undesirable effect (e.g., impaired cognition, dementia treatment side effects), unsafe medication (e.g., potentially inappropriate medications that can harm cognition), drug interaction, or high dose. Pharmacists identified 166 cognitive MTPs, with a mean (standard deviation) of 1.58 (1.35) [range 0–6] MTPs per subject. Indication MTPs represented 34% of total MTPs, of which 79% involved underuse and 21% overuse; effectiveness represented 13% of total MTPs; and safety represented over half (52%) of all MTPs, with benzodiazepines and anticholinergics frequently implicated. Recommendations commonly included medication reduction (discontinuation 23% and dose reduction 19%). We found MTPs involving cognition among most (79%) patients. Our study findings support the role of pharmacists on multidisciplinary teams to identify cognitively harmful medications, dementia treatment side effects, and untreated cognitive conditions. ClinicalTrials.gov NCT02945085.

Evidence suggests that senescent cells drive aging and age-related diseases, with interventions that clear them improving various conditions in preclinical models. Efforts to discover senolytics, drugs that can specifically kill senescent cells, are ongoing, guided by studies into their biology and several in vivo models. This review describes recently discovered senolytics and the pathways they target. Drugs targeting the BCL-2 family proteins, p53 activators, HSP90 inhibitors, cardiac glycosides, and fibrates along with several flavonoids are senolytic in vitro and in vivo. Methods for specifically delivering death to senescent cells to decrease non-specific off-target effects take advantage of their characteristic elevated level of p16 and increased β-galactosidase activity. Effects of senolytics on age-related diseases in pre-clinical models have been so striking that several proof-of-concept and safety phase I human trials have begun. The search continues for additional senolytics that can target more types of senescent cells with the least side effects.

OBJECTIVES: Delirium is common in older adults, especially following hospitalization. As low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship. DESIGN: Prospective cohort analysis. SETTING: Community-based cohort study of adults from 22 cities across the United Kingdom (the UK Biobank). PARTICIPANTS: Adults aged 60 years or greater by the end of follow-up in the linked hospital inpatient admissions data, up to 14 years after baseline (n=351,320). MEASUREMENTS: At baseline, serum vitamin D (25-OH-D) levels were measured. We used time-to-event models to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CIs) for the association between vitamin D deficiency and incident hospital-diagnosed delirium, adjusted for age, sex, assessment month, assessment center, and ethnicity. We performed Mendelian randomization genetic analysis in European participants to further investigate vitamin D and delirium risk. RESULTS: 3,634 (1.03%) participants had at least one incident hospital-diagnosed delirium episode. Vitamin D deficiency (50 nmol/L). Increased risk was not limited to the deficient group: insufficient levels (25–50 nmol/L) were also at increased risk (HR 1.38: 1.28 to 1.49, p=4*10(−18)). The association was independent of calcium levels, hospital-diagnosed fractures, dementia, and other relevant co-factors. In genetic analysis, participants carrying more vitamin D-increasing variants had reduced likelihood of incident delirium diagnosis (HR 0.80 per standard deviation increase in genetically instrumented vitamin D: 0.73 to 0.87; p=2*10(−7)). CONCLUSION: Progressively lower vitamin D levels predicted increased risks of incident hospital-diagnosed delirium, and genetic evidence supports a shared causal pathway. As low vitamin D levels are simple to detect and inexpensive and safe to correct, an intervention trial to confirm these results is urgently needed.

Skeletal muscle myopathies represent a common non-pulmonary manifestation of influenza infection, leading to reduced physical function and hospitalization in older adults. However, underlying mechanisms remain poorly understood. Our study examined the effects of influenza virus A pulmonary infection on contractile function at the cellular (single fiber) and molecular (myosin-actin interactions and myofilament properties) levels in soleus and extensor digitorum longus muscles of aged (20 months) C57BL/6 male mice that were healthy or flu-infected for 7 (7-days post-infection; 7-DPI) or 12 days (12-DPI). Cross-sectional area (CSA) of myosin heavy chain (MHC) IIA and IIB fibers was reduced at 12-DPI relative to 7-DPI and healthy. Maximal isometric force in MHC IIA fibers was also reduced at 12-DPI relative to 7-DPI and healthy, resulting in no change in specific force (maximal isometric force divided by CSA). In contrast, MHC IIB fibers produced greater isometric force and specific force at 7-DPI compared to 12-DPI or healthy. The increased specific force in MHC IIB fibers was likely due to greater myofilament lattice stiffness and/or an increased number or stiffness of strongly bound myosin-actin cross-bridges. At the molecular level, cross-bridge kinetics were slower in MHC IIA fibers with infection, while changes in MHC IIB fibers were largely absent. In both fiber types, greater myofilament lattice stiffness was positively related to specific force. This study provides novel evidence that cellular and molecular contractile function is impacted by influenza infection in a fiber type-specific manner, suggesting potential molecular mechanisms to help explain the impact of flu-induced myopathies.

The Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Artery Disease (CAD) and Alzheimer’s disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to assess their potential as targets for anti-aging interventions. Data were from 379,000 UK Biobank participants, aged 40 to 70 years. e2e3 (n=46,535) had mostly lower lipid-related biomarker levels including reduced total and LDL-cholesterol, and lower risks of CAD (Odds Ratio=0.87, 95% CI: 0.83 to 0.90, p=4.92×10−14) and hypertension(OR=0.94, 95% CI: 0.92 to 0.97, p=7.28×10−7) versus e3e3. However, lipid changes in e2e2 (n=2,398) were more extreme, including a marked increase in triglyceride levels (0.41 Standard Deviations, 95% CI: 0.37 to 0.45, p=5.42×10−92), with no associated changes in CAD risks. There were no associations with biomarkers of kidney function. The effects of both e2e2 and e2e3 were minimal on falls, muscle mass, grip strength or frailty. In conclusion, e2e3 has protective effects on some health outcomes, but the effects of e2e2 are not similar, complicating the potential usefulness of e2 as a target for anti-aging intervention.