Suchergebnisse

Abstract
Macronutrient intake impacts physiology, behavior, and gene expression in a wide range of organisms. We used the response surface methodology to compare how life history traits, lifespan, and reproduction differ as a function of protein and carbohydrate intakes under choice and no-choice feeding regimens in the fruit fly, Drosophila melanogaster. We found that when offered a choice of nutritionally complementary foods mated female flies regulated toward a protein to carbohydrate ratio (P:C) that was associated with shortened lifespan and maximal egg production when compared to response surfaces derived from flies fed 1 of a range of fixed diets differing in P:C (no-choice regimen). This difference in lifespan between choice and no-choice feeding was not seen in males or virgin flies, reflecting the fact that increased protein intake is triggered by mating to support egg production. However, whereas in mated females a higher P:C intake was associated with greater egg production under both choice and no-choice feeding, contrary to expectations, choice-fed mated flies laid fewer eggs than no-choice flies on equivalent macronutrient intakes, perhaps reflecting that they had to ingest twice the volume of food to attain an equivalent intake of nutrients than no-choice flies on a diet of equivalent P:C ratio.

Abstract

Background
Prescribing cholinesterase inhibitors (ChEIs) concurrently with beta-blockers might cause syncope that increases the risk of fall-related injuries (FRIs). This self-controlled case series study assesses the risk of FRIs associated with initiating ChEIs while receiving beta-blockers among Medicare fee-for-service-insured nursing home (NH) residents in the United States.


Methods
We identified individuals at their first dispensing of a beta-blocker between 2016 and 2019 after at least 45 days of long-stay NH residency. Individuals were followed from the first day of beta-blocker use until beta-blocker discontinuation, Medicare disenrollment, death, or study end. ChEI initiation was classified as the first 60 days of new ChEI dispensing after 45 days of no ChEI exposure. FRIs were assessed during beta-blocker use periods, and age-adjusted incidence rate ratios (IRR) for ChEI-initiation days versus other days were calculated using conditional Poisson regression models. Analyses were weighted for event-dependent observation periods due to the high risk of mortality after an FRI in this population. Subgroup analyses were conducted for several key time-fixed variables, including sex, age, ChEI type, ChEI dose, beta-blocker selectivity, and beta-blocker dose.


Results
The FRI risk after ChEI initiation was not elevated among 837 residents who experienced an FRI while using beta-blockers (IRR=0.90 [95%CLs 0.71, 1.15]). Analyses of ChEI initiation in several subgroups yielded similar results.


Conclusions
There was no substantial difference in FRI risk when initiating ChEIs among older NH residents receiving beta-blocker therapy versus periods without ChEI initiation, suggesting that there is no clinically significant pharmacodynamic drug–drug interaction between beta-blockers and ChEIs.

AbstractAging and multimorbidity are associated with inflammation. Polypharmacy is common in older people with multimorbidity. Given the potential for interactions between polypharmacy and inflammation, the relationship between inflammation and polypharmacy were studied in older adults with multimorbidity and in healthy aging mice. A cross-sectional analysis of data from the 5-year wave of the Concord Health and Ageing in Men Project, a population-based study of community-dwelling men aged ≥70 years. Serum concentrations of 27 cytokines were measured using a multiplex immunoassay. Associations between polypharmacy (≥5 medications) and cytokines were evaluated using multivariable linear regression adjusting for age, frailty, comorbidities, and individual drug classes. Interaction between polypharmacy and Drug Burden Index (DBI―drugs with anticholinergic and sedative effects) was analyzed. Effects of polypharmacy and DBI on serum levels of 23 cytokines were determined in aging male mice treated with chronic polypharmacy or control. Compared to the nonpolypharmacy group (n = 495), CHAMP participants with polypharmacy (n = 409) had significantly higher concentrations of IL-8, IL-6, CCL3, Eotaxin, IL-1ra, IL-1β, IP-10, and lower concentrations of anti-inflammatory cytokine IL-4. In fully-adjusted multivariable models, polypharmacy was positively associated with concentrations of IL-8 and CCL3. There were no significant differences in inflammatory profiles between control and polypharmacy-treated mice. The relationship was not influenced by DBI in men or in mice. Inflammatory markers associated with polypharmacy in older adults were not seen in healthy aged mice administered polypharmacy, and may be related to underlying diseases. The polypharmacy mouse model provides opportunities for mechanistic investigations in translational research.

AbstractPolypharmacy (use of ≥5 medications) and increasing Drug Burden Index (DBI) score (measure of person's total exposure to anticholinergic/sedative medications) are associated with impaired physical function in observational studies of older adults. Deprescribing, the supervised withdrawal of medications for which harms outweigh benefits for an individual, may be a useful intervention. Current knowledge is limited to clinical observational studies that are unable to determine causality. Here, we establish a preclinical model that investigates the effects of chronic polypharmacy, increasing DBI, and deprescribing on global health outcomes in aging. In a longitudinal study, middle-aged (12 months) male C57BL/6J (B6) mice were administered control feed or feed and/or water containing polypharmacy or monotherapy with different DBI scores. At 21 months, each treatment group was subdivided (stratified by frailty at 21 months) to either continue on treatment for life or to have treatment withdrawn (deprescribed). Frailty and physical function were evaluated at 12, 15, 18, and 24 months, and were analyzed using a mixed modeling approach. Polypharmacy with increasing DBI and monotherapy with citalopram caused mice to become frailer, less mobile, and impaired their strength and functional activities. Critically, deprescribing in old age reversed a number of these outcomes. This is the first preclinical study to demonstrate that chronic polypharmacy with increasing DBI augments frailty and impairs function in old age, and that drug withdrawal in old age reversed these outcomes. It was not the number of drugs (polypharmacy) but the type and dose of drugs (DBI) that caused adverse geriatric outcomes.

Abstract

Background
Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are 2 prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown.


Methods
We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these 2 diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in 5 ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of coexpressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms.


Results
We discovered 3 modules in ROSMAP that showed significant associations with ADRD and bone-related traits and 4 modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the 2 networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest.


Conclusions
These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.