Prospective Association of Daily Steps With Cardiovascular Disease: A Harmonized Meta-Analysis.

BACKGROUND: Taking fewer than the widely promoted "10 000 steps per day" has recently been associated with lower risk of all-cause mortality. The relationship of steps and cardiovascular disease (CVD) risk remains poorly described. A meta-analysis examining the dose-response relationship between steps per day and CVD can help inform clinical and public health guidelines. METHODS: Eight prospective studies (20 152 adults [ie, ≥18 years of age]) were included with device-measured steps and participants followed for CVD events. Studies quantified steps per day and CVD events were defined as fatal and nonfatal coronary heart disease, stroke, and heart failure. Cox proportional hazards regression analyses were completed using study-specific quartiles and hazard ratios (HR) and 95% CI were meta-analyzed with inverse-variance-weighted random effects models. RESULTS: The mean age of participants was 63.2±12.4 years and 52% were women. The mean follow-up was 6.2 years (123 209 person-years), with a total of 1523 CVD events (12.4 per 1000 participant-years) reported. There was a significant difference in the association of steps per day and CVD between older (ie, ≥60 years of age) and younger adults (ie, <60 years of age). For older adults, the HR for quartile 2 was 0.80 (95% CI, 0.69 to 0.93), 0.62 for quartile 3 (95% CI, 0.52 to 0.74), and 0.51 for quartile 4 (95% CI, 0.41 to 0.63) compared with the lowest quartile. For younger adults, the HR for quartile 2 was 0.79 (95% CI, 0.46 to 1.35), 0.90 for quartile 3 (95% CI, 0.64 to 1.25), and 0.95 for quartile 4 (95% CI, 0.61 to 1.48) compared with the lowest quartile. Restricted cubic splines demonstrated a nonlinear association whereby more steps were associated with decreased risk of CVD among older adults. CONCLUSIONS: For older adults, taking more daily steps was associated with a progressively decreased risk of CVD. Monitoring and promoting steps per day is a simple metric for clinician-patient communication and population health to reduce the risk of CVD.

The Association Between Objectively-Measured Physical Activity and Cognitive Functioning in Middle-Aged and Older People Living with HIV.

Middle-aged and older people living with HIV (PWH) are at higher risk for cognitive impairment and engage in lower levels of physical activity (PA) than seronegative counterparts. Research examining the association between objectively-measured PA and cognitive function in this population is scarce. This cross-sectional study examined the association between accelerometry-measured PA and cognitive functioning among 75 PWH (mean age 55.63). Light PA was the PA variable with the most consistent associations with cognition, with more minutes per week of light PA (performed in bouts of ≥ 10 min) being associated with better executive function, working memory/attention, and speed of processing performance, adjusted for age and current CD4 count. Findings suggest that although middle-aged and older PWH engage in more light than moderate-to-vigorous PA, light PA may be beneficial to cognition. Longitudinal studies are needed to understand PA dose-response associations with cognitive trajectories, cognitive domain specificity of PA effects, and underlying neural mechanisms of PA.

Preserving independence among under-resourced older adults in the Southeastern United States: existing barriers and potential strategies for research.

Disability prevention and preservation of independence is crucial for successful aging of older adults. To date, relatively little is known regarding disparities in independent aging in a disadvantaged older adult population despite widely recognized health disparities reported in other populations and disciplines. In the U.S., the Southeastern region also known as "the Deep South", is an economically and culturally unique region ravaged by pervasive health disparities - thus it is critical to evaluate barriers to independent aging in this region along with strategies to overcome these barriers. The objective of this narrative review is to highlight unique barriers to independent aging in the Deep South and to acknowledge gaps and potential strategies and opportunities to fill these gaps. We have synthesized findings of literature retrieved from searches of computerized databases and authoritative texts. Ultimately, this review aims to facilitate discussion and future research that will help to address the unique challenges to the preservation of independence among older adults in the Deep South region.

Mechanisms of exercise as a preventative measure to muscle wasting.

Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly results in rapid muscle wasting. Decline in muscle mass contributes to multimorbidity, reduces function, and exerts a substantial, negative impact on the quality of life. The principal mechanisms controlling muscle mass have been well described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways, and epigenetic regulation. In this review, we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.epigenetics; exercise; muscle wasting; resistance training; skeletal muscle.

A Role for Exercise to Counter Skeletal Muscle Clock Disruption.

Disruption of the skeletal muscle circadian clock leads to a preferential shift toward lipid oxidation while reducing carbohydrate oxidation. These effects are apparent at the whole-body level, including glucose intolerance, increased energy expenditure, and fasting hyperglycemia. We hypothesize that exercise counters these metabolic disturbances by modifying the skeletal muscle clock and reverting substrate metabolism back toward an optimal substrate balance.

Fatigue is independently associated with functional status limitations in older adults with gastrointestinal malignancies-results from the CARE registry.

PURPOSE: Fatigue is a component of frailty and may undermine functional well-being and independent living. The prevalence of fatigue and its impact on functional limitations among older adults with cancer remains understudied. METHODS: Using participants enrolled in the Cancer and Aging Resilience Evaluation (CARE), a prospective registry of patients (≥ 60 years) with cancer, who underwent a geriatric assessment (GA) at the first visit with oncology, we examined the presence of fatigue based on self-report of moderate to severe fatigue on PROMIS global health 10-item instrument at the time of GA. We examined the association of fatigue with impairments in instrumental activities of daily living (IADL) and activities of daily living (ADL) adjusting for age, sex, race/ethnicity, education, cancer type and stage, pain, comorbidities, and time from cancer. RESULTS: We included 374 older adults with cancer with a median age of 70 years; 56% were male and 23% black. Diagnoses included colorectal (33%) and pancreatic cancers (25%), with most patients with advanced stage disease (71% stage III/IV). Overall, 210 (58%) patients reported significant fatigue. Patients reporting significant fatigue had an increased odds of IADL (adjusted odds ratio, aOR 1.9; 95% CI 1.1-3.2) or ADL impairment (aOR 3.6; 95% CI 1.4-9.3), as compared to those without, after adjusting for aforementioned confounders. CONCLUSIONS: Over half of older adults with cancer reported moderate to severe fatigue that was independently associated with functional status limitations. Further understanding of the multifaceted aspects of fatigue and development of interventions combating fatigue in this population is urgently needed.

Lipopolysaccharide binding protein is associated with CVD risk in older adults.

BACKGROUND: Intestinal (i.e., "gut") permeability may be related to cardiovascular disease (CVD) risk, but biomarkers for gut permeability are limited and associations with CVD risk are unknown-particularly among older adults. AIMS: This cross-sectional study aimed to determine if serum biomarkers related to gut permeability [intestinal fatty acid-binding protein (iFABP)] and bacterial toxin clearing [cluster of differentiation 14 (CD14), lipopolysaccharide binding protein (LBP)] are associated with CVD risk among older adults. METHODS: Older adults (n = 74, 69.6 ± 6.5-years-old) were stratified by CVD risk category. One-way ANOVAs determined differences in each biomarker by risk category, and associations with risk score were evaluated with Pearson correlations. RESULTS: LBP (p = 0.007), but not iFABP and CD14, was significantly different between CVD risk categories. Post-hoc tests indicated LBP was higher in moderate risk and high-moderate risk compared to the high risk category (p < 0.005). Evaluation of LBP and individual components in the risk score demonstrated a moderate, negative correlation of LBP with age and systolic blood pressure (r = - 0.335 and r = - 0.297) and a small positive correlation between LBP and total cholesterol and LDL cholesterol (r = 0.204 and r = 0.220). DISCUSSION/CONCLUSION: Lower risk for CVD was associated with higher circulating concentrations of LBP, lower iFABP, and lower systemic inflammation in older adults. Further, there were small positive relationships between total and LDL cholesterol and circulating levels of LBP. These data suggest LBP may be a key component in reducing CVD risk in older adults.

Exercise and the Gut Microbiome: A Review of the Evidence, Potential Mechanisms, and Implications for Human Health.

The gastrointestinal tract contains trillions of microbes (collectively known as the gut microbiota) that play essential roles in host physiology and health. Studies from our group and others have demonstrated that exercise independently alters the composition and functional capacity of the gut microbiota. Here, we review what is known about the gut microbiota, how it is studied, and how it is influenced by exercise training and discuss the potential mechanisms and implications for human health and disease.

Circadian Rhythms, Exercise, and Cardiovascular Health.

Human circadian rhythmicity is driven by a circadian clock comprised of two distinct components: the central clock, located in the suprachiasmatic nucleus (SCN) within the hypothalamus, and the peripheral clocks, located in almost all tissues and organ systems in the body. Entrainment, or alignment, of circadian rhythmicity is dependent upon time of day and can occur through environmental influences such as light cues and physical activity exerted on skeletal muscle. Entrainment of the circadian clock through exercise has been reported to improve health by reducing risk of conditions such as cardiovascular disease (CVD), but further research is still needed. The purpose of this review is to discuss the effects exercise has on the regulation of circadian rhythmicity, specifically with respect to CVD risk factors - including hormonal levels, sleep/wake cycles, blood pressure, and heart rate. Additionally, the impact of exercise-induced circadian entrainment is discussed relative to hormone regulation, nocturnal blood pressure dipping, post-exercise hypotension, and overall cardiovascular health.

Sarcopenia: Relocating the Forest among the Trees.

As life expectancy continues to rise worldwide, health concerns associated with advanced age are increasingly becoming prominent public health concerns. Among these concerns, nearly 30 years of discussion and research have yielded a wealth of information regarding the pathophysiology, biologic etiology, and clinical implications of age-related declines in skeletal muscle mass and function (i.e., sarcopenia). Recent years have yielded several debates surrounding both the definition and terminology of sarcopenia, yet many questions remain regarding interventions to treat the condition. Among major future challenges in the area will be to design and conduct high-quality clinical trials to ultimately provide new therapeutic strategies for the treatment of sarcopenia.

Predictors of Change in Physical Function in Older Adults in Response to Long-Term, Structured Physical Activity: The LIFE Study.

OBJECTIVES: To evaluate the extent of variability in functional responses in participants in the Lifestyle Interventions and Independence for Elders (LIFE) study and to identify the relative contributions of intervention adherence, physical activity, and demographic and health characteristics to this variability. DESIGN: Secondary analysis. SETTING: Multicenter institutions. PARTICIPANTS: A volunteer sample (N=1635) of sedentary men and women aged 70 to 89 years who were able to walk 400m but had physical limitations, defined as a Short Physical Performance Battery (SPPB) score of ≤9. INTERVENTIONS: Moderate-intensity physical activity (n=818) consisting of aerobic, resistance, and flexibility exercises performed both center-based (2times/wk) and home-based (3-4times/wk) sessions or health education program (n=817) consisting of weekly to monthly workshops covering relevant health information. MAIN OUTCOME MEASURES: Physical function (gait speed over 400m) and lower extremity function (SPPB score) assessed at baseline and 6, 12, and 24 months. RESULTS: Greater baseline physical function (gait speed, SPPB score) was negatively associated with change in gait speed (regression coefficient ß=-.185; P<.001) and change in SPPB score (ß=-.365; P<.001), whereas higher number of steps per day measured by accelerometry was positively associated with change in gait speed (ß=.035; P<.001) and change in SPPB score (ß=.525; P<.001). Other baseline factors associated with positive change in gait speed and/or SPPB score include younger age (P<.001), lower body mass index (P<.001), and higher self-reported physical activity (P=.002). CONCLUSIONS: Several demographic and physical activity-related factors were associated with the extent of change in functional outcomes in participants in the LIFE study. These factors should be considered when designing interventions for improving physical function in older adults with limited mobility.

Increased inflammation but similar physical composition and function in older-aged, HIV-1 infected subjects.

BACKGROUND: Systemic immune activation (inflammation) and immunosenescence develop in some people with advancing age. This process, known as "inflamm-aging," is associated with physical frailty and sarcopenia. Meanwhile, successful antiretroviral therapy has led to a growing number of older HIV-1-infected individuals who face both age-related and HIV-1-related inflammation, which may synergistically promote physical decline, including frailty and sarcopenia. The purpose of our study was to determine if inflammation during treated HIV-1 infection worsens physical impairment in older individuals. METHODS: We determined the severity of HIV-associated inflammation and physical performance (strength and endurance) in 21 older HIV-infected individuals (54-69 years) receiving suppressive antiretroviral therapy, balanced for confounding variables including age, anthropometrics, and co-morbidities with 10 uninfected control individuals. Biomarkers for microbial translocation (lipopolysaccharide [LPS]), inflammation (soluble CD14 [sCD14], osteopontin, C-reactive protein [CRP], interleukin-6 [IL-6], soluble ICAM-1 [sICAM-1] and soluble VCAM-1 [sVCAM-1]), and coagulopathy (D-dimer) were assayed in plasma. Activation phenotypes of CD4(+)T cells, CD8(+) T cells and monocytes were measured by flow cytometry. Physical performance was measured by 400 m walking speed, a short physical performance battery [SPPB], and lower extremity muscle strength and fatigue. RESULTS: Overall physical function was similar in the uninfected and HIV-infected groups. Compared to uninfected individuals, the HIV-infected group had elevated levels of sCD14 (P < 0.001), CRP (P < 0.001) and IL-6 (P = 0.003) and an increased frequency of CD4(+) and CD8(+) T cells with an immunosenescent CD57(+) phenotype (P = 0.004 and P = 0.043, respectively). Neither plasma inflammatory biomarkers nor CD57(+) T cells correlated with CD4(+) T cell counts. Furthermore, none of the elevated inflammatory biomarkers in the HIV-infected subjects were associated with any of the physical performance results. CONCLUSIONS: When age-related co-morbidities were carefully balanced between the uninfected and HIV-infected groups, no evidence of inflammation-associated physical impairment was detected. Despite careful balancing for age, BMI, medications and co-morbidities, the HIV-infected group still displayed evidence of significant chronic inflammation, including elevated sCD14, CRP, IL-6 and CD57(+) T cells, although the magnitude of this inflammation was unrelated to physical impairment.

Genetic influence on exercise-induced changes in physical function among mobility-limited older adults.

To date, physical exercise is the only intervention consistently demonstrated to attenuate age-related declines in physical function. However, variability exists in seniors' responsiveness to training. One potential source of variability is the insertion (I allele) or deletion (D allele) of a 287 bp fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. This polymorphism is known to influence a variety of physiological adaptions to exercise. However, evidence is inconclusive regarding the influence of this polymorphism on older adults' functional responses to exercise. This study aimed to evaluate the association of ACE I/D genotypes with changes in physical function among Caucasian older adults (n = 283) following 12 mo of either structured, multimodal physical activity or health education. Measures of physical function included usual-paced gait speed and performance on the Short Physical Performance Battery (SPPB). After checking Hardy-Weinberg equilibrium, we used using linear regression to evaluate the genotype*treatment interaction for each outcome. Covariates included clinic site, body mass index, age, sex, baseline score, comorbidity, and use of angiotensin receptor blockers or ACE inhibitors. Genotype frequencies [II (19.4%), ID (42.4%), DD (38.2%)] were in Hardy-Weinberg equilibrium (P > 0.05). The genotype*treatment interaction was statistically significant for both gait speed (P = 0.002) and SPPB (P = 0.020). Exercise improved gait speed by 0.06 ± 0.01 m/sec and SPPB score by 0.72 ± 0.16 points among those with at least one D allele (ID/DD carriers), but function was not improved among II carriers. Thus, ACE I/D genotype appears to play a role in modulating functional responses to exercise training in seniors.

Physical activity and resting pulse rate in older adults: findings from a randomized controlled trial.

BACKGROUND: Elevated resting pulse rate (RPR) is a well-recognized risk factor for adverse outcomes. Epidemiological evidence supports the beneficial effects of regular exercise for lowering RPR, but studies are mainly confined to persons younger than 65 years. We set out to evaluate the utility of a physical activity (PA) intervention for slowing RPR among older adults. METHODS: A total of 424 seniors (ages 70-89 years) were randomized to a moderate intensity PA intervention or an education-based "successful aging" health program. Resting pulse rate was assessed at baseline, 6 months, and 12 months. Longitudinal differences in RPR were evaluated between treatment groups using generalized estimating equation models, reporting unstandardized ß coefficients with robust SEs. RESULTS: Increased frequency and duration of aerobic training were observed for the PA group at 6 and 12 months as compared with the successful aging group (P < .001). In both groups, RPR remained unchanged over the course of the 12-month study period (P = .67). No significant improvement was observed (ß [SE] = 0.58 [0.88]; P = .51) for RPR when treatment groups were compared using the generalized estimating equation method. Comparable results were found after omitting participants with a pacemaker, cardiac arrhythmia, or who were receiving ß-blockers. CONCLUSIONS: Twelve months of moderate intensity aerobic training did not improve RPR among older adults. Additional studies are needed to determine whether PA of longer duration and/or greater intensity can slow RPR in older persons.

Creatine supplementation post-exercise does not enhance training-induced adaptations in middle to older aged males.

PURPOSE: The present study evaluated the effects of creatine monohydrate (CrM) consumption post-exercise on body composition and muscle strength in middle to older males following a 12-week resistance training program. METHODS: In a double-blind, randomized trial, 20 males aged between 55 and 70 years were randomly assigned to consume either CrM-carbohydrate (CHO) [20 g days(-1) CrM + 5 g days(-1) CHO × 7 days, then 0.1 g kg(-1) CrM + 5 g CHO on training days (average dosage of ~8.8 g)] or placebo CHO (20 g days(-1) CHO × 7 days, then 5 g CHO on training days) while participating in a high intensity resistance training program [3 sets × 10 repetitions at 75% of 1 repetition maximum (1RM)], 3 days weeks(-1) for 12 weeks. Following the initial 7-day "loading" phase, participants were instructed to ingest their supplement within 60 min post-exercise. Body composition and muscle strength measurements, blood collection and vastus lateralis muscle biopsy were completed at 0, 4, 8 and 12 weeks of the supplement and resistance training program. RESULTS: A significant time effect was observed for 1RM bench press (p = 0.016), leg press (p = 0.012), body mass (p = 0.03), fat-free mass (p = 0.005) and total myofibrillar protein (p = 0.005). A trend for larger muscle fiber cross-sectional area in the type II fibers compared to type I fibers was observed following the 12-week resistance training (p = 0.08). No supplement interaction effects were observed. CONCLUSION: Post-exercise ingestion of creatine monohydrate does not provide greater enhancement of body composition and muscle strength compared to resistance training alone in middle to older males.

Microbiome-driven alterations in metabolic pathways and impaired cognition in aged female TgF344-AD rats.

Alzheimer's disease (AD) not only affects cognition and neuropathology, but several other facets capable of negatively impacting quality of life and potentially driving impairments, including altered gut microbiome (GMB) composition and metabolism. Aged (20 + mo) female TgF344-AD and wildtype rats were cognitively characterized on several tasks incorporating several cognitive domains, including task acquisition, object recognition memory, anxiety-like behaviors, and spatial navigation. Additionally, metabolic phenotyping, GMB sequencing throughout the intestinal tract (duodenum, jejunum, ileum, colon, and feces), neuropathological burden assessment and marker gene functional abundance predictions (PICRUSt2) were conducted. TgF344-AD rats demonstrated significant cognitive impairment in multiple domains, as well as regionally specific GMB dysbiosis. Relationships between peripheral factors were investigated using Canonical Correspondence Analysis (CCA), revealing correlations between GMB changes and both cognitive and metabolic factors. Moreover, communities of gut microbes contributing to essential metabolic pathways were significantly altered in TgF344-AD rats. These data indicate dysbiosis may affect cognitive outcomes in AD through alterations in metabolism-related enzymatic pathways that are necessary for proper brain function. Moreover, these changes were mostly observed in intestinal segments required for carbohydrate digestion, not fecal samples. These data support the targeting of intestinal and microbiome health for the treatment of AD.

Effects of resveratrol on changes in trimethylamine-N-oxide and circulating cardiovascular factors following exercise training among older adults.

PURPOSE: Trimethylamine-N-oxide (TMAO) is a gut-derived metabolite associated with cardiovascular disease (CVD). In preclinical and observational studies, resveratrol and exercise training have been suggested as potential strategies to reduce the systemic levels of TMAO. However, evidence from experimental studies in humans remains unknown. This project examined the dose-dependent effects of a combined resveratrol intervention with exercise training on circulating TMAO and other related metabolite signatures in older adults with high CVD risk. METHODS: Forty-one older adults [mean (±SD) age of 72.1 (6.8) years] participated in a 12-week supervised center-based, multi-component exercise training intervention [2×/week; 80 min/session] and were randomized to one of two resveratrol dosages [Low: 500 vs. High:1000 mg/day] or a cellulose-based placebo. Serum/plasma were collected at baseline and post-intervention and evaluated for TMAO and associated analytes. RESULTS: After the 12-week intervention, TMAO concentration increased over time, regardless of treatment [mean (±SD) Placebo: 11262 (±3970); Low:13252 (±1193); High: 12661(±3359) AUC; p = 0.04]. Each resveratrol dose produced different changes in metabolite signatures. Low dose resveratrol upregulated metabolites associated with bile acids biosynthesis (i.e., glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycocholic acid). High dose resveratrol modulated metabolites enriched for glycolysis, and pyruvate, propanoate, ß-alanine, and tryptophan metabolism. Different communities tightly correlated to TMAO and resveratrol metabolites were associated with the lipid and vascular inflammatory clinical markers [|r| > 0.4, p < 0.05]. CONCLUSION: These findings suggest a distinct dose-dependent adaptation response to resveratrol supplementation on circulating metabolite signatures but not on TMAO among high-risk CVD older adults when combined with an exercise training intervention.

Assessment of Frailty Among Older Adults in the Physical Activity Daily Trial.

Frailty is common among cardiac patients; however, frailty assessment data from patients with peripheral arterial disease (PAD) are limited. The purpose of this observational study was to identify the prevalence and factors related to frailty in addition to unique frailty marker groupings in a cohort of sedentary adults with PAD. We grouped three PAD-relevant frailty characteristics using Fried's frailty phenotype -1) exhaustion, (2) weakness, and (3) slowness-and observed the prevalence of pre-frailty (1-2 characteristics) and frailty (3 characteristics) in the PAD cohort. Of the 106 participants, 34.9% were robust/non-frail, 53.8% were pre-frail, and 2.8% were frail. Exhaustion (33.3%) was the most occurring characteristic followed by weakness (20.0%) and slowness (5.0%). The grouping of weakness + slowness (10.0%) was the most prevalent followed by exhaustion + weakness (8.3%) and exhaustion + slowness (5.0%). Among pre-frail participants, ankle brachial index was correlated with a reduction in gait speed.

Delirium Due to Potentially Avoidable Hospitalizations Among Older Adults.

BACKGROUND: Delirium is a common complication during acute care hospitalizations in older adults. A substantial percentage of admissions are for ambulatory care-sensitive conditions (ACSCs) or potentially avoidable hospitalizations-conditions that might be treated early in the outpatient setting to prevent hospitalization and hospital complications. METHODS: This retrospective cross-sectional study examined rates of delirium among older adults hospitalized for ACSCs. Participants were 39 933 older adults ≥65 years of age admitted from January 1, 2015 to December 31, 2019 to general inpatient units and ICUs of a large Southeastern academic medical center. Delirium was defined as a score ≥ 2 on the Nursing Delirium Screening Scale or positive on the Confusion Assessment Method for the Intensive Care Unit during admission, and ACSCs were identified from the primary admission diagnosis using standardized definitions. Generalized linear mixed models were used to examine the association between ACSCs and delirium, compared with admissions for non-ACSC diagnoses, adjusting for covariates and repeated observations for individuals with multiple admissions. RESULTS: Delirium occurred in 15.6% of admissions for older adults. Rates were lower for ACSC admissions versus admissions for other conditions (13.9% vs 15.8%, p < .001). Older age and higher comorbidity were significant predictors of the development of delirium. CONCLUSIONS: Rates of delirium among older adults hospitalized for ACSCs were lower than rates for non-ACSC hospitalization but still substantial. Optimizing the treatment of ACSCs in the outpatient setting is an important goal not only for reducing hospitalizations but also for reducing risks for hospital-associated complications such as delirium.

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation.

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.