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Alisa J Johnson,1,2,&ast; Taylor Buchanan,3,&ast; Chavier Laffitte Nodarse,1,2 Pedro A Valdes Hernandez,1,2 Zhiguang Huo,4 James H Cole,5,6 Thomas W Buford,3 Roger B Fillingim,1,2,7 Yenisel Cruz-Almeida1,2,7 1Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA; 2Department of Community Dentistry & Behavioral Science, College of Dentistry, University of Florida, Gainesville, FL, USA; 3Department of Medicine, University of Alabama, Birmingham, AL, USA; 4Department of Biostatistics, College of Public Health & Health Professions College of Medicine, University of Florida, Gainesville, FL, USA; 5Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK; 6Dementia Research Centre, Institute of Neurology, University College London, London, UK; 7Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA&ast;These authors contributed equally to this workCorrespondence: Yenisel Cruz-Almeida, University of Florida, PO Box 103628, 1329 SW 16th Street, Ste 5180, Gainesville, FL, 32608, USA, Tel +1 352-294-8584, Fax +1 352-273-5985, Email cryeni@ufl.eduPurpose: Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an “older” appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain’s impact.Patients and Methods: Participants (mean age = 57.8 ± 8.0 years) with/without knee OA-related pain were classified according to pain’s impact on daily function (ie, impact): low-impact (n=111), and high-impact (n=60) pain, and pain-free controls (n=31). Participants completed demographic, pain, and psychosocial assessments, and T1-weighted magnetic resonance imaging. Brain-predicted age difference (brain-PAD) was compared across groups using analysis of covariance. Partial correlations examined associations of brain-PAD with pain and psychosocial variables.Results: Individuals with high-impact chronic knee pain had significantly “older” brains for their age compared to individuals with low-impact knee pain (p < 0.05). Brain-PAD was also significantly associated with clinical pain, negative affect, passive coping, and pain catastrophizing (p’s< 0.05).Conclusion: Our findings suggest that high impact chronic knee pain is associated with an older appearing brain on MRI. Future studies are needed to determine the impact of pain-related interference and pain management on somatosensory processing and brain aging biomarkers for high-risk populations and effective intervention strategies.Keywords: knee osteoarthritis, high impact chronic pain, brain aging, experimental pain, psychosocial

Lisa M Roberts,1,2 Byron C Jaeger,3 Liliana C Baptista,1,2 Sara A Harper,1,2 Anna K Gardner,4 Elizabeth A Jackson,5 Dorothy Pekmezi,6 Bhanuprasad Sandesara,4 Todd M Manini,4 Stephen D Anton,4 Thomas W Buford1,2 1Department of Medicine, Division of Gerontology/Geriatrics/Palliative Care, University of Alabama at Birmingham, Birmingham, AL, USA; 2Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 3Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA; 4Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; 5Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA; 6Department of Health Behavior, School of Public Health, the University of Alabama at Birmingham, Birmingham, AL, USACorrespondence: Thomas W BufordDepartment of Medicine, Division of Gerontology/Geriatrics/Palliative Care, University of Alabama at Birmingham, 1313 13th Street S., Birmingham, AL 35205, USATel +1 205 996 3008Fax +1 205 996 3110Email twbuford@uabmc.eduBackground: Physical exercise is associated with decreased cardiovascular disease (CVD) risk, but recent large-scale trials suggest that exercise alone is insufficient to reduce CVD events in high-risk older adults.Purpose: This pilot randomized clinical trial aimed to collect critical data on feasibility, safety, and protocol integrity necessary to design a fully powered randomized controlled trial (RCT) and evaluate the impact of combining structured exercise with an intervention designed to enhance non-exercise physical activity (EX+NEPA) compared to EX alone.Methods: Forty participants aged ≥60 years with moderate-to-high risk of coronary heart disease events were randomly assigned to either the EX+NEPA or EX groups and followed for 20 weeks. Both groups underwent a twice-weekly, 8-week center-based exercise intervention with aerobic and resistance exercises. EX+NEPA group also received a wearable activity tracking device along with behavioral monitoring and feedback throughout the study. Study outcomes were evaluated at 8 and 20 weeks.Results: Data are presented as adjusted mean change of the differences over time with 95% confidence intervals at 20 weeks. Relative to EX, the change in steps/day at 20 weeks was 1994 (−40.27, 4028) higher for EX+NEPA. For sedentary time at close-out, the EX+NEPA group was −6.8 (−45.2, 31.6) min/day relative to EX. The between-group differences for systolic and diastolic blood pressure were −9.9 (−19.6, −0.3) and −1.8 (−6.9, 3.3) mmHg, respectively.Conclusion: The addition of wearable technology intervention appeared to positively influence daily activity patterns and changes in blood pressure – potentially improving risk factors for CVD. A fully powered randomized trial is needed to ultimately test this hypothesis.Keywords: aging, cardiovascular, exercise, physical activity, activity monitor

Katie A Butera,1 Shannon R Roff,2 Thomas W Buford,3 Yenisel Cruz-Almeida4 1Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32610, USA; 2Charles River Laboratories Inc., Frederick, MD 21701, USA; 3Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; 4Department of Aging & Geriatric Research, Institute on Aging, Pain Research & Intervention Center of Excellence, Center for Cognitive Aging & Memory, University of Florida, Gainesville, FL 32610, USA Abstract: Multisite pain, or pain that occurs simultaneously at >1 anatomical site, is more prevalent than single-site pain. While multisite pain affects over half of older adults, it remains an understudied pain entity that may have important functional implications in an aging population. Greater understanding of this complex pain entity from a biopsychosocial perspective is critical for optimizing clinical and functional outcomes in older adults with pain. Therefore, the primary purpose of this review is to summarize the relationship between multisite pain and functional outcomes in older adults to further elucidate the impact of multisite pain as a distinct entity within this population. A comprehensive literature search revealed 17 peer-reviewed articles. Multisite pain in older individuals is associated with reductions in several physical function domains: 1) lower-extremity mobility; 2) upper-extremity impairments; 3) balance and increased fall risk; and 4) general disability and poor physical function. Further, multisite pain in older individuals is associated with psychological dysfunction (eg, anxiety and depressive symptoms) and social factors (eg, income and education). Overall, this review highlights the scant literature investigating the functional implications of multisite pain in an aging population. Further, while multisite pain appears to have functional consequences, the neurobiological mechanisms contributing to this relationship are unknown. Thus, how this pain characteristic may contribute to the variability in pain-related functional outcomes among older adults is not clear. Future investigations are strongly warranted to advance the understanding of multisite pain and its broad impact on physical and psychosocial function in older adults. Keywords: multiple pain locations, multiple pain sites, social function, dysfunction, disability, physical function, social factors

Rodrigo Ramirez-Campillo,1–3 Daniela Diaz,4 Cristian Martinez-Salazar,5 Pablo Valdés-Badilla,6 Pedro Delgado-Floody,5 Guillermo Méndez-Rebolledo,7 Rodrigo Cañas-Jamet,8,9 Carlos Cristi-Montero,10 Antonio García-Hermoso,11 Carlos Celis-Morales,12 Jason Moran,13 Thomas W Buford,14 Leocadio Rodriguez-Mañas,15 Alicia M Alonso-Martinez,16 Mikel Izquierdo16 1Department of Physical Activity Sciences, 2Laboratory of Measurement and Assessment in Sports, Research Nucleus in Health, Physical Activity and Sports, Universidad de Los Lagos, Osorno, 3Unit of Integrative Physiology, Laboratory of Exercise Sciences, MEDS Clinic, Santiago, Chile; 4School of Occupational Therapy, Faculty of Health, Universidad Santo Tomás, Osorno, 5Department of Physical Education, Sport and Recreation, Universidad de La Frontera, 6Institute of Physical Activity and Health, Universidad Autónoma de Chile, Temuco, 7School of Kinesiology, Faculty of Health, University Santo Tomás, Talca, 8Laboratory of Physiology, Department of Biological Sciences, Faculty of Biological Sciences, Universidad Andres Bello, Viña del Mar, 9School of Kinesiology, Faculty of Medicine, Universidad Diego Portales, Santiago, 10IRyS Group, Physical Education School, Pontificia Universidad Católica de Valparaíso, Valparaíso, 11Laboratory of Physical Activity Sciences, Sport and Health, Faculty of Medical Sciences, Universidad de Santiago de Chile, USACH, Santiago, Chile; 12BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, 13Centre for Sports and Exercise Science, School of Biological Sciences, University of Essex, Colchester, UK; 14Department of Aging and Geriatric Research, Institute of Aging, University of Florida, College of Medicine, Gainesville, Florida, USA; 15Division of Geriatric Medicine, University Hospital of Getafe, Madrid, 16Department of Health Sciences, Public University of Navarre, Navarre, Spain Objective: This study aimed to compare the effects of two frequencies of high-speed resistance training (HSRT) on physical performance and quality of life of older women.Methods: A total of 24 older women participated in a 12-week HSRT program composed of either two or three sessions/week (equated for volume and intensity). Women were randomized into three arms: a control group (CG, n=8), a resistance training group performing two sessions/week (RT2, n=8), and a resistance training group performing three sessions/week (RT3, n=8). The training program for both experimental groups included exercises that required high-speed concentric muscle actions.Results: No baseline differences were observed among groups. Compared with the CG, both training groups showed similar small to moderate improvements (P

Ageing is an escalating global health issue, with the World Health Organization (WHO) reporting that one in six individuals will be 60 years or older by the year 2030. Therefore, understanding the mechanisms of complex biological ageing processes and associated healthcare challenges has become increasingly important. Intrinsic capacity (IC), defined by WHO as the composite of all physical and mental capacities an individual possesses, can be used as a proxy for defining healthy ageing. IC has five key components: locomotion, cognition, psychological, sensory, and vitality capacity (VC). This review paper specifically focuses on exercise as an effective tool to preserve VC in ageing populations. The physiological domains of VC discussed include energy and metabolism, neuromuscular function, immune and stress response, mitochondrial function, and the methylation clock. Additionally, we highlight potential outcome measures for assessing each of these domains. This review also covers areas of focus for future research and possible interventions. We ultimately conclude that ageing is a complex, multifaceted process resulting in deficits across multiple VC components. However, regular exercise is capable of producing physiological adaptations that may be beneficial in the context of healthy ageing and improving or preserving the status of VC components., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

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, β-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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD., Methods: Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype., Results: Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density., Conclusions: Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Low skeletal muscle mass (LSMM) and/or, function associated with an increased risk of treatment-related toxicities and inferior overall survival (OS) among adults with solid malignancies. However, the association between LSMM and treatment-related toxicities among adults with haematologic malignancies remains unclear., Methods: Using a pre-published protocol (CRD42020197814), we searched seven bibliographic databases from inception to 08/2021 for studies reporting the impact of LSMM among adults ≥18 years with a known haematologic malignancy. The primary outcome of interest was OS, and secondary outcomes included progression free survival (PFS) and non-relapse mortality (NRM). These effect sizes were quantified in terms of hazards ratio (HR) along with 95% confidence interval (CI) and pooled across studies using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the Cochran's Q and the I 2 statistic. All hypothesis testing was two-sided with an alpha of 0.05., Results: Of 3791 studies screened, we identified 20 studies involving 3468 patients with a mean age of 60 years; 44% were female and the most common malignancy was diffuse large B-cell lymphoma (42%). Most studies measured muscle mass using single slice computed tomography imaging at the L3 level. The presence of LSMM was associated with worse OS (pooled HR = 1.81, 95% CI = 1.48-2.22, P < 0.001) with moderate heterogeneity (Cochran's Q, I 2  = 60.4%), PFS (pooled HR = 1.61, 95% CI = 1.28-2.02, P < 0.001) with moderate heterogeneity (Cochran's Q, I 2  = 66.0%). Similarly, LSMM was associated with worse NRM (HR = 1.72, 95% CI = 1.34-2.22, P < 0.001) with little evidence of heterogeneity (Cochran's Q, I 2  = 0.0%)., Conclusions: LSMM is associated with worse survival outcomes among adults with haematologic malignancies. Further research into understanding the underlying mechanism of this association and mitigating the negative effects of LSMM among adults with haematologic malignancies is needed., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Among individuals with heart failure (HF), racial differences in comorbidities may be mediated by social determinants of health (SDOH)., Methods: Black and White US community-dwelling participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study aged ≥ 45 years with an adjudicated HF hospitalization between 2003 and 2017 were included in this cross-sectional analysis. We assessed whether higher prevalence of comorbidities in Black participants compared to White participants were mediated by SDOH in socioeconomic, environment/housing, social support, and healthcare access domains, using the inverse odds weighting method., Results: Black (n = 240) compared to White (n = 293) participants with HF with preserved ejection fraction (HFpEF) had higher prevalence of diabetes [1.38 (95% CI: 1.18 - 1.61)], chronic kidney disease [1.21 (95% CI: 1.01 - 1.45)], and anemia [1.33 (95% CI: 1.02 - 1.75)] and lower prevalence of atrial fibrillation [0.80 (95% CI: (0.65 - 0.98)]. Black (n = 314) compared to White (n = 367) participants with HF with reduced ejection fraction (HFrEF) had higher prevalence of hypertension [1.04 (95% CI: 1.02 - 1.07)] and diabetes [1.26 (95% CI: 1.09 - 1.45)] and lower prevalence of coronary artery disease [0.86 (95% CI: 0.78 - 0.94)] and atrial fibrillation [0.70 (95% CI: 0.58 - 0.83)]. Socioeconomic status explained 14.5%, 26.5% and 40% of excess diabetes, anemia, and chronic kidney disease among Black adults with HFpEF; however; mediation was not statistically significant and no other SDOH substantially mediated differences in comorbidity prevalence., Conclusions: Socioeconomic status partially mediated excess diabetes, anemia, and chronic kidney disease experienced by Black adults with HFpEF, but differences in other comorbidities were not explained by other SDOH examined., Competing Interests: Dr. Emily B. Levitan receives funding from Amgen Inc.

Introduction: Previous research indicates ethnic/race group differences in pain and neurodegenerative diseases. Accounting for socioenvironmental factors reduces ethnic/race group differences in clinical and experimental pain. In the current study sample, we previously reported that in individuals with knee pain, ethnic/race group differences were observed in bilateral temporal lobe thickness, areas of the brain associated with risk for Alzheimer's disease, and related dementias. The purpose of the study was to determine if socioenvironmental factors reduce or account for previously observed ethnic/race group differences and explore if a combined effect of socioenvironmental risk and chronic pain severity on temporal lobe cortices is evident., Methods: Consistent with the prior study, the sample was comprised of 147 adults (95 women, 52 men), 45-85 years of age, who self-identified as non-Hispanic Black (n = 72) and non-Hispanic White (n = 75), with knee pain with/at risk for osteoarthritis. Measures included demographics, health history, pain questionnaires, cognitive screening, body mass index, individual- and community-level socioenvironmental factors (education, income, household size, marital and insurance status, and area deprivation index), and brain imaging. We computed a summative socioenvironmental risk index., Results: Regression analyses showed that with the inclusion of socioenvironmental factors, the model was significant (p < .001), and sociodemographic (ethnic/race) group differences were not significant (p = .118). Additionally, findings revealed an additive stress load pattern indicating thinner temporal lobe cortices with greater socioenvironmental risk and chronic pain severity (p = .048)., Implications: Although individual socioenvironmental factors were not independent predictors, when collectively combined in models, ethnic/race group differences in bilateral temporal lobe structures were not replicated. Further, combined socioenvironmental risk factors and higher chronic pain severity were associated with thinner bilateral temporal lobes., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objectives: People with HIV (PWH) are aging and are experiencing higher rates of abdominal adiposity. Physical activity is an effective nonpharmacological strategy to reduce adiposity in the general aging population. Yet, the relationship between physical activity and adiposity in people with well controlled HIV is unclear. Our objective was to describe the association between objectively-measured physical activity and abdominal adiposity in PWH., Methods: As part of the multisite, observational PROSPER-HIV study, virologically suppressed, adult PWH wore an Actigraph accelerometer for 7-10 days and completed duplicate waist and hip circumference measures. Demographic and medical characteristics were abstracted from the CFAR Network of Integrated Clinical Systems dataset. Descriptive statistics and multiple linear regressions were used to analyze the data., Results: On average, our 419 PWH were 58 years of age [interquartile range (IQR): 50, 64], male (77%), Black (54%), and currently taking an integrase inhibitor (78%). PWH completed a mean of 7.06 (±2.74) days of total actigraphy wear time. They took an average of 4905 (3233, 7140) steps per day and engaged in 5.4 h of sedentary time per day. Controlling for age, sex, employment and integrase inhibitor use, the number of steps taken per day was associated with reduced abdominal adiposity ( F  = 3.27; P  < 0.001) and the hours of daily sedentary time was associated with increased abdominal adiposity ( F  = 3.24; P  < 0.001)., Conclusions: Greater physical activity is associated with reduced abdominal adiposity in aging PWH. Future work should investigate how to tailor the amount, type and intensity of physical activity needed to reduce adiposity in PWH taking contemporary HIV medication., Registration Number: NCT03790501., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Angiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the noncanonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction, and fibrosis. Preclinical evidence suggests that Ang (1-7) is a promising therapeutic target that may ameliorate physical and cognitive function in late life. However, treatment pharmacodynamics limits its clinical applicability. Therefore, this study explored the underlying mechanisms altered by a genetically modified probiotic (GMP) that expresses Ang (1-7) combined with and without exercise training in an aging male rat model as a potential adjunct strategy to exercise training to counteract the decline of physical and cognitive function. We evaluated cross-tissue (prefrontal cortex, hippocampus, colon, liver, and skeletal muscle) multi-omics responses. After 12 wk of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within- and between groups. The probiotic treatment enhanced α diversity (Inverse Simpson ( F [2,56] = 4.44; P = 0.02); Shannon-Wiener ( F [2,56] = 4.27; P = 0.02)) and β-diversity ( F [2,56] = 2.66; P = 0.01) among rats receiving our GMP. The analysis of microbes' composition revealed three genera altered by our GMP ( Enterorhabdus , Muribaculaceae unclassified , and Faecalitalea ). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuroremodeling pathways on prefrontal cortex (i.e., 140 genes), inflammation gene expression in the liver (i.e., 63 genes), and circadian rhythm signaling on skeletal muscle. Finally, the integrative network analysis detected different communities of tightly (| r | > 0.8 and P < 0.05) correlated metabolites, genera , and genes in these tissues. NEW & NOTEWORTHY This manuscript uses a multiomics approach (i.e., microbiome, metabolomics, and transcriptomics) to explore the underlying mechanisms driven by a genetically modified probiotic (GMP) designed to express angiotensin (1-7) combined with moderate exercise training in an aged male rat model. After 12 wk of intervention, our findings suggest that our GMP enhanced gut microbial diversity while exercise training altered the transcriptional response in relevant neuroremodeling genes, inflammation, and circadian rhythm signaling pathways in an aging animal model.

Exercise is a cornerstone of preventive medicine and a promising strategy to intervene on the biology of aging. Variation in the response to exercise is a widely accepted concept that dates back to the 1980s with classic genetic studies identifying sequence variations as modifiers of the VO 2 max response to training. Since that time, the literature of exercise response variance has been populated with retrospective analyses of existing datasets that are limited by a lack of statistical power from technical error of the measurements and small sample sizes, as well as diffuse outcomes, very few of which have included older adults. Prospective studies that are appropriately designed to interrogate exercise response variation in key outcomes identified a priori and inclusive of individuals over the age of 70 are long overdue. Understanding the underlying intrinsic (e.g., genetics and epigenetics) and extrinsic (e.g., medication use, diet, chronic disease) factors that determine robust versus poor responses to various exercise factors will be used to improve exercise prescription to target the pillars of aging and optimize the clinical efficacy of exercise training in older adults. This review summarizes the proceedings of the NIA-sponsored workshop entitled, "Understanding Heterogeneity of Responses to, and Optimizing Clinical Efficacy of, Exercise Training in Older Adults" and highlights the importance and current state of exercise response variation research, particularly in older adults, prevailing challenges, and future directions., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Endurance exercise alters the gut microbiome independently of diet. The extent to which gut microbes are responsible for physiologic adaptations to exercise training is unknown. The purpose of these experiments was to determine the role of gut microbes in performance and muscle adaptation to 6 wk of voluntary wheel running (VWR) in mice., Methods: We depleted microbes with broad-spectrum antibiotic (ABX) treatment and used germ-free (GF) mice to determine effects on adaptations to VWR. Male and female C57Bl/6 mice ( n = 56) were assigned to daily VWR or sedentary conditions. After the intervention, treadmill endurance and glucose tolerance were assessed, and gastrocnemius and soleus tissues were harvested and analyzed for citrate synthase (CS) enzyme activity and expression of exercise training-sensitive genes., Results: ABX treatment and GF status resulted in VWR volumes ~22% and 26% lower than controls, respectively. Analysis of variance revealed that, although VWR increased treadmill endurance, ABX had no effect. GF status significantly reduced treadmill performance in trained GF mice after training. VWR increased gastrocnemius CS enzyme activity in all groups, and ABX and GF status did not reduce the VWR effect. VWR also increased muscle expression of PGC1a, but this was not affected by ABX treatment., Conclusions: ABX treatment and GF status reduced VWR behavior but did not affect VWR-induced adaptations in endurance capacity, CS activity, or expression of muscle metabolic genes. However, GF status reduced endurance capacity. These data indicated that reducing microbes in adulthood does not inhibit endurance training adaptations in C57Bl/6 mice, but that GF mice possess a reduced responsiveness to endurance exercise training, perhaps because of a developmental defect associated with lack of microbes from birth., (Copyright © 2022 by the American College of Sports Medicine.)

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.

Declining health, gut dysbiosis, and cognitive impairments are hallmarks of advanced age. While caloric restriction is known to robustly extend the healthspan and alter gut microbiome composition, it is difficult maintain. Time-restricted feeding or changes in dietary macronutrient composition could be feasible alternatives for enhancing late life cognitive and physical health that are easier to comply with for extended periods of time. To investigate this possibility, 8-month-old rats were placed on time-restricted feeding with a ketogenic or micronutrient- and calorically matched control diet for 13 months. A third group of rats was permitted to eat standard chow ad libitum during this time. At 22 months, all rats were tested on a biconditional association task and fecal samples were collected for microbiome composition analysis. Regardless of dietary composition, time-restricted-fed rats had better cognitive performance than ad libitum-fed rats. This observation could not be accounted for by differences in motivation, procedural or sensorimotor impairments. Additionally, there were significant differences in gut microbiome diversity and composition between all diet conditions. Allobaculum abundance was associated with cognitive task performance, indicating a link between gut health and cognitive outcomes in aged subjects. Overall, time restricted feeding had the largest influence on cognitive performance in aged rats., Competing Interests: The authors declare no conflict of interest.

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., (© 2022. The Author(s).)

Both ketogenic diets (KD) and time-restricted feeding (TRF) regimens have the ability to influence several parameters of physical health, including gut microbiome composition and circulating cytokine concentration. Moreover, both of these dietary interventions prevent common impairments associated with the aging process. However, significantly altering macronutrient intake, which is required for a KD, may be unappealing to individuals and decrease compliance to dietary treatments. In contrast to a KD, TRF allows individuals to continue eating the foods they are used to, and only requires a change in the time of day at which they eat. Therefore, we investigated both a KD and a diet with a more Western-like macronutrient profile in the context of TRF, and compared both diets to animals allowed access to standard chow ad libitum in young adult and aged rats. While limited effects on cytokine levels were observed, both methods of microbiome analysis (16S sequencing and metagenomics) indicate that TRF and KDs significantly altered the gut microbiome in aged rats. These changes were largely dependent on changes to feeding paradigm (TRF vs. ad libitum) alone regardless of macronutrient content for many gut microbiota, but there were also macronutrient-specific changes. Specifically, functional analysis indicates significant differences in several pathways, including those involved in the tricarboxylic acid (TCA) cycle, carbohydrate metabolism and neurodegenerative disease. These data indicate that age- and disease-related gut dysbiosis may be ameliorated through the use of TRF with both standard diets and KDs.

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Chronic low back pain (cLBP) is the most common reason for individual suffering and health care utilization in adults. Ample evidence suggests sociodemographic variables and socioeconomic status (SES) influence pain. However, a framework informing associations on race, SES, and the utilization of pharmacologic therapies and provider type are limited-particularly in cLBP. Thus, this study examined the extent to which sociodemographic (i.e., age, race, and gender) and socioeconomic factors (i.e., national area deprivation index, NADI) influence pain treatment (i.e., NSAIDs, opioids, antidepressants, and non-NSAIDs) and provider utilization for cLBP (i.e., no provider care, primary care, or tertiary care). Eligible participants with cLBP completed a series of questionnaires. Of the 174 participants, 58% were women, 59% were non-Hispanic Black (NHB), and the mean age was 46.10 (SD 13.58). Based on NADI distributions by race, NHB participants lived in more socioeconomically disadvantaged neighborhoods ( p < 0.001) than non-Hispanic White (NHW) adults. Results suggested that the use of one or more pharmacologic therapies was associated with race ( p = 0.021). Specifically, NHW adults were two times more likely to take one or more pharmacologic therapies than NHBs ( p = 0.009). NHWs were also more likely to use NSAIDs ( p = 0.041) and antidepressants ( p < 0.001) than NHBs. Furthermore, provider utilization was significantly associated with gender ( p = 0.037) and age ( p = 0.018); which suggests older women were more likely to use primary or tertiary care. Findings from this study expand on the existing literature as it relates to associations between disparities in access to healthcare providers and access to medications. Future research should seek to understand differences in age and utilization of primary or tertiary care providers and continue to examine the influence of sociodemographic and SES factors to cLBP and compare with other types of chronic pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Allen-Watts, Sims, Buchanan, DeJesus, Quinn, Buford, Goodin and Rumble.)

Introduction: Growing research suggests that aerobic high-intensity interval training (HIIT) improves cardiovascular function and physical performance compared with moderate intensity continuous training (MICT). However relatively few animal models of HIIT are available to inform about the benefits of this exercise-particularly among older animals. In addition, there is little evidence for how HIIT training interacts with adjuvant pharmacological therapies known to enhance the impact of MCIT in older individuals such as Angiotensin Converting Enzyme (ACE) Inhibitors., Purpose: The aim of the present study was to establish a HIIT protocol in aged rats based on forced running wheel-bed, and to subsequently (1) establish the feasibility of the HIIT protocol in a proof-of-concept study evaluating interactions between HIIT and (2) the result of combining HIIT + ACE inhibitor treatment using the ACE inhibitor enalapril., Methods: Two groups of rats were used in this study. The feasibility of using wheel-bed for HIIT training was tested in group one (15- and 30-month-old male rats). In the second group, 37 24-month-old Fisher 344 × Brown Norway male rats were randomly divided into four subgroups: control, enalapril, HIIT training group, and HIIT training combined with enalapril administration. The training and administration lasted for 4 weeks. After the intervention, locomotor activity, exercise tolerance, and grip strength were tested., Results: Our feasibility study suggested that middle-aged and aged rats were able to successfully complete the HIIT training. In our intervention study, HIIT training alone, regardless of adjuvant enalapril intervention, did raise treadmill exercise tolerance vs. the sedentary condition. Measures of healthspan were not negatively impacted by HIIT training., Conclusion: The novel HIIT protocol based on forced running wheel-bed was successfully employed in aged rats. We conclude that future studies should compare the results and of multi-modal intervention strategies which include both HIIT and MICT in combination with adjuvant therapies such as enalapril to improve exercise tolerance and other global indices of healthspan., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The UAB Nathan Shock Center focuses on comparative energetics and aging. Energetics, as defined for this purpose, encompasses the causes, mechanisms, and consequences of the acquisition, storage, and use of metabolizable energy. Comparative energetics is the study of metabolic processes at multiple scales and across multiple species as it relates to health and aging. The link between energetics and aging is increasingly understood in terms of dysregulated mitochondrial function, altered metabolic signaling, and aberrant nutrient responsiveness with increasing age. The center offers world-class expertise in comprehensive, integrated energetic assessment and analysis from the level of the organelle to the organism and across species from the size of worms to rats as well as state-of-the-art data analytics. The range of services offered by our three research cores, (1) The Organismal Energetics Core, (2) Mitometabolism Core, and (3) Data Analytics Core, is described herein., (© 2021. American Aging Association.)

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.

Increasing life expectancies are unfortunately accompanied by increased prevalence of Alzheimer's disease (AD). Regrettably, there are no current therapeutic options capable of preventing or treating AD. We review here data indicating that AD is accompanied by gut dysbiosis and impaired renin angiotensin system (RAS) function. Therefore, we propose the potential utility of an intervention targeting both the gut microbiome and RAS as both are heavily involved in proper CNS function. One potential approach which our group is currently exploring is the use of genetically-modified probiotics (GMPs) to deliver therapeutic compounds. In this review, we specifically highlight the potential utility of utilizing a GMP to deliver Angiotensin (1-7), a beneficial component of the renin-angiotensin system with relevant functions in circulation as well as locally in the gut and brain., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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.

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA 4977 ) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope ( 56 Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA 4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

To (1) investigate the efficacy of multiple doses of an orally delivered probiotic bacteria Lactobacillus paracasei (LP) modified to express angiotensin (1-7) (LP-A) in altering physiologic parameters relevant to the gut-brain axis in older rats and to (2) compare this strategy with subcutaneous delivery of synthetic Ang(1-7) peptide on circulating Ang(1-7) concentrations and these gut-brain axis parameters. Male 24-month-old F344BN rats received oral gavage of LP-A, or subcutaneous injection of Ang(1-7) for 0×, 1×, 3×, or 7×/week over 4 weeks. Circulating RAS analytes, inflammatory cytokines, and tryptophan and its downstream metabolites were measured by ELISA, electrochemiluminescence, and LC-MS respectively. Microbiome taxonomic analysis of fecal samples was performed via 16S-based PCR. Inflammatory and tryptophan-related mRNA expression was measured in colon and pre-frontal cortex. All dosing regimens of LP-A induced beneficial changes in fecal microbiome including overall microbiota community structure and α-diversity, while the 3×/week also significantly increased expression of the anti-inflammatory species Akkermansia muciniphila. The 3×/week also increased serum serotonin and the neuroprotective analyte 2-picolinic acid. In the colon, LP-A increased quinolinate phosphoribosyltransferase expression (1×/week) and increased kynurenine aminotransferase II (1× and 3×/week) mRNA expression. LP-A also significantly reduced neuro-inflammatory gene expression in the pre-frontal cortex (3×/week: COX2, IL-1β, and TNFα; 7×/week: COX2 and IL-1β). Subcutaneous delivery of Ang(1-7) increased circulating Ang(1-7) and reduced angiotensin II, but most gut-brain parameters were unchanged in response. Oral-but not subcutaneous-Ang(1-7) altered physiologic parameters related to gut-brain axis, with the most effects observed in 3×/week oral dosing regimen in older rats.

Cognitive frailty is a geriatric condition defined by the coexistence of cognitive impairment and physical frailty. This "composite" aging phenotype is associated with a higher risk of several adverse health-related outcomes, including dementia. In the last decade, cognitive frailty has gained increased attention from the scientific community that has focused on understanding the clinical impact and the physiological and pathological mechanisms of development and on identifying preventive and/or rehabilitative therapeutic interventions. The emergence of gut microbiome in neural signaling increased the interest in targeting the gut-brain axis as a modulation strategy. Multiple studies on gastroenteric, metabolic, and neurodegenerative diseases support the existence of a wide bidirectional communication network of signaling mediators, e.g., bioactive lipids, that can modulate inflammation, gut permeability, microbiota composition, and the gut-brain axis. This crosstalk between the gut-brain axis, microbiome, and bioactive lipids may emerge as the basis of a promising therapeutic strategy to counteract cognitive frailty. In this review, we summarize the evidence in the literature regarding the link between the gut microbiome, brain, and several families of bioactive lipids. In addition, we also explore the applicability of several bioactive lipid members as a potential routes for therapeutic interventions to combat cognitive frailty., (Copyright © 2020 Baptista, Sun, Carter and Buford.)

Hypertension has been linked with peripheral and central reductions in vascular density, and with devastating effects on brain function. However, the underlying mechanisms in the relationship between blood pressure and cognitive impairment have yet to be fully elucidated. Here, we review compelling evidence from two lines of inquiry: one that links microvascular rarefaction with insulin-like growth factor 1 (IGF-1) deficiencies, and another which posits that vascular dysfunction precedes hypertension. Based on the findings from experimental and clinical studies, we propose that these lines of evidence converge, and suggest that age-related declines in IGF-1 concentrations precede microvascular rarefaction, initiate an increase in vascular resistance, and therefore are causally linked to onset of hypertension. Physical exercise provides a relevant model for supporting our premise, given the well-established effects of exercise in attenuating vascular dysfunction, hypertension, IGF-1 deficiency, and cognitive decline. We highlight here the role of exercise-induced increases in blood flow in improving vascular integrity and enhancing angiogenesis via the actions of IGF-1, resulting in reversal of rarefaction and hypertension, and enhancement of cerebral blood flow and cognition.

Prior evidence suggests that the choice of antihypertensive medication may influence functional status among older adults with hypertension, particularly in conjunction with exercise. In particular, angiotensin converting enzyme (ACE) inhibitors have shown potential to positively influence function. However, randomized, controlled trials are needed to confirm this hypothesis. This paper outlines an RCT designed to determine if choice of first-line antihypertensive medication influences functional and cardiovascular risk factor responses to exercise among older adults with hypertension. Two hundred and thirteen inactive, community-dwelling adults ≥60 years of age with hypertension and functional limitations will be recruited to engage in a 32-week intervention study. Participants will be randomized to one of three first-line antihypertensive agents: (1) the ACE inhibitor perindopril, (2) the AT1 receptor antagonist losartan, or (3) the thiazide diuretic hydrochlorothiazide (HCTZ). Six weeks after randomization, participants will begin a 20-week structured aerobic exercise intervention. Participants will perform two 45-min center-based sessions coupled with 60 min of home-based walking per week. The primary aim is to determine if perindopril improves self-paced gait speed when compared with losartan and HCTZ. The secondary aim is to determine the relative effect of perindopril on secondary outcomes such as: (a) exercise capacity, (b) body mass and composition, and (c) circulating indices of cardiovascular risk. This RCT is expected to identify differential effects of first-line antihypertensive medications when combined with physical exercise thus have potential implications for antihypertensive prescription guidelines for older adults. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03295734., (Copyright © 2020 Harper, Baptista, Roberts, Wherry, Boxer, Hildreth, Seay, Allman, Carter, Aban, Kohrt and Buford.)

Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters differed between HF and LF participants. Our findings suggest that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.

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.

In a pilot randomized clinical trial, participants aged ≥60 years ( n = 35) with physical limitations and symptomatic knee osteoarthritis (OA) were randomized to 12 weeks of lower-body low-load resistance training with blood-flow restriction (BFR) or moderate-intensity resistance training (MIRT) to evaluate changes in muscle strength, pain, and physical function. Four exercises were performed three times per week to volitional fatigue using 20% and 60% of one repetition maximum (1RM). Study outcomes included knee extensor strength, gait speed, Short Physical Performance Battery (SPPB) performance, and pain via the Western Ontario and McMaster Universities OA Index (WOMAC). Per established guidance for pilot studies, primary analyses for the trial focused on safety, feasibility, and effect sizes/95% confidence intervals of dependent outcomes to inform a fully-powered trial. Across three speeds of movement, the pre- to post-training change in maximal isokinetic peak torque was 9.96 (5.76, 14.16) Nm while the mean difference between groups (BFR relative to MIRT) was -1.87 (-10.96, 7.23) Nm. Most other directionally favored MIRT, though more spontaneous reports of knee pain were observed ( n = 14) compared to BFR ( n = 3). BFR may have lower efficacy than MIRT in this context-though a fully-powered trial is needed to definitively address this hypothesis.

This pilot randomized controlled trial (RCT) was designed to provide the preliminary data necessary to conduct a full-scale trial to compare the efficacy of differing first-line antihypertensive medications in improving functional status in older adults, when combined with exercise. The primary objectives were to assess study feasibility, safety, and protocol integrity. Dependent outcomes included gait speed, exercise capacity, body composition, and systemic cardiometabolic biomarkers. Thirty-one physically inactive older adults (70.6 ± 6.1 years) with hypertension and functional limitations were randomly assigned to 1) Perindopril (8 mg/day n = 10), 2) Losartan (100 mg/day; n = 13), or 3) Hydrochlorothiazide (HCTZ: 25 mg/day; n = 8). Participants were also assigned to a 24-week multimodal exercise intervention, separated into an aerobic and concurrent (aerobic + resistance) phase to evaluate potential mode effects. Retention was 84% (26/31), and compliance was >90% and >79% with medication and exercise, respectively. A total of 29 adverse events (Perindopril = 5; Losartan = 12; HCTZ = 11) and one unrelated serious adverse event were observed throughout the trial. Overall, this pilot RCT provided critical data and identified several challenges to ultimately designing and implementing a fully powered trial., Competing Interests: The authors declare no conflicts of interest

Declines in walking speed are associated with a variety of poor health outcomes including disability, comorbidity, and mortality. While genetic factors are putative contributors to variability in walking, few genetic loci have been identified for this trait. We examined the role of mitochondrial genomic variation on walking speed by sequencing the entire mitochondrial DNA (mtDNA). Data were meta-analyzed from 1758 Lifestyle Interventions and Independence for Elders (LIFE) Study and replication data from 730 Health, Aging, and Body Composition (HABC) Study participants with baseline walking speed information. Participants were 69+ years old of diverse racial backgrounds (African, European, and other race/ethnic groups) and had a wide range of mean walking speeds [4-6 m (0.78-1.09 m/s) and 400 m (0.83-1.24 m/s)]. Meta-analysis across studies and racial groups showed that m.12705C>T, ND5 variant was significantly associated (p < 0.0001) with walking speed at both short and long distances. Replication and meta-analysis also identified statistically significant walking speed associations (p < 0.0001) between the m.5460.G>A, ND2 and m.309C>CT, HV2 variants at short and long distances, respectively. All results remained statistically significant after multiple comparisons adjustment for 499 mtDNA variants. The m.12705C>T variant can be traced to the beginnings of human global migration and that cells carrying this variant display altered tRNA expression. Significant pooled effects related to stopping during the long-distance walk test were observed across OXPHOS complexes I (p = 0.0017) and III (p = 0.0048). These results suggest that mtDNA-encoded variants are associated with differences in walking speed among older adults, potentially identifying those at risk of developing mobility impairments.

Over the last few decades, considerable evidence shows that greater levels of aerobic exercise and cardiovascular fitness benefit cognitive performance. However, the degree to which free-living activity in community settings is related to cognitive performance remains unclear, particularly in older adults vulnerable to disability. Also, it is unknown whether the manner in which daily physical activity (PA) and sedentary time are accumulated throughout the day is associated with cognition. Cross-sectional associations between accelerometer-characterized PA and sedentary patterns and cognitive performance were examined in 1,274 mobility-limited older adults. Percent time spent in various bout lengths of PA (≥1, ≥2, and ≥5 min) and sedentary (≥1, ≥30, and ≥60 min) was defined as the number of minutes registered divided by total wear time × 100. Percent time was then tertiled for each bout length. Multiple linear regression models were used to estimate the associations between accelerometer bout variables and separate cognitive domains that included processing speed (Digit Symbol Coding; DSC), immediate and delayed recall (Hopkins Verbal Learning Test; HVLT), information processing and selective attention (Flanker), working memory ( n -back), reaction time (switch and non-switch reaction time), and a composite score that averaged results from all cognitive tests. After adjusting for demographics, behavioral factors, and morbid conditions, more time spent in PA was associated with higher DSC for all bout lengths ( p < 0.03 for all). Higher PA was associated with higher HVLT and global cognition scores but only for longer bout lengths ( p < 0.05 for all). The association was largely driven by participants who spent the lowest amount of time performing activity while awake ( p < 0.04). An inverse linear relationship was observed between total sedentary time and DSC ( p = 0.02), but not for other measures of cognition. These results suggest that, while higher PA was associated with higher cognitive performance, PA's association with memory was sensitive to bout duration. The time, but not the manner, spent in sedentary behaviors showed a minor association with executive function. Further research is warranted to characterize longitudinal changes in daily activity and sedentary patterns as potential biophysical markers of cognitive status in older adults.

Background Age-related changes in blood pressure are associated with a variety of poor health outcomes. Genetic factors are proposed contributors to age-related increases in blood pressure, but few genetic loci have been identified. We examined the role of mitochondrial genomic variation in blood pressure by sequencing the mitochondrial genome. Methods and Results Mitochondrial DNA (mt DNA ) data from 1755 participants from the LIFE (Lifestyle Interventions and Independence for Elders) studies and 788 participants from the Health ABC (Health, Aging, and Body Composition) study were evaluated using replication analysis followed by meta-analysis. Participants were aged ≥69 years, of diverse racial backgrounds, and assessed for systolic blood pressure ( SBP ), diastolic blood pressure, and mean arterial pressure. After meta-analysis across the LIFE and Health ABC studies, statistically significant associations of mt DNA variants with higher SBP (m.3197T>C, 16S rRNA ; P=0.0005) and mean arterial pressure (m.15924A>G, t-RNA-thr; P=0.004) were identified in white participants. Among black participants, statistically significant associations with higher SBP (m.93A>G, HVII ; m.16183A>C, HVI ; both P=0.0001) and mean arterial pressure (m.16172T>C, HVI ; m.16183A>C, HVI ; m.16189T>C, HVI ; m.12705C>T; all P's<0.0004) were observed. Significant pooled effects on SBP were observed across all transfer RNA regions ( P=0.0056) in white participants. The individual and aggregate variant results are statistically significant after multiple comparisons adjustment for the number of mt DNA variants and mitochondrial regions examined. Conclusions These results suggest that mt DNA -encoded variants are associated with variation in SBP and mean arterial pressure among older adults. These results may help identify mitochondrial activities to explain differences in blood pressure in older adults and generate new hypotheses surrounding mt DNA variation and the regulation of blood pressure. Clinical Trial Registration URL : http://www.ClinicalTrials.gov . Unique identifiers: NCT 01072500 and NCT 00116194.

Background: Cardiorespiratory fitness (CRF) is the only major risk factor that is not routinely assessed in the clinical setting, for preventive medicine. A valid and practical CRF test is needed for use in the clinics. The objective of this study is to demonstrate the validity of a 3-minute squat test to assess CRF in primary care., Methods: A cross-sectional study in which the participants performed both the Ruffier squat test and the Balke maximal treadmill test. The study was conducted in a clinical setting from September 2016 to March 2017. We recruited a convenient sample of 40 adults between 18 and 64 years from the general U.S. population. Participants completed 30 squats in 45 seconds, paced by a metronome. Heart rate was measured at rest (P1), immediately after the test (P2), one minute after the test (P3). [Formula: see text] was measured using the Balke maximal treadmill fitness test., Results: Of the 40 participants, there were 18 men and 22 women. Mean age was 31.2 years (SD = 9.9). We found that the best [Formula: see text] predictors were HR features P1/height and (P2-P3)/age3. Our best-performing model using these two features predicted individuals' CRF levels with an adjusted R2 of 0.637, sensitivity of 0.79, and specificity of 0.56., Conclusions: The study provided strong evidence for the validity of the squat test in the clinical setting. Further, the equation of our model along with [Formula: see text] normative tables provides an efficient and easy way to assess CRF in a primary care setting., Competing Interests: The authors have declared that no competing interests exist.

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.

Advanced age has been associated with alterations to the microbiome within the intestinal tract as well as intestinal permeability (i.e., "leaky gut"). Prior studies suggest that intestinal permeability may contribute to increases in systemic inflammation-an aging hallmark-possibly via microorganisms entering the circulation. Yet, no studies exist describing the state of the circulating microbiome among older persons. To compare microbiota profiles in serum between healthy young (20-35 years, n = 24) and older adults (60-75 years, n = 24) as well as associations between differential microbial populations and prominent indices of age-related inflammation. Unweighted Unifrac analysis, a measure of β-diversity, revealed that microbial communities clustered differently between young and older adults. Several measures of α-diversity, including chao1 (p = 0.001), observed species (p = 0.001), and phylogenetic diversity (p = 0.002) differed between young and older adults. After correction for false discovery rate (FDR), age groups differed (all p values ≤ 0.016) in the relative abundance of the phyla Bacteroidetes, SR1, Spirochaetes, Bacteria&#95;Other, TM7, and Tenericutes. Significant positive correlations (p values ≤ 0.017 after FDR correction) were observed between IGF1 and Bacteroidetes (ρ = 0.380), Spirochaetes (ρ = 0.528), SR1 (ρ = 0.410), and TM7 (ρ = 0.399). Significant inverse correlations were observed for IL6 with Bacteroidetes (ρ = - 0.398) and TM7 (ρ = - 0.423), as well as for TNFα with Bacteroidetes (ρ = - 0.344). Similar findings were observed at the class taxon. These data are the first to demonstrate that the richness and composition of the serum microbiome differ between young and older adults and that these factors are linked to indices of age-related inflammation.

Background: Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study., Methods and Results: Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P =0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [ P =0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [ P =0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [ P =0.002]) were significantly associated with lower cardiovascular event rates., Conclusions: Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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.

Chronic inflammation represents one of the most consistent biologic features of aging. However, the precise etiology of persistent low-grade increases in inflammation remains unclear. Recent evidence suggests that the gut microbiome may play a key role in age-related inflammation. Indeed, several studies have indicated that older adults display an altered composition of the gut microbiota, and early evidence indicates that this dysbiosis is associated with the presence of several key circulating inflammatory analytes. The present review summarizes knowledge on age-related inflammation and discusses how potential relationships with gut dysbiosis may lead to novel treatment strategies in the future."The pattern of disease is an expression of the response of man to his total environment (physical, biological, and social); this response is, therefore, determined by anything that affects man himself or his environment." - Rene Dubos, 1961.