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This article explores the relationship between aging and the decline in oxidative capacity of skeletal muscle mitochondria. Mitochondria play a crucial role in producing ATP, which is necessary for cellular energy. The decrease in mitochondrial function with age can lead to reduced energy supply, increased stress, inflammation, and impaired cell signaling. Various factors, such as physical activity, muscle fiber type, comorbidities, and genetic background, can influence mitochondrial energetics in skeletal muscle. The article highlights the importance of understanding the complex interplay between physical activity, mitochondrial function, and mobility performance in older adults. It provides a list of references to scientific articles that delve into topics like ATP utilization, inflammation regulation, and the impact of aging and exercise on muscle function. The article is published by The Journal of Physiology and The Physiological Society and is supported by funding from the Pepper Older American Independence Centers and Clinical and Translational Science Institutes. [Extracted from the article]

Findings from the Study of Muscle, Mobility and Aging (SOMMA) in this issue of Aging Cell show that several biological pathways in skeletal muscle cells play an important role in determining mobility in older adults. These are based on assays in skeletal muscle biopsies obtained from participants, aged 70 years and older in SOMMA tested for association with assessments related to mobility, including muscle mass, strength, power, cardiopulmonary fitness, and 400 m walking speed. The papers show that, using mass spectrometry, oxidative modifications of proteins essential to myocellular function are associated with poorer mobility. Using RNA‐seq to quantify gene expression, lower levels of expression of antioxidant enzymes located in mitochondria, autophagy, patterns of expression of genes involved in autophagy, and higher levels of RNA transcripts that increase with denervation were associated with poorer performance on tests of mobility. These results extend previous research from the Baltimore Longitudinal Study of Aging and recent studies from SOMMA showing the importance of mitochondrial energetics in mobility. Together, these findings are painting a picture of how fundamental cellular processes influence the loss of mobility with aging. They may also be a window on aging in other cells, tissues, and systems. The data collected in SOMMA are publicly available and SOMMA welcomes collaborations with scientists who are interested in research about human aging. [ABSTRACT FROM AUTHOR]

The National Institute on Aging (NIA), part of the National Institutes of Health (NIH), was founded in 1974 to support and conduct research on aging and the health and well‐being of older adults. Fifty years ago, the concept of studying aging generated much skepticism. Early NIA‐funded research findings helped establish the great value of aging research and provided the foundation for significant science advances that have improved our understanding of the aging process, diseases and conditions associated with aging, and the effects of health inequities, as well as the need to promote healthy aging lifestyles. Today, we celebrate the many important contributions to aging research made possible by NIA, as well as opportunities to continue to make meaningful progress. NIA emphasizes that the broad aging research community must continue to increase and expand our collective efforts to recruit and train a diverse next generation of aging researchers. [ABSTRACT FROM AUTHOR]

Physical activity is consistently associated with better health and longer life spans. However, the extent to which length and intensity of exercise across the life course impact health outcomes relative to current activity is undefined. Participants of the Baltimore Longitudinal Study of Aging were asked to categorize their level of physical activity in each decade of life from adolescence to the current decade. In linear mixed effects models, self‐reported past levels of physical activity were significantly associated with activity assessed at study visits in the corresponding decade of life either by questionnaire or accelerometry. A pattern of life course physical activity (LCPA) derived by ranking participants on reported activity intensity across multiple decades was consistent with the trajectories of activity estimated from standard physical activity questionnaires assessed at prior study visits. In multivariable linear regression models LCPA was associated with clinical characteristics, measures of body composition and indicators of physical performance independent of current physical activity. After adjustment for minutes of high intensity exercise, LCPA remained significantly associated with peak VO2, fasting glucose, thigh muscle area and density, abdominal subcutaneous fat, usual gait speed, lower extremity performance, and multimorbidity (all p < 0.01) at the index visit. The observed associations suggest that an estimate of physical activity across decades provides complementary information to information on current activity and reemphasizes the importance of consistently engaging in physical activity over the life course. [ABSTRACT FROM AUTHOR]

Aging adults experience increased health vulnerability and compromised abilities to cope with stressors, which are the clinical manifestations of frailty. Frailty is complex, and efforts to identify biomarkers to detect frailty and pre‐frailty in the clinical setting are rarely reproduced across cohorts. We developed a predictive model incorporating biological and clinical frailty measures to identify robust biomarkers across data sets. Data were from two large cohorts of older adults: "Invecchiare in Chianti (Aging in Chianti, InCHIANTI Study") (n = 1453) from two small towns in Tuscany, Italy, and replicated in the Atherosclerosis Risk in Communities Study (ARIC) (n = 6508) from four U.S. communities. A complex systems approach to biomarker selection with a tree‐boosting machine learning (ML) technique for supervised learning analysis was used to examine biomarker population differences across both datasets. Our approach compared predictors with robust, pre‐frail, and frail participants and examined the ability to detect frailty status by race. Unique biomarker features identified in the InCHIANTI study allowed us to predict frailty with a model accuracy of 0.72 (95% confidence interval (CI) 0.66–0.80). Replication models in ARIC maintained a model accuracy of 0.64 (95% CI 0.66–0.72). Frail and pre‐frail Black participant models maintained a lower model accuracy. The predictive panel of biomarkers identified in this study may improve the ability to detect frailty as a complex aging syndrome in the clinical setting. We propose several concrete next steps to keep research moving toward detecting frailty with biomarker‐based detection methods. [ABSTRACT FROM AUTHOR]

Objective: Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein‐based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. Methods: In 706 cognitively normal adults, we examined whether 14 protein‐based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma‐based biomarkers of AD pathology (amyloid‐β [Aβ]42/40, tau phosphorylated at threonine‐181 [pTau‐181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein‐based health indicators associated with neurodegeneration also predict 25‐year dementia risk. Results: Greater protein‐based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ42/40 and higher pTau‐181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau‐181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ42/40, pTau‐181, NfL, and GFAP levels, respectively. Only protein‐based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25‐year dementia risk, even among those without clinically defined cardiovascular disease. Interpretation: Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260–273 [ABSTRACT FROM AUTHOR]

Geroscience poses that core biological mechanisms of aging contribute to chronic diseases and disabilities in late life and that health span and longevity can be modulated by pharmacological and behavioral interventions. Despite strong evidence from studies in model organisms and great potentials for translation, most geriatricians remain skeptical that geroscience will help them in the day‐by‐day battle with the consequences of aging in their patients. We believe that a closer collaboration between gerontologists and geriatricians is the key to overcome this impasse. There is evidence that trajectories of health with aging are rooted in intrinsic and extrinsic exposures that occur early in life and affect the pace of molecular and cellular damage accumulation with aging, also referred to as the "pace" of biological aging. Tools that measure the pace of aging currently allow for the identification of individuals experiencing accelerated aging and at higher risk of multimorbidity and disability. What we term "Translational Geroscience", i.e., the merger of fundamental and translational science with clinical practice, is thus poised to extend the action of geriatric care to a life course perspective. By targeting core mechanisms of aging, gerotherapeutics should be effective in treating patients with multimorbidity and disability, phenotypes that are all too common among geriatric patients nowadays. We call for initiatives that enhance the flow of ideas between gerontologists and geriatricians to facilitate the growth of translational geroscience. This approach can widen the scope of geriatric care, including a new role for geroscience in the promotion and operationalization of healthy longevity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We assessed whether midlife sensory and motor functions added to prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS) improve risk predictions of 10‐year changes in biomarkers of neurodegeneration and Alzheimer's disease. METHODS: Longitudinal data of N = 1529 (mean age 49years) Beaver Dam Offspring Study participants from baseline, 5‐year, and 10‐year follow‐up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function measures improves CAIDE or FRS risk predictions of 10‐year incidence of biomarker positivity of serum‐based neurofilament light chain (NfL) and amyloid beta (Aβ)42/Aβ40 using logistic regression. RESULTS: Adding sensory and motor measures to CAIDE‐only and FRS‐only models significantly improved NfL and Aβ42/Aβ40 positivity predictions in adults above the age of 55. DISCUSSION: Including midlife sensory and motor function improved long‐term biomarker positivity predictions. Non‐invasive sensory and motor assessments could contribute to cost‐effective screening tools that identify individuals at risk for neurodegeneration early to target interventions and preventions. Highlights: Sensory and motor measures improve risk prediction models of neurodegenerative biomarkersSensory and motor measures improve risk prediction models of AD biomarkersPrediction improvements were strongest in late midlife (adults >55 years of age)Sensory and motor assessments may help identify high‐risk individuals early [ABSTRACT FROM AUTHOR]

INTRODUCTION: We aimed to assess whether midlife sensory and motor functions improve risk prediction of 10‐year cognitive decline and impairment when added to risk prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS). METHODS: Longitudinal data of N = 1529 (mean age 49 years; 54% women) Beaver Dam Offspring Study (BOSS) participants from baseline, 5 and 10‐year follow‐up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function improves CAIDE or FRS risk predictions of 10‐year cognitive decline or cognitive impairment incidence using logistic regressions. RESULTS: Adding sensory and motor measures to CAIDE‐only and FRS‐only models significantly improved areas under the curve for cognitive decline and impairment models. DISCUSSION: Including midlife sensory and motor function improved risk predictions of long‐term cognitive decline and impairment in middle‐aged to older adults. Sensory and motor assessments could contribute to cost‐effective and non‐invasive screening tools that identify high‐risk individuals earlier to target intervention and prevention strategies. Highlights: Sensory and motor measures improve risk prediction models of cognitive decline.Sensory and motor measures improve risk prediction models of cognitive impairment.Prediction improvements were strongest in midlife (adults < 55 years of age).Sensory and motor changes may help identify high‐risk individuals early. [ABSTRACT FROM AUTHOR]

The study of age‐related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age‐related changes within and between compartments as these changes are likely highly interconnected. Understanding age‐related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22–92 years, and identified 92, 34, and 35 age‐associated metabolites, respectively. The metabolic pathways that were identified across compartments included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function. [ABSTRACT FROM AUTHOR]

The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high‐depth RNA‐Seq (387–618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12‐ and 24‐month follow‐up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein‐coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans. [ABSTRACT FROM AUTHOR]

Background: Examine the relationship between balance test performance and the energetic cost of walking (ECW) and gait speed. Methods: Cross‐sectional and longitudinal analyses of data from the Baltimore Longitudinal Study of Aging. Men (48%) and women aged 60–96 years enrolled in the BLSA between 2007 and 2020 (n = 1132). Balance was assessed using narrow walk (NW) and progressive standing balance tests (SB). ECW measured during 2.5‐min usual paced walk while participants wore a portable indirect calorimeter. Gait speed assessed over 6‐m. Each test parameterized using validated methods. Statistical analysis to compare balance measures to ECW, and gait speed used generalized logistic regression models and adjustments for age, sex, race, height, weight, and comorbidities. Results: Cross‐sectionally, mean ECW was higher and gait speed slower in persons who failed the NW than those who passed (0.189 vs. 0.164 mL/kg/m, p < 0.0001 and 0.96 vs. 1.15 m/s, p < 0.0001, respectively). Mean ECW was increasingly higher and gait speed slower over three progressively challenging SB tests (0.207 vs. 0.171 vs. 0.164 mL/kg/m, p < 0.0001 and 0.95 vs. 1.05 vs. 1.15 m/s, p < 0.0001). Over an average 2.4 years, those who declined in SB and NW had a higher ECW and slower gait speed than persons who maintained performance (SB: 0.18 vs. 0.160 mL/kg/m, p = 0.0003, and 1.00 vs. 1.13 m/s, p = <0.001; NW: 0.175 vs. 0.160 mL/kg/m, p = 0.002, and 1.04 vs. 1.14 m/s, p = 0.001). Persons who improved had lower ECW and faster gait speed than those who failed at both visits (SB: 0.169 vs. 0.240 mL/kg/m, p = 0.0002, and 0.99 vs. 0.94 m/s, p = 0.67, NW: 0.163 vs. 0.195 mL/kg/m, p = 0.0005, and 1.10 vs. 0.92 m/s, p < 0.001). Conclusion: Instability contributes to higher ECW and slower gait speed which suggests that rehabilitation efforts to improve balance may help maintain function further into older adulthood and delay mobility limitation. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods: Diffusion MRI data from several well‐established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free‐water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow‐up time: 2.97 ± 2.09 years, follow‐up range: 1–13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results: While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions: There is a prevalent role of white matter microstructural decline in aging, and future large‐scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS: Longitudinal data were free‐water corrected and harmonized.Global effects of white matter decline were seen in normal and abnormal aging.The free‐water metric was most vulnerable to abnormal aging.Cingulum free‐water was the most vulnerable to abnormal aging. [ABSTRACT FROM AUTHOR]

Attaining personalized healthy aging requires accurate monitoring of physiological changes and identifying subclinical markers that predict accelerated or delayed aging. Classic biostatistical methods most rely on supervised variables to estimate physiological aging and do not capture the full complexity of inter‐parameter interactions. Machine learning (ML) is promising, but its black box nature eludes direct understanding, substantially limiting physician confidence and clinical usage. Using a broad population dataset from the National Health and Nutrition Examination Survey (NHANES) study including routine biological variables and after selection of XGBoost as the most appropriate algorithm, we created an innovative explainable ML framework to determine a Personalized physiological age (PPA). PPA predicted both chronic disease and mortality independently of chronological age. Twenty‐six variables were sufficient to predict PPA. Using SHapley Additive exPlanations (SHAP), we implemented a precise quantitative associated metric for each variable explaining physiological (i.e., accelerated or delayed) deviations from age‐specific normative data. Among the variables, glycated hemoglobin (HbA1c) displays a major relative weight in the estimation of PPA. Finally, clustering profiles of identical contextualized explanations reveal different aging trajectories opening opportunities to specific clinical follow‐up. These data show that PPA is a robust, quantitative and explainable ML‐based metric that monitors personalized health status. Our approach also provides a complete framework applicable to different datasets or variables, allowing precision physiological age estimation. [ABSTRACT FROM AUTHOR]

Extracellular vesicles and particles (EVPs) are secreted by organs across the body into different circulatory systems, including the bloodstream, and reflect pathophysiologic conditions of the organ. However, the heterogeneity of EVPs in the blood makes it challenging to determine their organ of origin. We hypothesized that small (s)EVPs (<100 nmin diameter) in the bloodstreamcarry distinctive protein signatures associated with each originating organ, and we investigated this possibility by studying the proteomes of sEVPs produced by six major organs (brain, liver, lung, heart, kidney, and fat). We found that each organ contained distinctive sEVP proteins: 68 proteins were preferentially found in brain sEVPs, 194 in liver, 39 in lung, 15 in heart, 29 in kidney, and 33 in fat. Furthermore, we isolated sEVPs from blood and validated the presence of sEVP proteins associated with the brain (DPP6, SYT1,DNM1L), liver (FABPL, ARG1, ASGR1/2), lung (SFPTA), heart (CPT1B), kidney (SLC31), and fat (GDN). We further discovered altered levels of these proteins in serum sEVPs obtained from old mice compared to young mice. In sum, we have cataloged sEVP proteins that can serve as potential biomarkers for organ identification in serum and show differential expression with age. [ABSTRACT FROM AUTHOR]

Diffusion‐tensor magnetic resonance imaging (DT‐MRI) offers objective measures of muscle characteristics, providing insights into age‐related changes. We used DT‐MRI to probe skeletal muscle microstructure and architecture in a large healthy‐aging cohort, with the aim of characterizing age‐related differences and comparing these to muscle strength. We recruited 94 participants (43 female; median age = 56, range = 22–89 years) and measured microstructure parameters—fractional anisotropy (FA) and mean diffusivity (MD)—in 12 thigh muscles, and architecture parameters—pennation angle, fascicle length, fiber curvature, and physiological cross‐sectional area (PCSA)—in the rectus femoris (RF) and biceps femoris longus (BFL). Knee extension and flexion torques were also measured for comparison to architecture measures. FA and MD were associated with age (β = 0.33, p = 0.001, R2 = 0.10; and β = −0.36, p < 0.001, R2 = 0.12), and FA was negatively associated with Type I fiber proportions from the literature (β = −0.70, p = 0.024, and R2 = 0.43). Pennation angle, fiber curvature, fascicle length, and PCSA were associated with age in the RF (β = −0.22, 0.26, −0.23, and −0.31, respectively; p < 0.05), while in the BFL only curvature and fascicle length were associated with age (β = 0.36, and −0.40, respectively; p < 0.001). In the RF, pennation angle and PCSA were associated with strength (β = 0.29, and 0.46, respectively; p < 0.01); in the BFL, only PCSA was associated with strength (β = 0.43; p < 0.001). Our results show skeletal muscle architectural changes with aging and intermuscular differences in the microstructure. DT‐MRI may prove useful for elucidating muscle changes in the early stages of sarcopenia and monitoring interventions aimed at preventing age‐associated microstructural changes in muscle that lead to functional impairment. [ABSTRACT FROM AUTHOR]

Age‐associated changes in the DNA methylation state can be used to assess the pace of aging. However, it is not understood what mechanisms drive these changes and whether these changes affect the development of aging phenotypes and the aging process in general. This study was aimed at gaining a more comprehensive understanding of aging‐related methylation changes across the whole genome, and relating these changes to biological functions. It has been shown that skeletal muscle and blood monocytes undergo typical changes with aging. Using whole‐genome bisulfite sequencing, we sought to characterize the genome‐wide changes in methylation of DNA derived from both skeletal muscle and blood monocytes, and link these changes to specific genes and pathways through enrichment analysis. We found that methylation changes occur with aging at the locations enriched for developmental and neuronal pathways regulated in these two peripheral tissues. These results contribute to our understanding of changes in epigenome in human aging. [ABSTRACT FROM AUTHOR]

Background: Anisocytosis reflects unequal‐sized red blood cells and is quantified using red blood cell distribution width (RDW). RDW increases with age and has been consistently associated with adverse health outcomes, such as cardiovascular disease and mortality. Why RDW increases with age is not understood. We aimed to identify plasma metabolomic markers mediating anisocytosis with aging. Methods: We performed mediation analyses of plasma metabolomics on the association between age and RDW using resampling techniques after covariate adjustment. We analyzed data from adults aged 70 or older from the main discovery cohort of the Baltimore Longitudinal Study of Aging (BLSA, n = 477, 46% women) and validation cohorts of the Health, Aging and Body Composition Study (Health ABC, n = 620, 52% women) and Invecchiare in Chianti, Aging in the Chianti Area (InCHIANTI) study (n = 735, 57% women). Plasma metabolomics was assayed using the Biocrates MxP Quant 500 kit in BLSA and Health ABC and liquid chromatography with tandem mass spectrometry in InCHIANTI. Results: In all three cohorts, symmetric dimethylarginine (SDMA) significantly mediated the association between age and RDW. Asymmetric dimethylarginine (ADMA) and 1‐methylhistidine were also significant mediators in the discovery cohort and one validation cohort. In the discovery cohort, we also found choline, homoarginine, and several long‐chain triglycerides significantly mediated the association between age and RDW. Conclusions and relevance: This metabolomics study of three independent aging cohorts identified a specific set of metabolites mediating anisocytosis with aging. Whether SDMA, ADMA, and 1‐methylhistidine are released by the damaged erythrocytes with high RDW or they affect the physiology of erythrocytes causing high RDW should be further investigated. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine associations of gut microbiome diversity and composition with directly measured regional fat distribution, including central fat, in a large community‐based cohort. Methods: A cross‐sectional investigation was conducted in the Baltimore Longitudinal Study of Aging (N = 815, 55.2% female, 65.9% White). The fecal microbiome was assessed using whole‐genome shotgun metagenomic sequencing, and trunk and leg fat was measured using dual x‐ray absorptiometry. Multivariable‐adjusted associations of regional fat measures, BMI, or waist circumference with microbiome alpha diversity metrics, microbiome beta diversity metrics, and species differential abundance (verified using two compositional statistical approaches) were examined. Results: Trunk fat, leg fat, BMI, and waist circumference all significantly explained similar amounts of variance in microbiome structure. Differential abundance testing identified 11 bacterial species significantly associated with at least one measure of body composition or anthropometry. Ruminococcus gnavus was strongly and consistently associated with trunk fat mass, which is congruent with prior literature. Conclusions: Microbiome diversity and composition, in particular higher abundance of Ruminococcus gnavus, were associated with greater trunk fat, in addition to other measures of obesity. Longitudinal studies are needed to replicate these findings, and if replicated, randomized trials are needed to determine whether interventions targeting microbiome features such as abundance of Ruminococcus gnavus can lead to reductions in trunk fat and its metabolic sequelae. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sensory impairment (SI) is linked to cognitive decline, but its association with early cognitive impairment (ECI) is unclear. METHODS: Sensory functions (vision, hearing, vestibular function, proprioception, and olfaction) were measured between 2012 and 2018 in 414 Baltimore Longitudinal Study of Aging (BLSA) participants (age 74 ± 9 years; 55% women). ECI was defined as 1 standard deviation below age‐, sex‐, race‐, and education‐specific mean performance in Card Rotations or California Verbal Learning Test immediate recall. Log binomial models (cross‐sectional analysis) and Cox regression models (time‐to‐event analysis) were used to examine the association between SI and ECI. RESULTS: Cross‐sectionally, participants with ≥3 SI had twice the prevalence of ECI (prevalence ratio = 2.10, p = 0.02). Longitudinally, there was no significant association between SI and incident ECI over up to 6 years of follow‐up. DISCUSSION: SI is associated with higher prevalence, but not incident ECI. Future studies with large sample sizes need to further elucidate the relationship between SI and ECI. Highlights: Sensory impairment is associated with high prevalence of early cognitive impairmentMultisensory impairment may pose a strong risk of early changes in cognitive functionIdentifying multisensory impairment may help early detection of dementia [ABSTRACT FROM AUTHOR]

Introduction: Beta‐amyloid (Aβ) plaque deposition is a biomarker of preclinical Alzheimer's disease (AD). Impairments in sensory function are associated with cognitive decline. We sought to investigate the relationship between PET‐indicated Aβ deposition and sensory impairment. Methods: Using data from 174 participants ≥55 years in the Baltimore Longitudinal Study of Aging, we analyzed associations between sensory impairments and Aβ deposition measured by PET and Pittsburgh Compound B (PiB) mean cortical distribution volume ratio (cDVR). Results: The combinations of hearing and proprioceptive impairment and hearing, vision, and proprioceptive impairment, were positively correlated with cDVR (β = 0.087 and p = 0.036, β = 0.110 and p = 0.018, respectively). In stratified analyses of PiB+ participants, combinations of two, three, and four sensory impairments (all involving proprioception) were associated with higher cDVR. Discussion: Our findings suggest a relationship between multi‐sensory impairment (notably proprioceptive impairment) and Aβ deposition, which could reflect sensory impairment as an indicator or potentially a risk factor for Aβ deposition. [ABSTRACT FROM AUTHOR]

Objective: We examined medical records to determine health conditions associated with dementia at varied intervals prior to dementia diagnosis in participants from the Baltimore Longitudinal Study of Aging (BLSA). Methods: Data were available for 347 Alzheimer's disease (AD), 76 vascular dementia (VaD), and 811 control participants without dementia. Logistic regressions were performed associating International Classification of Diseases, 9th Revision (ICD‐9) health codes with dementia status across all time points, at 5 and 1 year(s) prior to dementia diagnosis, and at the year of diagnosis, controlling for age, sex, and follow‐up length of the medical record. Results: In AD, the earliest and most consistent associations across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, urinary incontinence, non‐epithelial skin cancer, and pneumonia were not significant until 1 year before dementia diagnosis. In VaD, the earliest and most consistent associations across all time points included abnormal electrocardiogram (EKG), cardiac dysrhythmias, cerebrovascular disease, non‐epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, essential tremor, and abnormal reflexes were not significant until 1 year before dementia diagnosis. Interpretation: These findings suggest that some health conditions are associated with future dementia beginning at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health conditions associated with AD and VaD. These results reinforce the need for medical intervention and treatment to lessen the impact of health comorbidities in the aging population. ANN NEUROL 2023;93:805–818 [ABSTRACT FROM AUTHOR]

Electrophysiological alterations of the neuromuscular junction (NMJ) and motor unit potential (MUP) with unloading are poorly studied. We aimed to investigate these aspects and the underlying molecular mechanisms with short‐term unloading and active recovery (AR). Eleven healthy males underwent a 10‐day unilateral lower limb suspension (ULLS) period, followed by 21‐day AR based on resistance exercise. Quadriceps femoris (QF) cross‐sectional area (CSA) and isometric maximum voluntary contraction (MVC) were evaluated. Intramuscular electromyographic recordings were obtained during 10% and 25% MVC isometric contractions from the vastus lateralis (VL). Biomarkers of NMJ molecular instability (serum c‐terminal agrin fragment, CAF), axonal damage (neurofilament light chain) and denervation status were assessed from blood samples and VL biopsies. NMJ and ion channel transcriptomic profiles were investigated by RNA‐sequencing. QF CSA and MVC decreased with ULLS. Increased CAF and altered NMJ transcriptome with unloading suggested the emergence of NMJ molecular instability, which was not associated with impaired NMJ transmission stability. Instead, increased MUP complexity and decreased motor unit firing rates were found after ULLS. Downregulation of ion channel gene expression was found together with increased neurofilament light chain concentration and partial denervation. The AR period restored most of these neuromuscular alterations. In conclusion, the human NMJ is destabilized at the molecular level but shows functional resilience to a 10‐day unloading period at least at relatively low contraction intensities. However, MUP properties are altered by ULLS, possibly due to alterations in ion channel dynamics and initial axonal damage and denervation. These changes are fully reversed by 21 days of AR. Key points: We used integrative electrophysiological and molecular approaches to comprehensively investigate changes in neuromuscular integrity and function after a 10‐day unilateral lower limb suspension (ULLS), followed by 21 days of active recovery in young healthy men, with a particular focus on neuromuscular junction (NMJ) and motor unit potential (MUP) properties alterations.After 10‐day ULLS, we found significant NMJ molecular alterations in the absence of NMJ transmission stability impairment. These findings suggest that the human NMJ is functionally resilient against insults and stresses induced by short‐term disuse at least at relatively low contraction intensities, at which low‐threshold, slow‐type motor units are recruited.Intramuscular electromyography analysis revealed that unloading caused increased MUP complexity and decreased motor unit firing rates, and these alterations could be related to the observed changes in skeletal muscle ion channel pool and initial and partial signs of fibre denervation and axonal damage.The active recovery period restored these neuromuscular changes. [ABSTRACT FROM AUTHOR]

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone‐binding globulin (SHBG) with aggressive, overall and early‐onset prostate cancer. In blood‐based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse‐variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08‐1.40). In blood‐based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02‐1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08‐1.34; blood‐based: 1.03, 1.01‐1.05) and early‐onset prostate cancer (MR: 1.37, 1.09‐1.73; blood‐based: 1.08, 0.98‐1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood‐based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups. [ABSTRACT FROM AUTHOR]

Stress is implicated in models of personality and health as a mechanism that explains why traits like conscientiousness and neuroticism are associated with long‐term health outcomes. Evidence for an association between personality and cortisol, a biological marker of stress, however, has been inconsistent. This study examined the association between Five‐Factor Model personality traits and 24‐h urinary cortisol (operationalised as a ratio of urinary free cortisol to creatinine) measured up to 12 times over intervals as long as 30 years in the Baltimore Longitudinal Study of Aging (Mage = 61.21, SD = 15.46; 49% female). There was a modest association between conscientiousness and lower mean‐level cortisol that was attenuated only slightly in the fully‐adjusted model. Neuroticism and the other traits were unrelated to cortisol levels, and none of the traits was related to cortisol change over time. The null association for neuroticism suggests that its relation with long‐term health may be primarily through pathways other than cortisol. The modest association between conscientiousness and 24‐h urinary cortisol replicates a previous finding with a longer‐term measure of cortisol measured from hair, which calls for more research on the robustness and replicability of this finding. Cortisol may be one pathway through which conscientiousness is associated with health outcomes. [ABSTRACT FROM AUTHOR]

This document is a response by David J. Marcinek and Luigi Ferrucci to an argument presented by Lanza et al. The authors concede that physical activity is a significant factor in modulating mitochondrial oxidative capacity and acknowledge that there are multiple factors, including muscle group, fiber type, body mass index, and co-morbidities, that affect the measurement of oxidative capacity in aged skeletal muscles. They present data from large datasets that indicate a statistically significant effect of age on in vivo oxidative capacity of the vastus lateralis muscle, independent of physical activity. The authors argue that age has an intrinsic effect on mitochondrial energetics and emphasize the importance of maintaining physical activity while aging for various biological functions. They also suggest that future studies on mitochondrial function and energetics should consider the independent effects of aging and physical activity in their design and analyses. [Extracted from the article]

Background: Up to 15% of people aged 60 and over are anemic, and the prevalence of anemia increases with age. In older men and women, anemia is associated with increases in the risk of death and all‐cause hospitalization, poor functional capacity, quality of life, and depression. Methods and Results: We reviewed the literature describing anemia in aging populations, focusing on the specific diagnostic criteria of anemia and potential causes in older men and women. Even after extensive etiologic workup that involves careful medical history, physical examination, laboratory measurements, and additional studies such as bone marrow biopsy, anemia of aging is unexplained in up to 40% of older patients with anemia. As a result, treatment options remain limited. Conclusions: The prevalence of unexplained anemia of aging (UAA; also called unexplained anemia of the elderly, UAE), its deleterious impacts on health, physical function, and quality of life, and the lack of effective treatment or therapy guidelines represent a compelling unmet clinical need. In this review and consensus document, we discuss the scope of the problem, possible causes of UAA, diagnostic criteria, and potential treatment options. Because even mild anemia is strongly linked to poor clinical outcomes, it should receive clinical attention rather than simply being considered a normal part of aging. [ABSTRACT FROM AUTHOR]

Background: Muscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown. Methods: We examined 380 cognitively normal participants aged 60 and older (53%women, 22%Black) who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr). Mobility was measured by four walking tests. Associations of baseline kPCr with mobility changes were examined using linear mixed-effects models, adjusted for covariates. In a subset, we examined whether changes in muscle strength and mass affected these associations by adjusting for longitudinal muscle strength, lean mass, and fat mass. Results: Lower baseline kPCr was associated with greater decline in all four mobility measures (β, p-value: (0.036, 0.020) 6-m usual gait speed; (0.029, 0.038) 2.5-min usual gait speed; (0.034, 0.011) 6-m rapid gait speed; (-0.042, <0.001) 400-m time). In the subset, further adjustment for longitudinal muscle strength, lean mass, and fat mass attenuated longitudinal associations with changes in mobility (Δβ reduced 26-63%). Conclusion: Among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance. [ABSTRACT FROM AUTHOR]