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Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [ n  = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%–92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p  < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p  > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se. [ABSTRACT FROM AUTHOR]

Background Daily physical activity patterns differ by Alzheimer's disease (AD) status and might signal cognitive risk. It is critical to understand whether patterns are disrupted early in the AD pathological process. Yet, whether established AD risk markers (β-amyloid [Aβ] or apolipoprotein E-ε4 [ APOE-ε4 ]) are associated with differences in objectively measured activity patterns among cognitively unimpaired older adults is unclear. Methods Wrist accelerometry, brain Aβ (+/−), and APOE-ε4 genotype were collected in 106 (Aβ) and 472 (APOE-ε4) participants (mean age 76 [standard deviation{ SD }: 8.5) or 75 [ SD : 9.2] years, 60% or 58% women) in the Baltimore Longitudinal Study of Aging. Adjusted linear and function-on-scalar regression models examined whether Aβ or APOE-ε4 status was cross-sectionally associated with activity patterns (amount, variability, or fragmentation) overall and by time of day, respectively. Differences in activity patterns by combinations of Aβ and APOE-ε4 status were descriptively examined (n  = 105). Results There were no differences in any activity pattern by Aβ or APOE-ε4 status overall. Aβ+ was associated with lower total amount and lower within-day variability of physical activity overnight and early evening, and APOE-ε4 carriers had higher total amount of activity in the evening and lower within-day variability of activity in the morning. Diurnal curves of activity were blunted among those with Aβ+ regardless of APOE-ε4 status, but only when including older adults with mild cognitive impairment/dementia. Conclusions Aβ+ in cognitively unimpaired older adults might manifest as lower amount and variability of daily physical activity, particularly during overnight/evening hours. Future research is needed to examine changes in activity patterns in larger samples and by other AD biomarkers. [ABSTRACT FROM AUTHOR]

Background Lower urinary tract symptoms (LUTS) in older men are associated with an increased risk of mobility limitations. Lower extremity muscle quality may represent a novel shared mechanism of both LUTS and mobility limitations. Methods We evaluated associations of thigh skeletal muscle measures (strength, area, and specific force) with total LUTS severity (American Urologic Association Symptom Index; AUASI) and voiding and storage subscores among 352 men aged ≥60 years enrolled in the Baltimore Longitudinal Study of Aging. Thigh muscle strength (Nm) was defined as maximum concentric 30°/s knee extensor torque, area (cm2), and specific force (Nm/cm2) defined as strength/area. Associations with AUASI score were estimated using multivariable linear regression and linear mixed models. Results Mean thigh muscle strength at baseline was 139.7Nm. In cross-sectional multivariable models, each 39Nm increment in thigh muscle strength and 0.28Nm/cm2 increment in specific force was associated with −1.17 point (95% CI: −1.93 to −.41) and −0.95 point (95% CI: −1.63 to −0.27) lower AUASI score, respectively. Similar associations were observed for voiding and storage subscores, although somewhat attenuated. In longitudinal analyses, baseline muscle measures were not associated with annual change in AUASI, and current changes in muscle measures and AUASI were unrelated. Conclusions Cross-sectionally, higher thigh muscle strength and specific force were associated with decreased LUTS severity in older men. However, we did not observe concurrent worsening LUTS severity with declining thigh muscle strength, area, or specific force in longitudinal analyses. [ABSTRACT FROM AUTHOR]

There is consistent evidence that immune response declines with aging, with wide interindividual variability and a still unclear relationship with the development of frailty. To address this question, we assessed the role of immune resilience (capacity to restore immune functions), operationalized as the neutrophil-to-lymphocytes ratio (NL-ratio) and monocytes-to-lymphocytes ratio (ML-ratio), in the pathway that from robust status shifts to pre-frailty and frailty, and finally to death. The InCHIANTI study enrolled representative samples from the registry lists of 2 towns in Tuscany, Italy. Baseline data were collected in 1998, with follow-up visits every 3 years. The 1 453 participants enrolled were assessed and followed for lifestyle, clinical condition, physical performance, clinical, and physiological measures. For the purpose of this analysis, we used only 1 022 subjects aged 65 or older at baseline. Participants in the 3 highest deciles of distribution for NL-ratio (>2.44) were more likely to experience a transition from robust to pre-frail, and to overt frailty status. Moreover, NL-ratio (tenth decile > 3.53) and ML-ratio (tenth decile > 2.02) were both predictors of mortality. These results were independent of chronological age, sex, comorbidities, and chronic low-grade inflammation assessed by high sensitivity C-reactive protein measurement. The 2 leucocytes-derived ratios, NL-ratio and ML-ratio, represent markers of immune resilience and predict changes in physical resilience and mortality. These biomarkers are inexpensive because they are based on data routinely collected in clinical practice and can be used to assess the risk of frailty progression and mortality. Clinical Trials Registration Number: NCT01331512 [ABSTRACT FROM AUTHOR]

The article describes the effects of ageism on health and social care and social care and proposes actions that can health reduce ageism and promote healthy longevity through education and policies. Topics discussed include focus of the medical approach to health for a long time and manifestations, consequences and actions of ageism in health care.

Background Pain is associated with reports of restricted physical activity (PA), yet the association between musculoskeletal pain characteristics and objectively measured PA quantities and patterns in late life is not well understood. Methods A total of 553 adults (mean age 75.8 ± 8.4 years, 54.4% women) in the Baltimore Longitudinal Study of Aging (BLSA) completed a health interview and subsequent 7-day wrist-worn ActiGraph assessment in the free-living environment between 2015 and 2020. Pain characteristics, including pain presence in 6x sites (ie, shoulders, hands/wrists, low back, hip, knees, and feet), pain laterality in each site, and pain distribution were assessed. PA metrics were summarized into total daily activity counts (TAC), activity fragmentation, active minutes/day, and diurnal patterns of activity. Linear regression models and mixed-effects models examined the association between pain characteristics and PA outcomes, adjusted for demographics and comorbidities. Results Unilateral knee pain was associated with 184 070 fewer TAC (p  = .039) and 36.2 fewer active minutes/day (p  = .032) compared to those without knee pain. Older adults with shoulder pain or hand/wrist pain had more active minutes compared to those without pain (p  < .05 for all). For diurnal patterns of activity, participants with knee pain had fewer activity counts during the afternoon (12:00 pm to 5:59 pm). Analyses stratified by sex showed that these associations were only significant among women. Conclusions Our study highlights the importance of assessing pain laterality in addition to pain presence and suggests that pain interferes with multiple aspects of daily activity. Longitudinal studies are needed to assess the temporality of these findings. [ABSTRACT FROM AUTHOR]

Background Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. Methods We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4 years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). Results The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. Conclusion Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes. [ABSTRACT FROM AUTHOR]

Cellular senescence, a hallmark of aging, results in a senescence-associated secretory phenotype (SASP) with an increased production of proinflammatory cytokines, growth factors, and proteases. Evidence from nonhuman models demonstrates that SASP contributes to tissue dysfunction and pathological effects of aging. However, there are relatively few human studies on the relationship between SASP and aging-related health outcomes. Proteins from the SASP Atlas were measured in plasma using aptamer-based proteomics (SomaLogic). Regression models were used to identify SASP protein associations with aging-related traits representing multiple aspects of physiology in 1 201 participants from 2 human cohort studies (BLSA/GESTALT and InCHIANTI). Traits examined were fasting glucose, C-reactive protein, interleukin-6, alkaline phosphatase, blood urea nitrogen, albumin, red blood cell distribution width, waist circumference, systolic and diastolic blood pressure, gait speed, and grip strength. Study results were combined with a fixed-effect inverse-variance weighted meta-analysis. In the meta-analysis, 28 of 77 SASP proteins were significantly associated with age. Of the 28 age-associated SASP proteins, 18 were significantly associated with 1 or more clinical traits, and 7 SASP proteins were significantly associated with 3 or more traits. Growth/differentiation factor 15, Insulin-like growth factor-binding protein 2, and Cystatin-C showed significant associations with inflammatory markers and measures of physical function (grip strength or gait speed). These results support the relevance of SASP proteins to human aging, identify specific traits that are potentially affected by SASP, and prioritize specific SASP proteins for their utility as biomarkers of human aging. [ABSTRACT FROM AUTHOR]

This document discusses the issue of ageism in healthcare and its negative impact on the health and well-being of older individuals. It emphasizes the need for a shift in the medical approach to prioritize the care of older patients with multiple chronic conditions, frailty, and disability. The document identifies various manifestations of ageism in healthcare, such as undervaluing older people, lack of education on aging, and a focus on disease treatment rather than prevention. It proposes actions to address ageism, including education about aging, integrating aging into educational curricula, prioritizing prevention and health promotion, and involving older patients in care choices. The document highlights the exclusion of older patients from life-saving treatments and preventive measures, the lack of evidence-based medicine for this population, inadequate care for older patients with multiple chronic conditions, and reduced access to healthcare and healthcare technologies. It calls for action to address ageism in healthcare and improve the care and well-being of older patients. [Extracted from the article]

Background Poor motor function is associated with brain atrophy and cognitive impairment. Less is known about the relationship between motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. Methods We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6 ± 10.1 years, 56% women, 27% Black), 525 of whom had repeat MRI scans over an average of 5.0 ± 2.1 years. Two motor domains, manual dexterity and gross motor, were operationalized as latent variables. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. Results Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p  < .05). Manual dexterity was also cross-sectionally associated with parietal gray matter (B  = 0.14; 95% CI: 0.05, 0.23), hippocampus (B  = 0.10; 95% CI: 0.01, 0.20), postcentral gyrus (B  = 0.11; 95% CI: 0.01, 0.20), and occipital white matter (B  = 0.10; 95% CI: 0.01, 0.21) volumes, and gross motor function with temporal gray matter volume (B  = 0.16; 95% CI: 0.05, 0.26). Longitudinally, both higher manual dexterity and gross motor function were associated with less temporal white matter and occipital gray matter atrophy (all p  < .05). Manual dexterity was also associated with a slower rate of ventricular enlargement (B  = −0.17; 95% CI: −0.29, −0.05) and less atrophy of occipital white matter (B  = 0.39; 95% CI: 0.04, 0.71). Conclusions Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time. [ABSTRACT FROM AUTHOR]

Aging is characterized by chronic low-level inflammation and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocyte ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow-up visits every 3 years. Out of the 1 453 participants enrolled at baseline, this study includes 1 179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and body mass index (BMI). Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocyte-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, interleukine-6 (IL-6), male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult. [ABSTRACT FROM AUTHOR]

Background The relationship between amino acids, B vitamins, and their metabolites with D3-creatine (D3Cr) dilution muscle mass, a more direct measure of skeletal muscle mass, has not been investigated. We aimed to assess associations of plasma metabolites with D3Cr muscle mass, as well as muscle strength and physical performance in older men from the Osteoporotic Fractures in Men cohort study. Methods Out of 1 425 men (84.2 ± 4.1 years), men with the lowest D3Cr muscle mass (n  = 100), slowest walking speed (n  = 100), lowest grip strength (n  = 100), and a random sample (n  = 200) serving as a comparison group to the low groups were included. Metabolites were analyzed using liquid chromatography–tandem mass spectrometry. Metabolite differences between the low groups and random sample and their relationships with the muscle outcomes adjusted for confounders and multiple comparisons were assessed using t -test/Mann–Whitney–Wilcoxon and partial correlations, respectively. Results For D3Cr muscle mass, significant biomarkers (p  < .001) with ≥10% fold difference and largest partial correlations were tryptophan (Trp; r  = 0.31), kynurenine (Kyn)/Trp; r  = −0.27), nicotinamide (Nam)/quinolinic acid (Quin; r  = 0.21), and alpha-hydroxy-5-methyl-tetrahydrofolate (hm-THF; r  = −0.25). For walking speed, hm-THF, Nam/Quin, and Quin had the largest significance and fold difference, whereas valine (r  = 0.17), Trp (r  = 0.17), HKyn/Xant (r  = −0.20), neopterin (r  = −0.17), 5-methyl-THF (r  = −0.20), methylated folate (r  = −0.21), and thiamine (r  = −0.18) had the strongest correlations. Only hm-THF was correlated with grip strength (r  = −0.21) and differed between the low group and the random sample. Conclusions Future interventions focusing on how the Trp metabolic pathway or hm-THF influences D3Cr muscle mass and physical performance declines in older adults are warranted. [ABSTRACT FROM AUTHOR]

Background A decade ago, we proposed an index of physiological dysregulation based on Mahalanobis distance (DM) that measures how far from the norm an individual biomarker profile is. While extensive validation has been performed, focus was mostly on Western populations with little comparison to developing countries, particularly at a physiological system level. The degree to which the approach would work in other sociocultural contexts and the similarity of dysregulation signatures across diverse populations are still open questions. Methods Using 2 data sets from China and 3 from Western countries (United States, United Kingdom, and Italy), we calculated DM globally and per physiological system. We assessed pairwise correlations among systems, difference with age, prediction of mortality and age-related diseases, and sensitivity to interchanging data sets with one another as the reference in DM calculation. Results Overall, results were comparable across all data sets. Different physiological systems showed distinct dysregulation processes. Association with age was moderate and often nonlinear, similarly for all populations. Mahalanobis distance predicted most health outcomes, although differently by physiological system. Using a Chinese population as the reference when calculating DM for Western populations, or vice versa, led to similar associations with health outcomes, with a few exceptions. Conclusions While small differences were noticeable, they did not systematically emerge between Chinese and Western populations, but rather diffusively across all data sets. These findings suggest that DM presents similar properties, notwithstanding sociocultural backgrounds, and that it is equally effective in capturing the loss of homeostasis that occurs during aging in diverse industrial human populations. [ABSTRACT FROM AUTHOR]

The brainstem functions as a relay and integrative brain center and plays an essential role in motor function. Whether brainstem tissue deterioration, including demyelination, affects motor function has not been studied. Understanding the potential relationship between brainstem demyelination and motor function may be useful for the early diagnosis of neurodegenerative diseases and to understand age-related gait impairments that have no apparent cause. In this work, we investigated the associations between rapid or usual gait speeds, as integrative measures of motor function, and cerebral myelin content. In 118 individuals (age 22–94 years) free of neurodegenerative diseases or cognitive impairment, myelin content was assessed as the myelin water fraction, a direct magnetic resonance imaging measure of myelin content, and longitudinal and transverse relaxation rates (R 1 and R 2), which are sensitive magnetic resonance imaging measures of myelin content. Our results indicate that participants with lower usual or rapid gait speed exhibited lower values of myelin water fraction and R 1 in the main brainstem regions, which were more evident and statistically significant in the midbrain. In contrast, we found no significant associations between gait speeds and R 2, an expected result because various physiological factors confound R 2. These original findings provide evidence that the level of brainstem myelination may affect gait performance among cognitively unimpaired adults who are free from any clinically detectable neurodegenerative diseases. Further studies are needed to understand the longitudinal changes in brainstem myelination with aging and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. Methods Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). Results GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. Conclusions GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength. [ABSTRACT FROM AUTHOR]

Although growth/differentiation factor 11 (GDF11), growth/differentiation factor 8 (GDF8), and their circulating antagonists, which include GDF11 and GDF8 propeptides, follistatin (FST), WAP, Follistatin/Kazal, Immunoglobulin, Kunitz And Netrin Domain Containing (WFIKKN)1, and WFIKKN2, have been shown to influence skeletal muscle and aging in mice, the relationship of these circulating factors with human phenotypes is less clear. This study aimed to characterize the relationship between plasma GDF8, GDF11, FST, WFIKKN1, and WFIKKN2 concentrations with the decline of grip strength in 534 adults, ≥65 years, who participated in the Baltimore Longitudinal Study of Aging and had grip strength measured over time. Plasma GDF8 and GDF11 mature proteins, GDF8 and GDF11 propeptides, FST (isoform FST315 and cleaved form FST303), WFIKKN1, and WFIKKN2 concentrations were measured using selected reaction monitoring–tandem mass spectrometry at baseline. Grip strength was measured at baseline and at follow-up visits (median follow-up 8.87 years). Mean (standard deviation) grip strength declined in men and women by −0.84 (2.45) and −0.60 (1.32) kg/year, respectively. Plasma GDF8 and GDF11 mature proteins, GDF8 and GDF11 propeptides, FST315, FST303, WFIKKN1, and WFIKKN2 concentrations were not independently predictive of the decline of grip strength in men or women in multivariable linear regression analyses that adjusted for potential confounders. In conclusion, circulating GDF8, GDF11, and their antagonists do not appear to influence the decline of grip strength in older men or women. [ABSTRACT FROM AUTHOR]

In recent years, several new classes of therapies have been investigated with their potential for restoring or improving physical functioning in older adults. These have included Mas receptor agonists, regulators of mitophagy, skeletal muscle troponin activators, anti-inflammatory compounds, and targets of orphan nuclear receptors. The present article summarizes recent developments of the function-promoting effects of these exciting new compounds and shares relevant preclinical and clinical data related to their safety and efficacy. The development of novel compounds in this area is expanding and likely will need the advent of a new treatment paradigm for age-associated mobility loss and disability. [ABSTRACT FROM AUTHOR]

This document is a response to a letter to the editor regarding a study on the relationship between skeletal muscle and lower urinary tract symptoms (LUTS) in older men. The authors agree that the relationship between skeletal muscle and LUTS is complex and potentially bidirectional. They also acknowledge the co-occurrence of LUTS and poor sleep, which may accelerate biological aging mechanisms and worsen the functional impact of LUTS. The authors express skepticism about the proposed role of testosterone in this relationship and suggest that other factors, such as decreased mobility and physical activity, may play a more significant role. They propose further research to identify and test plausible conceptual models and interventions to improve symptom burden and functional status in older men with LUTS. The study was supported by various grants and the authors declare no conflicts of interest. [Extracted from the article]

There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of pre-frail state and frailty syndrome increases exponentially with advancing age and is associated with greater morbidity, disability, hospitalization, institutionalization, mortality, and health care resource use. Frailty represents a global problem, making early identification, evaluation, and treatment to prevent the cascade of events leading from functional decline to disability and death, one of the challenges of geriatric and general medicine. Cardiac arrhythmias are common in advancing age, chronic illness, and frailty and include a broad spectrum of rhythm and conduction abnormalities. However, no systematic studies or recommendations on the management of arrhythmias are available specifically for the elderly and frail population, and the uptake of many effective antiarrhythmic therapies in these patients remains the slowest. This European Heart Rhythm Association (EHRA) consensus document focuses on the biology of frailty, common comorbidities, and methods of assessing frailty, in respect to a specific issue of arrhythmias and conduction disease, provide evidence base advice on the management of arrhythmias in patients with frailty syndrome, and identifies knowledge gaps and directions for future research. [ABSTRACT FROM AUTHOR]

Background This study examined associations of actigraphy-estimated sleep parameters with concurrent and future cognitive performance in adults aged ≥ 50 years and explored interactions with race. Methods Participants were 435 cognitively normal adults in the Baltimore Longitudinal Study of Aging who completed wrist actigraphy at baseline (mean = 6.6 nights) and underwent longitudinal testing of memory, attention, executive function, language, and visuospatial ability. On average, participants with follow-up data were followed for 3.1 years. Primary predictors were baseline mean total sleep time, sleep onset latency, sleep efficiency (SE), and wake after sleep onset (WASO). Fully adjusted linear mixed-effects models included demographics, baseline health-related characteristics, smoking status, sleep medication use, APOE e4 carrier status, and interactions of each covariate with time. Results In adjusted models, higher SE (per 10%; B  = 0.11, p  = .012) and lower WASO (per 30 minutes; B  = −0.12, p  = .007) were associated with better memory cross-sectionally. In contrast, higher SE was associated with greater visuospatial ability decline longitudinally (B  = −0.02, p  = .004). Greater WASO was associated with poorer visuospatial ability cross-sectionally (B  = −0.09, p  = .019) but slower declines in visuospatial abilities longitudinally (B  = 0.02, p  = .002). Several sleep-cognition cross-sectional and longitudinal associations were stronger in, or limited to, Black participants (compared to White participants). Conclusions This study suggests cross-sectional sleep-cognition associations differ across distinct objective sleep parameters and cognitive domains. This study also provides preliminary evidence for racial differences across some sleep-cognition relationships. Unexpected directions of associations between baseline sleep and cognitive performance over time may be attributable to the significant proportion of participants without follow-up data and require further investigation. [ABSTRACT FROM AUTHOR]

Background Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Methods Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. Results In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. Conclusions These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease. [ABSTRACT FROM AUTHOR]

Background healthy dietary patterns have been associated with lower risk for age-related cognitive decline. However, little is known about the specific role of dietary fibre on cognitive decline in older adults. Objective this study aimed to examine the association between dietary fibre and cognitive decline in older adults and to assess the influence of genetic, lifestyle and clinical characteristics in this association. Design and participants the Invecchiare in Chianti, aging in the Chianti area study is a cohort study of community-dwelling older adults from Italy. Cognitive function, dietary and clinical data were collected at baseline and years 3, 6, 9 and 15. Our study comprised 848 participants aged ≥ 65 years (56% female) with 2,038 observations. Main outcome and measures cognitive decline was defined as a decrease ≥3 units in the Mini-Mental State Examination score during consecutive visits. Hazard ratios for cognitive decline were estimated using time-dependent Cox regression models. Results energy-adjusted fibre intake was not associated with cognitive decline during the 15-years follow-up (P  > 0.05). However, fibre intake showed a significant interaction with Apolipoprotein E (APOE) haplotype for cognitive decline (P  = 0.02). In participants with APOE-ɛ4 haplotype, an increase in 5 g/d of fibre intake was significantly associated with a 30% lower risk for cognitive decline. No association was observed in participants with APOE-ɛ2 and APOE-ɛ3 haplotypes. Conclusions and relevance dietary fibre intake was not associated with cognitive decline amongst older adults for 15 years of follow-up. Nonetheless, older subjects with APOE-ɛ4 haplotype may benefit from higher fibre intakes based on the reduced risk for cognitive decline in this high-risk group. [ABSTRACT FROM AUTHOR]

Background Human motor function is optimised for energetic efficiency, however, age-related neurodegenerative changes affects neuromotor control of walking. Energy utilisation has been associated with motor performance, but its association with cognitive performance is unknown. Methods The study population included 979 Baltimore Longitudinal Study of Aging participants aged |$\ge$| 50 years (52% female, mean age: 70 |$\pm$| 10.2 years) with a median follow-up time of 4.7 years. Energy utilisation for walking was operationalised as a ratio of the energy cost of slow walking to peak walking energy expenditure during standardised tasks ('cost-ratio'). Cognitive functioning was measured using the Trail Making Tests, California Verbal Learning Test, Wechsler Adult Intelligence Scale (WAIS), letter and category fluency and card rotation tests. Linear mixed models adjusted for demographics, education and co-morbidities assessed the association between baseline cost-ratio and cognitive functioning, cross-sectionally and longitudinally. To investigate the relationship among those with less efficient energy utilisation, subgroup analyses were performed. Results In fully adjusted models, a higher cost-ratio was cross-sectionally associated with poorer performance on all cognitive tests except WAIS (P  < 0.05 for all). Among those with compromised energy utilisation, the baseline cost-ratio was also associated with a faster decline in memory (long-delay free recall: β  = −0.4, 95% confidence interval [CI] = [−0.8, −0.02]; immediate word recall: β  = −1.3, 95% CI = [−2.7, 0.1]). Conclusions These findings suggest cross-sectional and longitudinal links between energy utilisation and cognitive performance, highlighting an intriguing link between brain function and the energy needed for ambulation. Future research should examine this association earlier in the life course to gauge the potential for interventive mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes. Methods: We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up. Results: Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88-1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82-1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87-1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88-1.29). The results were robust in all sub-group and sensitivity analyses. Conclusions: This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes. Significance statement: Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future. [ABSTRACT FROM AUTHOR]

Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 ± 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of "baseline GDF-15 × time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences. [ABSTRACT FROM AUTHOR]

Background: In older persons, neuropsychological function, especially sensorimotor function, is strongly associated with mobility. Hearing impairment is related to poor mobility, and we hypothesize that such relationships would be stronger in persons with compromised sensorimotor function than those with preserved sensorimotor function.Methods: We analyzed 601 cognitively normal (Mini-Mental State Examination ≥24 or free of cognitive impairment/dementia) Baltimore Longitudinal Study of Aging participants aged 50 or older with concurrent data on hearing (better ear pure-tone average [PTA]), mobility (6 m usual gait, 400 m endurance walk), and neuropsychological function including attention via Trail Making Test (TMT)-A, executive function via the difference between TMT-A and B, and Digit Symbol Substitution Test, and manual dexterity via Pegboard performance. We examined the association of PTA, each cognitive measure, and their interaction with mobility using multivariable linear regression, adjusted for covariates.Results: After covariate adjustment, there were significant interactions between PTA and all cognitive measures in the association with 400 m endurance walking speed as the outcome. There was also a significant interaction between PTA and pegboard nondominant hand performance in the association with 6 m gait as the outcome. In all these cases, the PTA-mobility relationship was stronger among participants with lower cognition.Conclusion: Impaired hearing more strongly relates to poor mobility among those with compromised neuropsychological performance, especially manual dexterity reflecting the motor-cognitive interface and sensorimotor function, than those with preserved neuropsychological performance. Future longitudinal studies are needed to test whether hearing impairment more strongly predicts mobility decline over time in older persons with compromised neuropsychological function. [ABSTRACT FROM AUTHOR]

Background: Higher energetic costs for mobility are associated with declining gait speed, and slow gait is linked to cognitive decline and Alzheimer's disease. However, the physiological underpinnings of gait and brain health have not been well explored. We examined the associations of the energetic cost of walking with brain volume in cognitively unimpaired adults from the Baltimore Longitudinal Study of Aging.Methods: We used brain magnetic resonance imaging (MRI) data from 850 participants (mean baseline age 66.3 ± 14.5 years), of whom 451 had longitudinal MRI data (2.8 ± 1.0 MRI scans over 4.0 ± 2.0 years). The energetic cost of walking was assessed as the average energy expended (V̇O2) during 2.5 minutes of customary-paced overground walking. Multivariable linear mixed-effects models examined the associations between baseline energetic cost of walking and regional brain volumes adjusting for covariates.Results: At baseline, higher energetic cost of walking was cross-sectionally associated with lower gray and white matter volumes within the frontal, parietal, and temporal lobes, as well as hippocampal, total brain, and larger ventricular volumes (all false-discovery rate [FDR] p < .05). A baseline energetic cost of walking × time interaction demonstrated that participants with higher energetic cost of walking had faster annual decline in hippocampal volume (FDR p = .02) and accelerated annual increase in ventricular volumes (FDR p = .02).Conclusions: The energetic cost of walking is associated with gray and white matter volumes and subsequent hippocampal atrophy and ventricular enlargement. Collectively, these data suggest the energetic cost of walking may be an early marker of neurodegeneration that contributes to the gait brain connection. [ABSTRACT FROM AUTHOR]

Background: Much is known about individual sensory deficits among older adults, but there is a dearth of information about the prevalence of multiple concurrent sensory deficits in this population.Methods: We evaluated the prevalence of individual and multiple sensory impairments at the most recent clinic visit among participants aged 24 years and older in the Baltimore Longitudinal Study of Aging (BLSA) (hearing, vision, olfaction, proprioception, and vestibular function) and Atherosclerosis Risk in Communities Study (ARIC) (hearing, vision, olfaction). We compared observed prevalence of multiple sensory impairments with expected prevalence based on compounded probabilities of multiple impairments using Fisher Exact Tests. Also, we evaluated the comparability of different measures used between these two studies.Results: In both studies, the prevalence of each individual sensory impairment was common (>10%), and higher with older age, and the most common pattern of co-occurring sensory impairments was hearing and visual impairments (17.4% [BLSA]; 50.2% [ARIC]). In BLSA, the pattern that differed the most between observed and expected prevalence was combined hearing, vision, and olfactory impairments (observed 5.2% vs 1.4% expected, p = .01). In ARIC, this difference was much smaller (observed 8.1% vs 7.2% expected, p = .49).Conclusions: Although concurrent hearing and vision impairments were the most common co-occurring deficits, combined hearing, vision, and olfactory impairments are most likely to co-occur above chance, especially at older ages. [ABSTRACT FROM AUTHOR]

Background: In general, plant protein intake was inversely associated with mortality in studies in middle-aged adults. Our aim was to evaluate the long-term associations of animal and plant protein intake with mortality in older adults.Methods: A prospective cohort study including 1 139 community-dwelling older adults (mean age 75 years, 56% women) living in Tuscany, Italy, followed for 20 years (InCHIANTI study) was analyzed. Dietary intake by food frequency questionnaires and clinical information were assessed 5 times during the follow-up. Protein intakes were expressed as percentages of total energy. Time-dependent Cox regression models adjusted for confounders were used to assess the association between plant and animal protein intake, and mortality.Results: During the 20 years of follow-up (mean: 12 years), 811 deaths occurred (292 of cardiovascular- and 151 of cancer-related causes). Animal protein intake was inversely associated with all-cause (hazard ratio [HR] per 1% of total energy from protein increase, 95% confidence interval [CI]: 0.96, 0.93-0.99) and cardiovascular mortality (HR per 1% of total energy from protein increase, 95% CI: 0.93, 0.87-0.98). Plant protein intake showed no association with any of the mortality outcomes, but an interaction with baseline hypertension was found for all-cause and cardiovascular mortality (p < .05).Conclusions: Animal protein was inversely associated with all-cause and cardiovascular mortality in older adults. Further studies are needed to provide recommendations on dietary protein intake for older adults. [ABSTRACT FROM AUTHOR]

Background: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear.Methods: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n = 74) over 5.05 (2.74 SD) years.Results: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital, and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas.Conclusion: Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function. [ABSTRACT FROM AUTHOR]

Background: Motor function affects ability to perform daily activities and maintain independence. Yet, the interrelatedness of upper and lower extremity motor impairments and the magnitude of their contribution to slow gait and mobility difficulty are not well investigated.Methods: Participants in the Baltimore Longitudinal Study of Aging (N = 728, aged 50-99) completed motor and physical function tests including grip and knee extension strength, pegboard, finger tapping, standing balance, chair stands, fast-paced 400-m walk, and usual gait speed. Slow gait was defined as usual gait speed <1.0 m/s. Mobility difficulty was defined as self-reported difficulty walking ¼ mile or climbing stairs. Structural equation modeling examined the interrelationships of motor measures and their contributions to slow gait and mobility difficulty, adjusting for demographics and comorbidities.Results: Poorer manual dexterity (-0.571 standard deviation [SD] units, p < .001) and lower muscle strength (upper and lower extremity; -0.447 SD units, p = .014) were most strongly associated with slow gait speed, followed by slower chair stand pace (-0.195 SD units, p = .002) and greater lap time variation (0.102 SD units, p = .028). Lower muscle strength (-0.582 SD units, p = .001) was most strongly associated with mobility difficulty, followed by slower chair stand pace (-0.322 SD units, p < .001), slower gait speed (-0.247 SD units, p < .001), and poorer standing balance (-0.190 SD units, p = .043).Conclusions: Components of manual dexterity and strength were the strongest correlates of slow gait and mobility difficulty in mid-to-late life. Longitudinal studies examining relationships between changes in these motor parameters and mobility are needed to elucidate possible causal effects. [ABSTRACT FROM AUTHOR]

Age-dependent differences in methylation at specific cytosine-guanine (CpG) sites have been used in "epigenetic clock" formulas to predict age. Deviations of epigenetic age from chronological age are informative of health status and are associated with adverse health outcomes, including mortality. In most cases, epigenetic clocks are performed on methylation from DNA extracted from circulating blood cells. However, the effect of neoplastic cells in the circulation on estimation and interpretation of epigenetic clocks is not well understood. Here, we explored this using Fischer 344 (F344) rats, a strain that often develops large granular lymphocyte leukemia (LGLL). We found clear histological markers of LGLL pathology in the spleens and livers of 27 out of 61 rats aged 17-27 months. We assessed DNA methylation by reduced representation bisulfite sequencing with coverage of 3 million cytosine residues. Although LGLL broadly increased DNA methylation variability, it did not change epigenetic aging. Despite this, the inclusion of rats with LGLL in clock training sets significantly altered predictor selection probability at 83 of 121 commonly utilized CpG sites. Furthermore, models trained on rat samples that included individuals with LGLL had greater absolute age error than those trained exclusively rats free of LGLL (39% increase; p < .0001). We conclude that the epigenetic signals for aging and LGLL are distinct, such that LGLL assessment is not necessary for valid measures of epigenetic age in F344 rats. The precision and architecture of constructed epigenetic clock formulas, however, can be influenced by the presence of neoplastic hematopoietic cells in training set populations. [ABSTRACT FROM AUTHOR]

Background Comprehensive geriatric assessment (CGA) has been in use for the last three decades. However, some doubts remain regarding its clinical use. Therefore, we aimed to capture the breadth of outcomes reported and assess the strength of evidence of the use of comprehensive geriatric assessment (CGA) for health outcomes in older persons. Methods Umbrella review of systematic reviews of the use of CGA in older adults searching in Pubmed, Embase, Scopus, Cochrane library and CINHAL until 05 November 2021. All possible health outcomes were eligible. Two independent reviewers extracted key data. The grading of evidence was carried out using the GRADE for intervention studies, whilst data regarding systematic reviews were reported as narrative findings. Results Among 1,683 papers, 31 systematic reviews (19 with meta-analysis) were considered, including 279,744 subjects. Overall, 13/53 outcomes were statistically significant (P  < 0.05). There was high certainty of evidence that CGA reduces nursing home admission (risk ratio [RR] = 0.86; 95% confidence interval [CI]: 0.75–0.89), risk of falls (RR = 0.51; 95%CI: 0.29–0.89), and pressure sores (RR = 0.46; 95%CI: 0.24–0.89) in hospital medical setting; decreases the risk of delirium (OR = 0.71; 95%CI: 0.54–0.92) in hip fracture; decreases the risk of physical frailty in community-dwelling older adults (RR = 0.77; 95%CI: 0.64–0.93). Systematic reviews without meta-analysis indicate that CGA improves clinical outcomes in oncology, haematology, and in emergency department. Conclusions CGA seems to be beneficial in the hospital medical setting for multiple health outcomes, with a high certainty of evidence. The evidence of benefits is less strong for the use of CGA in other settings. [ABSTRACT FROM AUTHOR]

Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through 3 angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using postmortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-β and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-β scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology. [ABSTRACT FROM AUTHOR]

Background and Objectives There is an urgent need to better understand frailty and its predisposing factors. Although numerous cross-sectional studies have identified various risk and protective factors of frailty, there is a limited understanding of longitudinal frailty progression. Furthermore, discrepancies in the methodologies of these studies hamper comparability of results. Here, we use a coordinated analytical approach in 5 independent cohorts to evaluate longitudinal trajectories of frailty and the effect of 3 previously identified critical risk factors: sex, age, and education. Research Design and Methods We derived a frailty index (FI) for 5 cohorts based on the accumulation of deficits approach. Four linear and quadratic growth curve models were fit in each cohort independently. Models were adjusted for sex/gender, age, years of education, and a sex/gender-by-age interaction term. Results Models describing linear progression of frailty best fit the data. Annual increases in FI ranged from 0.002 in the Invecchiare in Chianti cohort to 0.009 in the Longitudinal Aging Study Amsterdam (LASA). Women had consistently higher levels of frailty than men in all cohorts, ranging from an increase in the mean FI in women from 0.014 in the Health and Retirement Study cohort to 0.046 in the LASA cohort. However, the associations between sex/gender and rate of frailty progression were mixed. There was significant heterogeneity in within-person trajectories of frailty about the mean curves. Discussion and Implications Our findings of linear longitudinal increases in frailty highlight important avenues for future research. Specifically, we encourage further research to identify potential effect modifiers or groups that would benefit from targeted or personalized interventions. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated that age-related hearing loss is associated with cognitive decline. We investigated whether subclinical hearing loss (SCHL) or imperfect hearing traditionally categorized as normal (pure-tone average ≤25 dB) may be similarly linked to cognitive decline and risk of incident mild cognitive impairment (MCI)/dementia.Methods: Participants from the Baltimore Longitudinal Study of Aging were cognitively normal adults at least 50 years old with cognitive assessments from 1991 to 2019 and pure-tone average ≤25 dB measured between 1991 and 1994 (n = 263). The exposure was hearing based on the better ear pure-tone average. Outcomes were test scores in various cognitive domains. Multivariable linear-mixed effects models were developed to analyze the association between hearing and change in cognition over time, adjusting for age, sex, education, vascular burden, and race. Kaplan-Meier survival curves and Cox proportional hazards models portrayed associations between hearing and incident MCI/dementia diagnosis based on predefined criteria.Results: Of 263 participants, 145 (55.1%) were female; mean age was 68.3 years (SD = 8.9). Follow-up ranged up to 27.7 years (mean = 11.7 years). Adjusting for multiple comparisons, a 10-dB increase in hearing loss was associated with an annual decline of -0.02 SD (95% confidence interval: -0.03, -0.01) in Letter Fluency. No significant relationships were observed between hearing and incident MCI/dementia.Conclusions: A relationship between SCHL and cognitive decline was observed for the Letter Fluency test. Further studies are necessary to determine where in the spectrum of hearing loss there begins to be an observable relationship between hearing and cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Vision loss is associated with increased risk of falls and restricted physical activity, yet the relationship between multiple vision measures and objectively measured physical activity, especially activity patterns, in mid-to-late life is not well understood.Method: This study included 603 participants aged 50 years and older (mean age = 73.5) in the Baltimore Longitudinal Study of Aging who had the following assessments: presenting and best-corrected visual acuity, contrast sensitivity, visual fields, stereo acuity, and free-living physical activity using a wrist-worn ActiGraph accelerometer for 7 days. Linear regression models were used to examine the association between vision measures and daily activity counts, active minutes, and activity fragmentation (defined as an active-to-sedentary transition probability), adjusting for potential confounders. Mixed-effects models estimated differences in activity by time of day comparing those with and without each visual impairment.Results: In the fully adjusted model, worse presenting visual acuity, contrast sensitivity, and visual fields were associated with fewer activity counts, less active time, and more fragmented activity patterns (p < .05 for all). Participants with presenting or best-corrected visual acuity impairment had 19.2 and 29.3 fewer active minutes (p = .05 and p = .03, respectively) per day. Visual field impairment was associated with 268 636 fewer activity counts (p = .02), 46.2 fewer active minutes (p = .02) per day, and 3% greater activity fragmentation (p = .009). Differences in activity levels tended to be greatest from 6 am to 6 pm (p < .05).Conclusions: Older adults with visual impairment have restricted and more fragmented patterns of daily activity. Longitudinal studies to quantify the long-term impacts of visual impairments on activity decline are warranted. [ABSTRACT FROM AUTHOR]

Background: Although hearing impairment (HI) is linked to poorer physical functioning, the longitudinal associations between HI and higher-level functional measures are unclear.Method: Data are from the Baltimore Longitudinal Study of Aging (2012-2019). Using pure-tone audiometry, we categorized hearing into normal, mild, and moderate or greater HI. Physical function was assessed with the expanded Short Physical Performance Battery (eSPPB) and walking endurance with time to walk 400 m. Multivariable and mixed-effects linear models tested the hypotheses that participants with HI, at baseline, have poorer physical performance and walking endurance, and faster decline over time (up to 6 measurements). In a subset (n = 526), we further adjusted for vestibular function. Among participants with HI, we evaluated the differences in eSPPB scores and walking endurance between hearing aid users and nonusers.Results: Of 831 participants, 26% had mild, and 17% moderate or greater HI. After adjustment for demographics and medical history, moderate or greater impairment versus normal hearing was associated with poorer function (0.17 [95% CI: 0.09, 0.26] lower eSPPB score, and 13.3 [95% CI: 3.31, 23.4] seconds slower 400-m walk time) and faster decline in these parameters over 6 years. Adjustment for vestibular function did not attenuate these associations. Hearing aid users walked 400 m 24 seconds faster than nonusers (p = .001).Conclusion: Moderate or greater HI is associated with poorer initial and greater decline in higher-level physical performance. The observation that hearing aid users had better walking endurance suggests that screening for and treatment of HI may delay or slow progression of hearing-related functional decline. [ABSTRACT FROM AUTHOR]

Background: Physical activity becomes increasingly fragmented with age, which may be an early marker of functional decline. Energetic cost of walking and energy capacity are also linked with functional decline, but their associations with activity fragmentation, and the potential modifying roles of total daily physical activity and age, remains unclear.Method: A total of 493 participants (50-93 years) from the Baltimore Longitudinal Study of Aging underwent measures of energetic cost of usual-paced overground walking (mL/kg/m), energy demand during slow walking (mL/kg/min) on a treadmill (0.67 m/s, 0% grade), and average peak walking energy expenditure (mL/kg/min) during a fast-paced 400-m walk. A ratio of slow walking to peak walking energy expenditure ("cost-to-capacity ratio") was calculated. Activity fragmentation was quantified as an active-to-sedentary transition probability (ASTP) using Actiheart accelerometer data. Linear regression models with ASTP as the dependent variable were used to test whether poorer energy cost and capacity were associated with higher ASTP and whether the associations differed by daily physical activity or age.Results: After adjusting for demographics, body composition, comorbidities, and daily physical activity, every 10% higher cost-to-capacity ratio was associated with 0.4% greater ASTP (p = .005). This association was primarily driven by the least active participants (pinteraction = .023). Peak walking energy expenditure was only associated with ASTP among participants aged ≥70 years.Conclusions: Higher cost-to-capacity ratio and lower energy capacity may manifest as more fragmented physical activity, especially among those less active or aged ≥70 years. Future studies should examine whether an increasing cost-to-capacity ratio or declining energy capacity predicts subsequent activity fragmentation. [ABSTRACT FROM AUTHOR]

Background: Multidimensional Prognostic Index (MPI) is recognized as a prognostic tool in hospitalized patients, but data on the value of MPI in community-dwelling older persons are limited. Using data from a representative cohort of community-dwelling persons, we tested the hypothesis that MPI explains mortality during 15 years of follow-up.Methods: A standardized comprehensive geriatric assessment was used to calculate the MPI and to categorize participants in low-, moderate-, and high-risk classes. The results were reported as hazard ratios (HRs) and the accuracy was evaluated with the area under the curve (AUC), with 95% confidence intervals (CIs) and the C-index. We also reported the median survival time by standard age groups.Results: All 1453 participants (mean age 68.9 years, women = 55.8%) enrolled in the InCHIANTI study at baseline were included. Compared to low-risk group, participants in moderate (HR = 2.10; 95% CI: 1.73-2.55) and high-risk MPI group (HR = 4.94; 95% CI: 3.91-6.24) had significantly higher mortality risk. The C-index of the model containing age, sex, and MPI was 82.1, indicating a very good accuracy of this model in explaining mortality. Additionally, the time-dependent AUC indicated that the accuracy of the model incorporating MPI to age and sex was excellent (>85.0) during the whole follow-up period. Compared to participants in the low-risk MPI group across different age groups, those in moderate- and high-risk groups survived 2.9-7.0 years less and 4.3-8.9 years less, respectively.Conclusions: In community-dwelling individuals, higher MPI values are associated with higher risk of all-cause mortality with a dose-response effect. [ABSTRACT FROM AUTHOR]

Background: Larger brain volumes are often associated with more free-living physical activity (PA) in cognitively normal older adults. Yet, whether greater brain volumes are associated with more favorable (less fragmented) PA patterns, and whether this association is stronger than with total PA, remains unknown.Methods: Brain magnetic resonance imaging and wrist-worn accelerometer data were collected in 301 participants (mean age = 77 [SD = 7] years, 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Linear regression models were fit to examine whether brain volumes (cc) were cross-sectionally associated with: (a) total daily PA minutes and (b) activity fragmentation (mean number of PA bouts / total PA minutes × 100). Sensitivity analyses were conducted by adjusting for counterpart PA variables (eg, fragmentation covariate included in the PA minutes model).Results: Greater white matter volumes in the parietal and temporal lobes were associated with higher daily PA minutes (2.6 [SE = 1.0] and 3.8 [0.9] min/day, respectively; p < .009 for both) after adjusting for demographics, behavioral factors, medical conditions, gait speed, apolipoprotein E e4 status, and intracranial volume. Greater temporal white matter volume was associated with lower fragmentation (-0.16% [0.05], p = .003). In sensitivity analyses, observed associations between brain volumes and daily PA minutes remained significant while associations with fragmentation no longer remained significant.Conclusions: Our results suggest white matter brain structure in cognitively normal older adults is associated with the total amount of PA and, to a lesser extent, the PA accumulation patterns. More work is needed to elucidate the longitudinal relationship between brain structure and function and PA patterns with aging. [ABSTRACT FROM AUTHOR]

Background: The operational definition of resilience is elusive and resilient people are difficult to identify. We used self-reported "major health event" (srMHE) to identify resilience and evaluate the functional and mortality trajectories associated with this condition.Method: We selected from the InCHIANTI study persons aged 65 or older who could perform the Short Physical Performance Battery at baseline and attended the 3 years follow-up visit. We identified 4 groups: Controls: no srMHE and no decline in physical function; Decliners: no srMHE and decline in physical function; Resilient: srMHE and no decline in physical function; and Non-resilient: srMHE and decline in physical function. Linear mixed models and Cox regression were used to analyze changes in activities of daily living (ADL) score over 9- and 10-year mortality across groups, respectively.Results: The 313 participants that reported a srMHE had worse perceived health status and higher number of GP visits and prescribed drugs at baseline. Of these, 78 were Resilient and 235 Non-resilient; of the remaining, 136 were Controls and 277 Decliners. Compared to the Controls, Resilient had similar change of ADL score over time (β: -.03, p = .92) and mortality (hazard ratio: 1.31, 95% confidence interval: 0.76-2.23), while Decliners and Non-resilient showed significantly higher mortality and, the latter, worsening of ADL score. Additional srMHE during follow-up affected the rate of change of ADL score and mortality more in the Controls group than in the Resilient group.Conclusions: A srMHE along with repeated evaluation of physical function may be used to identify resilience in older people, and may complement the standard functional evaluation of geriatric patients. [ABSTRACT FROM AUTHOR]

Anemia is common in older adults and associated with greater morbidity and mortality. The causes of anemia in older adults have not been completely characterized. Although elevated circulating growth and differentiation factor 15 (GDF-15) has been associated with anemia in older adults, it is not known whether elevated GDF-15 predicts the development of anemia. We examined the relationship between plasma GDF-15 concentrations at baseline in 708 nonanemic adults, aged 60 years and older, with incident anemia during 15 years of follow-up among participants in the Invecchiare in Chianti (InCHIANTI) Study. During follow-up, 179 (25.3%) participants developed anemia. The proportion of participants who developed anemia from the lowest to highest quartile of plasma GDF-15 was 12.9%, 20.1%, 21.2%, and 45.8%, respectively. Adults in the highest quartile of plasma GDF-15 had an increased the risk of developing anemia (hazards ratio 1.15, 95% confidence interval 1.09, 1.21, p < .0001) compared to those in the lower 3 quartiles in a multivariable Cox proportional hazards model adjusting for age, sex, serum iron, soluble transferrin receptor, ferritin, vitamin B12, congestive heart failure, diabetes mellitus, and cancer. Circulating GDF-15 is an independent predictor for the development of anemia in older adults. [ABSTRACT FROM AUTHOR]

Aging is associated with functional and metabolic decline and is a risk factor for all noncommunicable diseases. Even though mice are routinely used for modeling human aging and aging-related conditions, no comprehensive assessment to date has been conducted on normative mouse aging. To address this gap, the Study of Longitudinal Aging in Mice (SLAM) was designed and implemented by the National Institute on Aging (NIA/NIH) as the mouse counterpart to the Baltimore Longitudinal Study of Aging (BLSA). In this manuscript, we describe the premise, study design, methodologies, and technologies currently employed in SLAM. We also discuss current and future study directions. In this large population mouse study, inbred C57BL/6J and outbred UM-HET3 mice of both sexes are longitudinally evaluated for functional, phenotypic, and biological health, and collection of biospecimens is conducted throughout their life span. Within the longitudinal cohorts, a cross-sectional arm of the study has also been implemented for the well-controlled collection of tissues to generate a biorepository. SLAM and studies stemming from SLAM seek to identify and characterize phenotypic and biological predictors of mouse aging and age-associated conditions, examine the degrees of functional and biomolecular variability that occur within inbred and genetically heterogeneous mouse populations with age, and assess whether these changes are consistent with alterations observed in human aging in BLSA. The findings from these studies will be critical for evaluating the utility of mouse models for studying different aspects of aging, both in terms of interpreting prior findings and designing and implementing future studies. [ABSTRACT FROM AUTHOR]

Background: We evaluated whether frailty and multimorbidity predict in-hospital mortality in patients with COVID-19 beyond chronological age.Method: A total of 165 patients admitted from March 8th to April 17th, 2020, with COVID-19 in an acute geriatric ward in Italy were included. Predisease frailty was assessed with the Clinical Frailty Scale (CFS). Multimorbidity was defined as the co-occurrence of ≥2 diseases in the same patient. The hazard ratio (HR) of in-hospital mortality as a function of CFS score and number of chronic diseases in the whole population and in those aged 70+ years were calculated.Results: Among the 165 patients, 112 were discharged, 11 were transferred to intensive care units, and 42 died. Patients who died were older (81.0 vs 65.2 years, p < .001), more frequently multimorbid (97.6 vs 52.8%; p < .001), and more likely frail (37.5 vs 4.1%; p < .001). Less than 2.0% of patients without multimorbidity and frailty, 28% of those with multimorbidity only, and 75% of those with both multimorbidity and frailty died. Each unitary increment in the CFS was associated with a higher risk of in-hospital death in the whole sample (HR = 1.3; 95% CI = 1.05-1.62) and in patients aged 70+ years (HR = 1.29; 95% CI = 1.04-1.62), whereas the number of chronic diseases was not significantly associated with higher risk of death. The CFS addition to age and sex increased mortality prediction by 9.4% in those aged 70+ years.Conclusions: Frailty identifies patients with COVID-19 at risk of in-hospital death independently of age. Multimorbidity contributes to prognosis because of the very low probability of death in its absence. [ABSTRACT FROM AUTHOR]