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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]

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]

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]

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]

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]

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: 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]

Background: Increasingly, lifestyle factors in midlife are reported to impact health and functional status in old age. This work examines associations between dietary trajectories in middle age and subsequent impairments in physical function.Method: Data are from 851 participants (61% men, mean age at first dietary assessment = 47 years, range 30-59 years) from the Baltimore Longitudinal Study of Aging. We used latent class analysis to derive dietary trajectories based on adherence to the Alternative Healthy Eating Index-2010 (AHEI), and further classified them based on tertiles, as poor (score <39.3), intermediate (39.3-48.9), or good (>48.9). Physical function was assessed with the Short Physical Performance Battery (SPPB). Random effects tobit regression models were used to examine associations between dietary trajectories and later physical function.Results: Two latent classes of AHEI scores were generated and labeled "greatly improved" or "moderately improved." In the greatly improved class, participants showed a trend in overall AHEI score from poor/intermediate to good diet categories across dietary assessments with age, over time. In the moderately improved class, the overall AHEI score shifted from poor to intermediate diet categories over time, and the prevalence of the good diet category remained low. Mean AHEI score between ages 30 and 59 years was higher in the greatly, than moderately, improved class. The moderately improved class had 1.6 points lower SPPB score (indicating poorer physical function) at older age than the greatly improved class (p = .022).Conclusions: Findings suggest that improving diet quality in middle age may contribute to better physical function in older age. [ABSTRACT FROM AUTHOR]

Previous work has shown that poorer mitochondrial function is associated with age-related perceived fatigability. However, whether glucose oxidation and anaerobic metabolism are intermediate factors underlying this association remains unclear. We examined the total cross-sectional association between mitochondrial function and perceived fatigability in 554 adults aged 22-99 years. Mitochondrial function was assessed by skeletal muscle oxidative capacity (kPCr) using 31P magnetic resonance spectroscopy. Perceived fatigability was measured by rating of perceived exertion after a 5-minute (0.67 m/s) treadmill walk. The intermediate role of glucose oxidation (measured by the rate of change of respiratory exchange ratio [RER change rate] during the 5-minute treadmill walk) and anaerobic metabolism (measured by ventilatory threshold [VeT] during a maximal treadmill test) was evaluated by examining their cross-sectional associations with kPCr and perceived exertion. For each 0.01/s lower kPCr, perceived fatigability was 0.47 points higher (p = .002). A 0.01/s lower kPCr was also associated with 8.3 L/min lower VeT (p < .001). Lower VeT was associated with higher fatigability at lower levels of kPCr but not at higher kPCr levels (β for interaction = 0.017, p = .002). kPCr and RER change rate were not significantly associated (p = .341), but a 0.01/min higher RER change rate was associated with 0.12-point higher fatigability (p = .001). Poorer mitochondrial function potentially contributes to higher perceived fatigability through higher glucose oxidation and higher anaerobic metabolism. Future studies to further explore the longitudinal mechanisms between these metabolic changes and fatigability are warranted. [ABSTRACT FROM AUTHOR]

Background: Although mitochondrial dysfunction appears to be a contributing factor in the pathogenesis of cardiovascular and metabolic diseases, empirical data on this association are still lacking. This study evaluated whether mitochondrial oxidative capacity, as assessed by phosphorus magnetic resonance spectroscopy, was associated with cardiovascular risk, as estimated by the Framingham Risk Score (FRS), and with a clinical history of cardiovascular disease (CVD), in community-dwelling adults.Method: A total of 616 subjects from the Baltimore Longitudinal Study of Aging (mean age 66 years) underwent a comprehensive clinical evaluation. Mitochondrial oxidative capacity in skeletal muscle was assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy. Multivariate regression models were employed to determine the cross-sectional association of mitochondrial oxidative capacity with FRS and history of CVD.Results: Decreased mitochondrial oxidative capacity was strongly associated with higher FRS independent of age, body composition, and physical activity. Lower oxidative capacity was also associated with a history of positive of CVD and higher number of CVD events.Conclusions: We speculate that the observed association could reflect the effect of an excessive production of oxidative species by dysfunctional mitochondria. Furthermore, decreased energy production could hamper the functionality of heart and vessels. In turn, a malfunctioning cardiovascular apparatus could fail to deliver the oxygen necessary for optimal mitochondrial energy production, therefore creating a vicious cycle. Longitudinal studies are necessary to ascertain the directionality of the association and the eventual presence of common pathogenetic roots. In conclusion, mitochondria could represent an important target for intervention in cardiovascular health. [ABSTRACT FROM AUTHOR]

Background: Muscle strength and brain volume decline with aging; changes in the brain manifested as change in volume may play a role in age-related strength loss, but this hypothesis has never been tested longitudinally. We examined longitudinal associations between brain volume changes and knee extension peak torque change in participants of the Baltimore Longitudinal Study of Aging.Methods: Brain volumes and isokinetic concentric knee extension peak torque at 30 deg/s were measured in 678 participants (55.2% women; baseline age, 50.1-97.2 years; median follow-up time in those who visited two or more times (n = 375, 4.0 [interquartile range {IQR}, 2.3-5.0] years). Correlations between longitudinal changes in brain volumes and knee extension peak torque were examined using bivariate linear mixed-effects models, adjusted for baseline age, sex, race, education, and intracranial volume.Results: Greater decline in muscle strength was associated with greater atrophies in global gray matter, temporal lobe, frontal gray matter, temporal gray matter, superior frontal gyrus, inferior frontal gyrus, supramarginal gyrus, middle temporal gyrus, inferior temporal gyrus, and occipital pole (r ranging from .30 to .77, p < .05). After multiple comparison adjustment, only larger decrease in middle temporal gyrus remained significantly related to larger decrease in muscle strength (q = 0.045).Conclusions: In older adults, declines in knee extension muscle strength co-occurred with atrophies in frontal, temporal, and occipital gray matter. These findings support the idea that age-related knee extension muscle strength is linked with atrophy in some specific brain regions related to motor control. [ABSTRACT FROM AUTHOR]

Resting metabolic rate (RMR) tends to decline with aging. The age-trajectory of decline in RMR is similar to changes that occur in muscle mass, muscle strength, and fitness, but while the decline in these phenotypes has been related to changes of mitochondrial function and oxidative capacity, whether lower RMR is associated with poorer mitochondrial oxidative capacity is unknown. In 619 participants of the Baltimore Longitudinal Study of Aging, we analyzed the cross-sectional association between RMR (kcal/day), assessed by indirect calorimetry, and skeletal muscle maximal oxidative phosphorylation capacity, assessed as postexercise phosphocreatine recovery time constant (τ PCr), by phosphorous magnetic resonance spectroscopy. Linear regression models were used to evaluate the relationship between τ PCr and RMR, adjusting for potential confounders. Independent of age, sex, lean body mass, muscle density, and fat mass, higher RMR was significantly associated with shorter τ PCr, indicating greater mitochondrial oxidative capacity. Higher RMR is associated with a higher mitochondrial oxidative capacity in skeletal muscle. This association may reflect a relationship between better muscle quality and greater mitochondrial health. [ABSTRACT FROM AUTHOR]

Changes in DNA methylation have been found to be highly correlated with aging in humans, but causes or consequences of these changes are not understood. We characterized the DNA methylomes of several hundred people in the Invecchiare in Chianti study to identify DNA sites in which percent methylation was systematically different with age. Then, we tested the hypothesis that changes of percent methylation in the same DNA sites occur longitudinally for the same DNA sites in the same subjects. We identified six differentially methylated regions in which percent methylation showed robust longitudinal changes in the same direction. We then describe functions of the genes near these differentially methylated regions and their potential relationship with aging, noting that the genes appear to regulate metabolism or cell type specificity. The nature of transcription factor binding sites in the vicinity of these differentially methylated regions suggest that these age-associated methylation changes reflect modulation of two biological mechanisms: the polycomb repressive complex 2, a protein complex that trimethylates histone H3 on lysine 27, and the transcriptional repressor CCCTC-binding factor or CTCF, both of which are regulators of chromatin architecture. These findings are consistent with the idea that changes in methylation with aging are of adaptive nature. [ABSTRACT FROM AUTHOR]

In 1863, Rudolph Virchow published "Cellular Pathology as Based upon Physiological and Pathological Histology", establishing for the first time that cellular pathology was tightly connected with human pathology ([1]). The geroscience hypothesis acknowledges that aging causes global susceptibility to diseases clinically emerging as multimorbidity and frailty. There is strong evidence that complex biological, environmental, sociocultural, and behavioral factors affect the quality of aging and substantially influence health disparities across individuals and communities. [Extracted from the article]

Background: Cognitive decline is consistently associated with diminished life satisfaction and inability to live independently. Identifying early, novel markers of cognitive decline is imperative for improving clinical detection and promoting long-term quality of life. Fatigability, one's perceived exertion after a standardized walking task, has been associated with declines in physical function; however, it remains unclear as to whether these effects may also extend to cognitive function.Methods: We examined whether perceived fatigability, assessed as the rating of perceived exertion (RPE) after a 5 min slow-paced treadmill walk (0.67 m/s, 0% grade), is longitudinally associated with cognitive performance in the domains of memory, executive functions, language, and attention among 934 cognitively intact individuals aged at least 50 years participating in the Baltimore Longitudinal Study of Aging (BLSA); Mage = 69.6 ± 10.1, 51.9% female participants. Continuous associations between RPE and each domain (individual test and composite scores) were assessed using linear mixed-effect models adjusted for demographics and comorbid conditions.Results: In fully adjusted models, higher fatigability at baseline was associated with declines in all cognitive domains over an average 2.2 years of follow-up (p < .04 for all). Longitudinally, increased fatigability over time was associated with worsened executive functions (β= -0.01, p = .002).Conclusions: These findings suggest that perceived fatigability after a standardized walking task may aid in identification of individuals at a higher risk of future cognitive decline. Future research should examine underlying biological mechanisms contributing to this relationship as well as whether future interventions may target fatigability in midlife to attenuate age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target. [ABSTRACT FROM AUTHOR]

Background: Poor sleep may increase the likelihood of fatigue, and both are common in later life. However, prior studies of the sleep-fatigue relationship used subjective measures or were conducted in clinical populations; thus, the nature of this association in healthier community-dwelling older adults remains unclear. We studied the association of actigraphic sleep parameters with perceived fatigability-fatigue in response to a standardized task-and with conventional fatigue symptoms of low energy or tiredness.Methods: We studied 382 cognitively normal participants in the Baltimore Longitudinal Study of Aging (aged 73.1 ± 10.3 years, 53.1% women) who completed 6.7 ± 0.9 days of wrist actigraphy and a perceived fatigability assessment, including rating of perceived exertion (RPE) after a 5-minute treadmill walk or the Pittsburgh Fatigability Scale (PFS). Participants also reported non-standardized symptoms of fatigue.Results: After adjustment for age, sex, race, height, weight, comorbidity index, and depressive symptoms, shorter total sleep time (TST; <6.3 hours vs intermediate TST ≥6.3 to 7.2 hours) was associated with high RPE fatigability (odds ratio [OR] = 2.56, 95% confidence interval [CI] = 1.29, 5.06, p = .007), high PFS physical (OR = 1.88, 95% CI = 1.04, 3.38, p = .035), and high mental fatigability (OR = 2.15, 95% CI = 1.02, 4.50, p = .044), whereas longer TST was also associated with high mental fatigability (OR = 2.19, 95% CI = 1.02, 4.71, p = .043). Additionally, longer wake bout length was associated with high RPE fatigability (OR = 1.53, 95% CI = 1.14, 2.07, p = .005), and greater wake after sleep onset was associated with high mental fatigability (OR = 1.14, 95% CI = 1.01, 1.28, p = .036).Conclusion: Among well-functioning older adults, abnormal sleep duration and sleep fragmentation are associated with greater perceived fatigability. [ABSTRACT FROM AUTHOR]

Background: Deficits in energy production and utilization have been linked to higher fatigue and functional decline with aging. Lesser known is whether individuals with a combination of low peak energy capacity and high energy costs for mobility (eg, impaired energy regulation) are more likely to experience the onset and progression of high fatigability with aging.Methods: Participants in the Baltimore Longitudinal Study of Aging (n = 651, 49.0% male, mean age 71.9, range 50-94) with ≥2 visits who completed fatigability (Borg rating of perceived exertion [RPE] after a 5-minute 1.5 mph treadmill walk), slow walking energy expenditure (VO2 mL/kg/min), and peak walking energy expenditure (VO2 mL/kg/min), testing between 2007 and 2018. The longitudinal association between each measure of energy expenditure, a ratio of energy cost-to-capacity, and perceived fatigability was modeled using mixed effects models adjusted for age, body composition, and comorbidities. Time to higher perceived fatigability (RPE ≥ 10) was modeled using Cox proportional hazards models.Results: In continuous analyses, higher slow walking energy expenditure (p < .05) and a higher cost ratio (p ≤ .001) were associated with greater perceived fatigability over time. Cox proportional hazards models using tertiles of the cost ratio suggest that, compared to those in the lowest tertile, those in the middle and highest tertiles had 1.89 (95% confidence interval [CI]: 1.57-5.16) and 2.85 (95% CI: 1.05-3.40) times greater risk of developing higher fatigability, respectively.Conclusion: Findings suggest that strategies to prevent fatigability should consider methods to improve energy regulation by targeting both the independent and combined effects of declining peak capacity and rising energy costs for mobility with aging. [ABSTRACT FROM AUTHOR]

Background: A universal definition of sarcopenia is still lacking. Since the European criteria have been recently revised, we aimed at studying prevalence of low muscle strength (LMS) and low muscle mass (LMM), as defined according to the European Working Group of Sarcopenia in Older People (EWGSOP) 2 and 1 definitions, and their individual contribution toward mortality and incident mobility disability in a cohort of community-dwelling older people.Methods: Longitudinal analysis of 535 participants of the InCHIANTI study. LMS and LMM were defined according to the criteria indicated in the EWGSOP2 and 1. Cox and log-binomial regressions were used to examine association with mortality and 3-year mobility disability (inability to walk 400 m).Results: We observed a lower prevalence of the combination LMM/LMS according to EWGSOP2 compared to EWGSOP1 (3.2% vs 6.2%). Using the new criteria, all sarcopenia components were associated with mortality, although the hazard ratio [HR] for the group LMM/LMS was no longer significant after adjustment for confounders (LMM: HR 2.69, 95% confidence interval [CI] 1.04-6.94; LMS: HR 3.18, 95% CI 1.44-7.01; LMM/LMS: HR 2.95, 95% CI 0.86-10.16). Using EWGSOP1, LMS alone was independently associated with mortality (HR 4.43, 95% CI 1.85-10.57). None of the sarcopenia components conferred a higher risk of mobility disability.Conclusions: The EWGSOP2 algorithm leads to a reduction in the estimated prevalence of sarcopenia defined as combination of LMM/LMS. The finding that, independent of the adopted criteria, people with LMS and normal mass have a higher mortality risk compared to robust individuals, confirms that evaluation of muscle strength has a central role for prognosis evaluation. [ABSTRACT FROM AUTHOR]

Background: Whereas the independent effects of biomarkers, including 25-hydroxy vitamin D (25(OH)D), insulin-like growth factor 1, C-reactive protein, and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood.Methods: Study subjects aged at least 65 at baseline (N = 970) were enrolled in the population-based Invecchiare in Chianti (InCHIANTI) study from 1998 to 2000 and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the three time points. Using a generalized estimating equation approach, we determined if slow gait speed (<0.8 m/s) was associated with the biomarkers. Further investigation was conducted for interactions between high IL-6 (≥.87 pg/mL) and other biomarkers focusing on low 25(OH)D (<20 ng/mL).Results: After controlling for other biomarkers and potential confounders, IL-6 emerged as the only biomarker independently associated with gait speed. The association between high IL-6 and slow gait speed was enhanced by low 25(OH)D, with significant interaction between high IL-6 and low 25(OH)D (p = .038). The odds ratio of slow gait speed for low 25(OH)D and high IL-6 was 1.63 (95% confidence interval [CI]: 1.15, 2.32) compared with the reference groups with both biomarker levels at the other ends.Conclusion: The association of low vitamin D with slow gait speed statistically interacts with high IL-6. Coexisting vitamin D insufficiency and inflammation may provide a better biomarker for identifying those at risk of developing impairments in gait speed than either factor alone. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to evaluate the relationship between anticholinergic drug burden (ACB) cognitive impairment, physical frailty, and cognitive frailty, and to determine if ACB is predictive of these phenotypes when modeled with biological and genomic biomarkers.Methods: In a retrospective cohort study, a total of 1,453 adults aged 20-102 years were used to examine ACB as a predictor for cognitive impairment, physical frailty, and cognitive frailty. Anticholinergic burden is examined as a predictor for all phenotypes in a cross-sectional analysis using logistic, ordinal regression models, and Extreme Gradient Boosting for population predictive modeling.Results: A significant association was found between ACB and cognitive decline (p = .02), frailty (p < .001), and cognitive frailty (p < .001). The odds of cognitive impairment increased by 1.21 (95% confidence interval [CI] = 1.06-1.37, p < .001), odds of being frail increased by 1.33 (95% CI = 1.18-1.50, p < .001), and odds of having cognitive frailty increased by 1.36 (95% CI = 1.21-1.54, p < .001). Population modeling results indicated ACB score as one of the stronger predictors for cognitive impairment, physical frailty, and cognitive frailty with area under the curves ranging from 0.81 to 0.88.Conclusions: Anticholinergic medications are a potentially modifiable risk factor for the prevention of cognitive and physical decline. Identification of reversible causes for cognitive and physical impairment is critical for the aging population. These findings encourage new research that may lead to effective interventions for deprescribing programs for the prevention of cognitive and physical decline in older adults. [ABSTRACT FROM AUTHOR]