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1.
Aging Cell ; : e13552, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35048491

RESUMO

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

2.
Artigo em Inglês | MEDLINE | ID: mdl-34984437

RESUMO

BACKGROUND: Motor function impacts 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 400m walk, and usual gait speed. Slow gait was defined as usual gait speed <1.0m/s. Mobility difficulty was defined as self-reported difficulty walking » mile or climbing stairs. Structural equation modeling (SEM) 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<0.001) and lower muscle strength (upper and lower extremity) (-0.447 SD units, p=0.014) were most strongly associated with slow gait speed, followed by slower chair stand pace (-0.195 SD units, p=0.002) and greater lap time variation (0.102 SD units, p=0.028). Lower muscle strength (-0.582 SD units, p=0.001) was most strongly associated with mobility difficulty, followed by slower chair stand pace (-0.322 SD units, p<0.001), slower gait speed (-0.247 SD units, p<0.001), and poorer standing balance (-0.190 SD units, p=0.043). 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.

3.
Aging (Albany NY) ; 13(undefined)2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857670

RESUMO

Tongue fungiform papillae contain taste buds crucial for taste and hormone-producing taste receptor cells; therefore, they may be considered as endocrine organs and have important age-associated physiological implications. We examine the cross-sectional and longitudinal trajectories of fungiform papillae density in 1084 participants from the Baltimore Longitudinal Study of Aging using linear regression models and mixed effects models. At baseline, the mean age was 67.86 ± 14.20 years, with a mean follow-up time among those with repeat visits of 4.24 ± 1.70 years. Women (53%) were younger (66.85 ± 13.78 vs. 69.04 ± 14.61 years, p < 0.001) and had a higher fungiform papillae density than men (16.14 ± 9.54 vs. 13.77 ± 8.61 papillae/cm2, p < 0.001). Whites (67%) had a lower fungiform papillae density than non-Whites after adjusting for age and sex. Factors cross-sectionally associated with a lower fungiform papillae density included a higher waist-hip ratio (ß = -8.525, p = 0.029), current smoking status (ß = -5.133, p = 0.014), and alcohol use within the past 12 months (ß = -1.571, p = 0.025). Longitudinally, fungiform papillae density decreased linearly with follow-up time (ß = -0.646, p < 0.001). The rate of decline was not affected by sex, race, BMI, waist-hip ratio, smoking, or alcohol use. The longitudinal decline of fungiform papillae density over time needs to be explored further in order to identify other possible age-associated physiological determinants.

4.
Anal Chem ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34859676

RESUMO

Modern biomarker and translational research as well as personalized health care studies rely heavily on powerful omics' technologies, including metabolomics and lipidomics. However, to translate metabolomics and lipidomics discoveries into a high-throughput clinical setting, standardization is of utmost importance. Here, we compared and benchmarked a quantitative lipidomics platform. The employed Lipidyzer platform is based on lipid class separation by means of differential mobility spectrometry with subsequent multiple reaction monitoring. Quantitation is achieved by the use of 54 deuterated internal standards and an automated informatics approach. We investigated the platform performance across nine laboratories using NIST SRM 1950-Metabolites in Frozen Human Plasma, and three NIST Candidate Reference Materials 8231-Frozen Human Plasma Suite for Metabolomics (high triglyceride, diabetic, and African-American plasma). In addition, we comparatively analyzed 59 plasma samples from individuals with familial hypercholesterolemia from a clinical cohort study. We provide evidence that the more practical methyl-tert-butyl ether extraction outperforms the classic Bligh and Dyer approach and compare our results with two previously published ring trials. In summary, we present standardized lipidomics protocols, allowing for the highly reproducible analysis of several hundred human plasma lipids, and present detailed molecular information for potentially disease relevant and ethnicity-related materials.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34849845

RESUMO

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 five 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: 12y), 811 deaths occurred (292 of cardiovascular- and 151 of cancer-related causes). Animal protein intake was inversely associated with all-cause (HR per 1% of total energy from protein increase, 95%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<0.05). 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.

6.
BMJ Open ; 11(12): e053905, 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34903548

RESUMO

OBJECTIVE: To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. DESIGN: Retrospective cohort analysis. SETTING: Primary care practices in the UK from January 1999 to September 2017. PARTICIPANTS: 7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36-79 years at time of first clopidogrel prescription. INTERVENTIONS: Clopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years). MAIN OUTCOME MEASURE: Hospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel. RESULTS: 28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79. CONCLUSIONS: A substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34914835

RESUMO

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 three angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using post-mortem 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-ß 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-ß scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

8.
Int J Food Sci Nutr ; : 1-12, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34783276

RESUMO

Blood pressure (BP) control is a key target for interventions to reduce cognitive decline. This cross-sectional study explored associations between objective (24-hour urine excretion) and subjective (food frequency questionnaire [FFQ]) measures of dietary sodium and nitrate intakes with cognitive function and resting BP in the InCHIANTI cohort. Baseline data from 989 participants aged >50 years were included. In fully adjusted models, participants with concurrent high nitrate and low sodium (Odds Ratio (OR)=0.49, 95%CI 0.32-0.76, p = 0.001) and high nitrate and high sodium (OR = 0.49, 95%CI 0.32-0.77, p = 0.002) 24-hour urinary concentrations had lower odds of high BP than participants with low nitrate and high sodium concentrations. We found no significant associations between sodium and nitrate intakes (24-hour urinary concentrations and FFQ) and poor cognitive performance. Urinary nitrate excretion was associated with lower BP and results appeared to be independent of sodium intake. Further analyses in longitudinal studies are required to substantiate these findings.

9.
J Am Geriatr Soc ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34796957

RESUMO

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

11.
Clin Nutr ; 40(12): 5764-5770, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34763261

RESUMO

BACKGROUND & AIMS: Body weight changes reflect and impact several health conditions in older age, but little is known about its relationship with multimorbidity. We aimed to study the association of long-terms trajectories of body mass index (BMI) with contemporaneous changes in multimorbidity -and multimorbidity type- development in a population-based cohort of older adults. METHODS: Twelve-year BMI trajectories (2001-2013) were identified in subjects aged 60+ years from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) using growth mixture models (N = 2189). Information on 60 chronic diseases and multimorbidity was ascertained based on clinical examinations, lab tests, medications, and inpatient and outpatient medical records. Linear mixed models were used to study the association between BMI trajectories and the speed of chronic disease accumulation, in general and by groups of cardiovascular and neuropsychiatric diseases. RESULTS: Eighty percent of the study population was included in what we defined a stable BMI trajectory, 18% in a slow-decline trajectory with an accelerated BMI decline from age 78 onwards, and 2% in a fast-decline trajectory that reached underweight values before age 85. A significantly higher yearly rate of chronic disease accumulation was observed in the fast-decline versus stable trajectory (ß = 0.221, 95% CI 0.090-0.352) after adjusting the model for age cohort, sex, education and time to death. Subjects in the slow-decline trajectory showed a significantly higher yearly rate of cardiovascular disease accumulation (ß = 0.016, 95% CI 0.000-0.031); those in the fast-decline trajectory showed a faster accumulation of both cardiovascular (ß = 0.020, 95% CI -0.025, 0.064) and neuropsychiatric diseases (ß = 0.102, 95% CI 0.064-0.139), even if the former association did not reach statistical significance. CONCLUSION: Our results provide further evidence of the importance of carefully monitoring older adults with sustained weight loss, which is an early indicator of accelerated health deterioration, reflected in our study by a faster accumulation of chronic -especially neuropsychiatric- diseases.

12.
BMC Med ; 19(1): 280, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34814922

RESUMO

BACKGROUND: Dietary biomarkers may complement dietary intake assessment made by dietary questionnaires. We developed an a-posteriori dietary biomarkers score based on Mediterranean diet food groups and evaluated its association with mortality. METHODS: 642 participants (56% female), aged ≥65 years, with complete data on dietary biomarkers were followed during 20 years in the InCHIANTI cohort study (Tuscany, Italy). The main outcomes were all-cause, cardiovascular, and cancer mortality. Dietary biomarkers were selected from literature and from correlation analyses with dietary intakes of Mediterranean diet food groups in the study. The baseline levels of the following dietary biomarkers were chosen: urinary total polyphenols and resveratrol metabolites, and plasma carotenoids, selenium, vitamin B12, linolenic, eicosapentaenoic and docosahexaenoic acids, and the mono-unsaturated/saturated fatty acid ratio. Associations of the Mediterranean diet score using dietary biomarkers and a validated food frequency questionnaire (FFQ) (as tertiles) with mortality were assessed through Cox regression. RESULTS: During the 20-year follow-up [median (Q1-Q3), 14 (8-18) years], and 435 deaths occurred (139 from cardiovascular diseases and 89 from cancer-related causes). In the fully adjusted models, the dietary biomarker-Mediterranean diet score was inversely associated with all-cause (HRT3vs.T1 0.72; 95%CI 0.56-0.91) and cardiovascular (HRT3vs.T1 0.60; 95%CI 0.38-0.93), but not with cancer mortality. Associations between the FFQ-Mediterranean diet score and mortality were not statistically significant. CONCLUSIONS: A greater adherence at baseline to a Mediterranean diet assessed by a dietary biomarker score was associated with a lower risk of mortality in older adults during a 20-year follow-up. The measurement of dietary biomarkers may contribute to guide individualized dietary counseling to older people. TRIAL REGISTRATION: NCT01331512.

13.
JAMA Netw Open ; 4(11): e2135168, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34792590

RESUMO

Importance: Among older people, slow walking is an early indicator of risk for Alzheimer disease (AD). However, studies that have assessed this association have not considered that slow walking may have different causes, some of which are not necessarily associated with higher AD risk. Objective: To evaluate whether low activity fragmentation among older adults with slow gait speed indicates neurological causes of slow walking that put these individuals at higher risk of AD. Design, Setting, and Participants: This prospective cohort study performed survival analyses using data from the Baltimore Longitudinal Study of Aging. Participants included 520 initially cognitively normal persons aged 60 years or older. New diagnoses of mild cognitive impairment (MCI) or AD were adjudicated during a mean (SD) follow-up of 7.3 (2.7) years. Initial assessment of gait speed and activity fragmentation occurred from January 3, 2007, to May 11, 2015, with follow-up completed on December 31, 2020. Data were analyzed from February 1 to May 15, 2021. Exposures: Gait speed for 6 m and activity fragmentation assessed by accelerometry. Main Outcomes and Measures: Associations of gait speed, activity fragmentation, and their interaction with incident MCI/AD were evaluated using Cox proportional hazards models, adjusted for covariates. Results: Among the 520 participants (265 women [51.0%]; 125 Black participants [24.0%]; 367 White participants [70.6%]; mean [SD] age, 73 [8] years), MCI/AD developed in 64 participants. Each 0.05-m/s slower gait was associated with a 7% increase in risk of developing MCI/AD (hazard ratio [HR], 1.07 [95% CI, 1.00-1.15]; P = .04). Activity fragmentation alone was not associated with MCI/AD risk (HR, 0.83 [95% CI, 0.56-1.23]; P = .35), but there was a significant interaction between gait speed and activity fragmentation (HR, 0.92 [95% CI, 0.87-0.98]; P = .01). At low activity fragmentation (-1 SD), each 0.05-m/s slower gait speed was associated with a 19% increase in hazard of developing MCI/AD (HR, 1.19 [95% CI, 1.07-1.32]), whereas at higher activity fragmentation (+1 SD), gait speed was not associated with MCI/AD (HR, 1.01 [95% CI, 0.93-1.10]). Among participants with slow gait, higher activity fragmentation was associated with higher odds of having lower extremity osteoarthritis (odds ratio, 1.31 [95% CI, 1.01-1.69]) and less decline in pegboard dominant hand performance (ß = 0.026 [SE, 0.009]; P > .05). Conclusions and Relevance: These findings suggest that frequent rests among older adults with slow gait speed are associated with lower risk of future MCI/AD and that this behavioral strategy is associated with a lower likelihood of subclinical neurological impairment.

15.
Ageing Res Rev ; 72: 101498, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34700009

RESUMO

Frailty is a common condition in older people. The epidemiological data available, however, are mainly based on the physical frailty phenotype. An extensive literature has suggested that frailty should be identified using a multidimensional approach. Based on these recommendations, we estimated the prevalence of frailty and pre-frailty in the older population, using the multidimensional prognostic index (MPI), a common tool for defining multidimensional frailty. We searched several databases until 10th May 2021 for studies reporting the prevalence of frailty according to MPI values. MPI was categorized, where possible, in < 0.33 (robustness), 0.33-0.66 (pre-frailty) and > 0.66 (frailty) or using a RECursive Partition and AMalgamation approach. A meta-analysis of the prevalence, with the correspondent 95% confidence intervals (CIs) of pre-frailty and frailty was performed stratified by setting (population-based, ambulatory, nursing home, and hospital). Among 177 papers initially screened, we included 57 studies for a total of 56,407 older people. The mean age was 78.6 years, with a slight prevalence of women (58%). The overall prevalence of multidimensional frailty (MPI-3) was 26.8% (95%CI: 22.1-31.5), being higher in nursing home setting (51.5%) and lower in population-based studies (13.3%). The prevalence of pre-frailty (MPI-2) was 36.4% (95%CI: 33.1-39.7), being higher in hospital setting (39.3%) and lower in nursing home (20%). In conclusion, frailty and pre-frailty, according to a multidimensional definition, are common in older people affecting, respectively, one person over four and one over three. Our work further strengths the importance of screening frailty in older people using a multidimensional approach.

16.
Aging (Albany NY) ; 13(20): 23471-23516, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34718232

RESUMO

It is widely thought that individuals age at different rates. A method that measures "physiological age" or physiological aging rate independent of chronological age could therefore help elucidate mechanisms of aging and inform an individual's risk of morbidity and mortality. Here we present machine learning frameworks for inferring individual physiological age from a broad range of biochemical and physiological traits including blood phenotypes (e.g., high-density lipoprotein), cardiovascular functions (e.g., pulse wave velocity) and psychological traits (e.g., neuroticism) as main groups in two population cohorts SardiNIA (~6,100 participants) and InCHIANTI (~1,400 participants). The inferred physiological age was highly correlated with chronological age (R2 > 0.8). We further defined an individual's physiological aging rate (PAR) as the ratio of the predicted physiological age to the chronological age. Notably, PAR was a significant predictor of survival, indicating an effect of aging rate on mortality. Our trait-based PAR was correlated with DNA methylation-based epigenetic aging score (r = 0.6), suggesting that both scores capture a common aging process. PAR was also substantially heritable (h2~0.3), and a subsequent genome-wide association study of PAR identified significant associations with two genetic loci, one of which is implicated in telomerase activity. Our findings support PAR as a proxy for an underlying whole-body aging mechanism. PAR may thus be useful to evaluate the efficacy of treatments that target aging-related deficits and controllable epidemiological factors.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34718551

RESUMO

Age-dependent differences in methylation at specific cytosine-guanosine sites (CpGs) 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 (LGL). We found clear histological markers of LGL 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 LGL broadly increased DNA methylation variability, it did not change epigenetic aging. Despite this, inclusion of rats with LGL in clock training sets significantly altered predictor selection probability at 83 of 121 commonly utilized CpGs. Furthermore, models trained on rat samples that included individuals with LGL had greater absolute age error than those trained exclusively on LGL-free rats (39% increase; p<0.0001). We conclude that the epigenetic signals for aging and LGL are distinct, such that LGL 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.

18.
Immunity ; 54(11): 2465-2480.e5, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34706222

RESUMO

Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34628503

RESUMO

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 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 FDR p< 0.05). 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= 0.01) and accelerated annual increase in ventricular volumes (FDR p= 0.01). 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.

20.
Am J Clin Nutr ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34637504

RESUMO

BACKGROUND: Diet quality may be protective of physical function and muscle strength during aging. OBJECTIVES: We aimed to investigate associations of the Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay (MIND) diet with physical function and grip strength. METHODS: Data were obtained from men and women in the Baltimore Longitudinal Study of Aging (mean ± SD age: 68 ± 14 y at first diet visit; n = 1358). Diet was assessed by FFQ. MIND diet score was calculated from 15 food groups, with a higher score indicating better diet quality; tertile categories of averaged MIND score across visits were used. Physical function was assessed using the Short Physical Performance Battery (SPPB), with a score < 10 indicative of impaired function, and the Health, Aging and Body Composition Physical Performance Battery (HABCPPB). The highest value of grip strength over 3 trials was used. Multivariable logistic and linear mixed-effects models were examined with repeated measurements of physical function and grip strength, respectively. RESULTS: MIND score was inversely associated with physical function impairment (per 1-point increment: OR: 0.81; 95% CI: 0.71, 0.93; P < 0.01), and with each SPPB component, over a median 6 y of follow-up. Participants in the highest compared with the lowest tertile of MIND diet score had 57% lower odds of functional impairment (OR: 0.43; 95% CI: 0.25, 0.73; P < 0.01), and slower decline by the HABCPPB. Men and women in the highest compared with the lowest tertiles of MIND score had 1.86-kg (95% CI: 0.33, 3.40 kg; P < 0.05) and 1.24-kg (95% CI: 0.04, 2.45 kg; P < 0.05) greater grip strength, respectively. CONCLUSIONS: Adherence to the MIND dietary pattern was associated with lower odds of physical function impairment and decline, and with better muscle strength, indicating that the MIND dietary pattern may be protective of physical functional health in older adults.

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