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1.
JAMA Netw Open ; 2(10): e1912352, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577355

RESUMO

Importance: Fragmented daily physical activity may be a sign of physiological decline that provides more powerful insight into impending mortality than total daily activity. Objective: To compare and contrast the association between total daily activity and activity fragmentation, which encompasses activity bouts and duration, and mortality risk. Design, Setting, and Participants: In this cohort study, accelerometer data from 2007 through 2015 and mortality data from 2007 through 2017 were collected from 548 adults aged 65 years and older participating in the Baltimore Longitudinal Study of Aging. The dates of analysis were November 2016 to June 2019, with data collected through December 31, 2017. Using Cox proportional hazards regression, the association between accelerometer-derived patterns of physical activity and mortality was estimated after adjusting for demographic characteristics, lifestyle factors, and comorbidities. Exposures: Minute-by-minute physical activity data were collected over a 24-hour, 7-day period (excluding times between 11:00 pm and 4:59 am) using an accelerometer. Each minute was labeled either active or sedentary, and 5 features of accelerometer data were extracted: total daily activity (defined as any activity performed throughout the day), activity fragmentation (defined as an active-to-sedentary transition probability), and 3 measures of activity bouts (<5, 5-10, and ≥10 active minutes). Main Outcomes and Measures: All-cause mortality. Results: Among 548 well-functioning older adults (mean [SD] age, 75.8 [7.2] years; 262 [47.8%] women), 61 participants (11.1%) died. Total daily physical activity was not associated with mortality risk (hazard ratio [HR], 0.90 [95% CI, 0.75-1.08]; P = .28). However, more fragmented physical activity patterns were associated with greater mortality risk (HR, 1.49 [95% CI, 1.02-2.19]; P = .04) after adjusting for age, sex, race/ethnicity, body mass index, smoking history, employment, self-reported health, grip strength, usual gait speed, comorbidities, and device wear time. In addition, more frequently engaging in activity bouts lasting less than 5 minutes was associated with greater mortality risk (HR, 1.28 [95% CI, 1.01-1.61]; P = .04), whereas activity bouts of 5 to 10 minutes (HR, 0.99 [95% CI, 0.58-1.69]; P = .97) and 10 minutes or longer (HR, 0.81 [95% CI, 0.65-1.01]; P = .06) were not associated with mortality risk. Conclusions and Relevance: In this cohort study of well-functioning adults aged 65 years and older, fragmented daily physical activity, particularly activity bouts lasting less than 5 minutes, was associated with greater mortality risk. These findings suggest that activity fragmentation in older adults may precede declines in functional capability and overall physical activity that typically indicate impending mortality.

2.
Aging Cell ; : e13032, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31478346

RESUMO

Skeletal muscle aging is a major cause of disability and frailty in the elderly. The progressive impairment of skeletal muscle function with aging was recently linked to a disequilibrium between damage and repair. Macrophages participate in muscle tissue repair, first as pro-inflammatory M1 subtype and then as anti-inflammatory M2 subtype. However, information on the presence of macrophages in skeletal muscle is still sporadic and the effect of aging on macrophage phenotype remains unknown. In this study, we sought to characterize the polarization status of macrophages in skeletal muscle of persons across a wide range of ages. We found that most macrophages in human skeletal muscle are M2, and that this number increased with advancing age. On the contrary, M1 macrophages declined with aging, making the total number of macrophages invariant with older age. Notably, M2 macrophages colocalized with increasing intermuscular adipose tissue (IMAT) in aging skeletal muscle. Similarly, aged BALB/c mice showed increased IMAT and M2 macrophages in skeletal muscle, accompanied by slightly increased collagen protein production. Collectively, we report that polarization of macrophages to the major M2 subtype is associated with IMAT and propose that increased M2 in aged skeletal muscle may impact upon muscle metabolism associated with aging.

3.
Maturitas ; 128: 81-86, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31561828

RESUMO

OBJECTIVES: The association between frailty, mortality and sex is complex, but a limited literature is available on this topic, particularly for older hospitalized patients. Therefore, the objective of our study was to prospectively evaluate sex differences in frailty, assessed by the Multidimensional Prognostic Index (MPI) and mortality, institutionalization, and re-hospitalization in an international cohort of older people admitted to hospital. STUDY DESIGN: We used data from nine public hospitals in Europe and Australia, to evaluate sex differences in mortality, frailty and the risk of institutionalization and re-hospitalization, during one year of follow-up. MAIN OUTCOME MEASURES: People aged 65 years or more admitted to hospital for an acute medical condition or for a relapse of a chronic disease were included. A standardized comprehensive geriatric assessment, which evaluated functional, nutritional, and cognitive status, risk of pressure sores, comorbidities, medications and co-habitation status, was used to calculate the MPI to measure frailty in all hospitalized older people. Data regarding mortality, institutionalization and re-hospitalization were also recorded for one year. RESULTS: Altogether, 1140 hospitalized patients (mean age = 84.2 years; 694 women = 60.9%) were included. The one-year mortality rate was 33.2%. In multivariate analysis, adjusted for age, MPI score, centre and diagnosis at baseline, although women had higher MPI scores than men, the latter had higher in-hospital (odds ratio, OR = 2.26; 95% confidence intervals, CI = 1.27-4.01) and one-year post-discharge mortality (OR = 2.04; 95%CI = 1.50-2.79). Furthermore, men were less frequently institutionalized in a care home than female patients (OR = 0.55; 95%CI: 0.34-0.91), but they were also more frequently re-hospitalized (OR = 1.42; 95%CI: 1.06-1.91) during the year after hospital discharge. CONCLUSION: Older hospitalized men were less frail, but experienced higher in-hospital and one-year mortality than women. Women were admitted more frequently to nursing homes and experienced a lower risk of re-hospitalization. These findings suggest important differences between the sexes and extends the 'male-female health-survival paradox' to acutely ill patient groups.

4.
Alzheimers Dement ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31561966

RESUMO

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31523937

RESUMO

The term sarcopenia was introduced in 1988. The original definition was a "muscle loss" of the appendicular muscle mass in the older people as measured by dual energy x-ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC-F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease-related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age-related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age-related and disease-related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life-long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.

6.
Aging Cell ; : e13017, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31444995

RESUMO

Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.

8.
J Am Geriatr Soc ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31441513

RESUMO

OBJECTIVES: Given the need to detect subclinical changes in brain health that sometimes occur with aging in apparently healthy older adults, we assessed whether bimanual gesture imitation performance, simple to assess clinically, can detect age effects and alterations in cognition, olfaction, and movement. DESIGN: Cross-sectional study. SETTING: Baltimore Longitudinal Study of Aging. PARTICIPANTS: Men and women, aged 22 to 101 years, without cognitive impairment, dementia, stroke, Parkinson disease, resting tremor, abnormal muscle tone, or abnormal coordination (N = 507). MEASUREMENTS: Bimanual gesture imitation was measured using a test validated in older adults. We assessed (1) cognition, including verbal memory, executive function, attention, visuospatial ability, visuoperceptual speed, and language; (2) manual dexterity with the Purdue Pegboard Test; (3) olfaction, using the 16-item Sniffin' Sticks Identification Test; (4) upper extremity motor function, using a computer-based finger tapping test; and (5) lower extremity motor function, including 6-meter usual and rapid gait speeds, 400-meter walk time, Health ABC Physical Performance Battery, and total standing balance time. Cross-sectional associations between bimanual gesture imitation performance and each measure were examined using linear regression after adjustment for age, sex, race, education, and body mass index. Models with mobility measures also adjusted for height. RESULTS: Higher gesture imitation performance was associated with younger age. After adjustment, a worse score was associated with worse olfaction, executive function, and visuospatial ability. Gesture imitation score was not associated with other cognitive measures or motor function. CONCLUSION: In persons without clinically detectable neurological conditions, poor bimanual gesture imitation is associated with other indicators of brain health, including olfaction and selected cognitive function domains. Bimanual gesture imitation may be useful clinically to detect subtle brain changes in apparently healthy older adults.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31428775

RESUMO

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 from 379,758 European-descent UK Biobank participants, aged 40 to 70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers ≥96) was more common in CC versus TT (Odds Ratio =1.18, 95% 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.

10.
Aging Cell ; : e13023, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385390

RESUMO

The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late-onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e2 allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOE e2 , with aptamer-based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late-onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOE e2 molecularly may preserve cognitive function.

11.
Circulation ; 140(8): 645-657, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985

RESUMO

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

12.
Nutr Metab Cardiovasc Dis ; 29(10): 1061-1067, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377184

RESUMO

BACKGROUND AND AIMS: Increased uric acid levels correlate with cardiovascular disease and cardiovascular/overall mortality. To identify a uric acid threshold above which cardiovascular mortality rises, we studied the relationship between uric acid concentration and overall/cardiovascular mortality. METHODS AND RESULTS: We analyzed data from the InCHIANTI study, a cohort study of Italian community-dwelling people with 9 years of follow-up. We selected a sample of 947 individuals over 64 years of age, free from cardio-cerebrovascular disease and with available uric acid measurement at baseline. The sample was divided according to plasma uric acid tertiles. The Hazard ratio (HR) for mortality was calculated by multivariate Cox proportional hazard model. Mean age of participants was 75.3 ± 7.3 years; the mean value of uric acid was 5.1 ± 1.4 mg/dl. Over 9-years of follow-up, 342 (36.1%) participants died, 143 deaths (15.1%) were due to cardiovascular disease. Subjects with higher uric acid concentrations presented a higher cardiovascular mortality [II (4.6-5.5 mg/dl) vs I (1.8-4.5 mg/dl) tertile HR: 1.98, 95%C.I. 1.22-3.23; III (≥5.6 mg/dl) vs I tertile HR: 1.87, 95%C.I. 1.13-3.09]. We found a non-linear association between uric acid concentrations and cardiovascular mortality with the lowest mortality for values of about 4.1 mg/dl and a significant risk increment for values above 4.3 mg/dl. CONCLUSION: In community-dwelling older individuals free from cardio-cerebrovascular events, the lowest 9-year cardiovascular mortality was observed for uric acid values far below current target values. If confirmed, these data might represent the background for investigating the efficacy of uric acid levels reduction in similar populations.

13.
Aging (Albany NY) ; 11(16): 5895-5923, 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31422385

RESUMO

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

14.
J Am Heart Assoc ; 8(15): e011650, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31379300

RESUMO

Background Aging is associated with a modest decline in ankle-brachial index (ABI); however, the underpinnings of this decline are not fully understood. The greater systolic ankle than brachial blood pressure, a normal ABI implies, is partially attributed to lower central than peripheral arterial stiffness. Hence, we examined the hypothesis that the age-associated decline in ABI is associated with central arterial stiffening with aging, assessed by pulse wave velocity. Methods and Results We analyzed longitudinal data from 974 participants aged 27 to 95 years from the Baltimore Longitudinal Study of Aging who were free of clinically significant cardiovascular disease. Participants had an average of 4 visits with a 6.8-year average follow-up time. Linear mixed-effects models showed that the average ABI decline beyond the age of 70 years was 0.03 per decade. In multiple regression analysis, the ABI rate of change was inversely associated with initial age (standardized ß=-0.0711, P=0.0282), independent of peripheral disease factors and baseline ABI. After adjustment, the pulse wave velocity rate of change was inversely associated with ABI rate of change (standardized ß=-0.0993, P=0.0040), rendering the association of the latter with initial age nonsignificant (standardized ß=-0.0265, P=0.5418). Conclusions A modest longitudinal decline in ABI beyond the age of 70 years was shown to be independent of traditional risk factors for peripheral arterial disease but was accounted for by an increase in pulse wave velocity. A modest decline in ABI with aging might be a manifestation of changes in central hemodynamics and not necessarily attributable to peripheral flow-limiting factors.

15.
J Am Heart Assoc ; 8(16): e013049, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31409206

RESUMO

Background Cardiovascular disease (CVD) and fatigue commonly co-occur in older adults, yet the subjective nature of fatigue and its situational dependence leave the true magnitude of this association undefined. Methods and Results Six-hundred and twenty-five participants with no history of CVD (aged 68.1+12.0 years), from the Baltimore Longitudinal Study of Aging who underwent ≥2 clinic visits between 2007 and 2015 were classified according to sex-specific predicted 10-year CVD risk scores using the Framingham CVD risk score (Framingham) and the Pooled Cohort Equation at baseline. Perceived fatigability was assessed using the Borg rating of perceived exertion scale after a 5-minute treadmill walk (0.67 m/s, 0% grade). Linear models were used to assess the association between baseline CVD risk and perceived fatigability an average of 4.5 years later, adjusted for demographics, behaviors, and medical history. In final models, a 5% higher baseline Pooled Cohort Equation score was associated with greater perceived fatigability at follow-up (ß=0.13 rating of perceived exertion, P=0.008). Stratified analyses suggested this association was stronger among those aged ≤70 years and those with obesity. Of the individual CVD risk score components, older age was most strongly associated with perceived fatigability (ß=0.48, P<0.001), followed by women (ß=0.11, P=0.002), and treated hypertension (ß=0.11, P=0.003). There was no association with the Framingham risk score. Conclusions Perceived fatigability was higher among participants with greater CVD risk measured using the Pooled Cohort Equation risk score. The strong associations with hypertension and obesity suggest prevention and promotion of cardiovascular health may also lower perceived fatigability, particularly among those aged ≤70 years or living with obesity.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31273957

RESUMO

BACKGROUND: Slow gait speed is a powerful predictor of disability in activities of daily living and mortality. Muscle strength and body composition change over time, but their changes differ by sex. How these parameters jointly affect gait speed decline is unknown. Understanding this association could help develop and evaluate the sex-specific effects of lifestyle interventions to delay gait speed decline in older adults. We assessed whether changes in strength (Δstrength), appendicular lean mass (ΔALM), and fat mass (Δfat) jointly relate to change in gait speed and whether the association differs by sex. METHODS: The analytic sample comprised 575 women and 539 men aged 22-95 years enrolled in the Baltimore Longitudinal Study of Aging. Mean follow-up was 4.0 years. Measures included isometric knee extension strength, dual-energy X-ray absorptiometry-assessed ALM and fat mass, and gait speed from the 400 m fast pace walk. Sex-specific linear mixed models were adjusted for follow-up time and baseline age, race, height, ALM, fat mass, peak torque, and gait speed. We also included second-order interaction terms of the key predictive variables (e.g. Δstrength × ΔALM). To interpret the interactions, we estimated average gait declines using the 25th or 75th percentile of the two significant predictive variables and then assessed which condition relates to larger decline in gait speed. RESULTS: In both sexes, independent of ΔALM and Δfat, larger decline in strength significantly related to larger decline in gait speed (P = 0.01 for both sexes). In men, interactions between Δstrength × ΔALM and Δfat by ΔALM were associated with change in gait speed; men with greater declines in both muscle strength and ALM or greater declines in both ALM and fat have steeper gait speed decline. In contrast, in women, the interaction between Δfat and ΔALM was associated with change in gait speed; women with an increase in fat mass combined with less decline in ALM have steeper gait speed decline. CONCLUSIONS: While change in strength affects change in gait speed in both sexes, the effects of body composition change differ by sex. Dual-energy X-ray absorptiometry-based estimates of lean mass may be confounded by intramuscular fat. Future studies should examine sex-specific combined effects of change in strength and body composition on mobility using multiple techniques to measure body composition. Intervention studies should consider testing sex-specific interventions on body composition.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31282535

RESUMO

BACKGROUND: Whereas the independent effects of biomarkers, including vitamin D (25(OH)D), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP) 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 ≥ 65 at baseline (N = 970) were enrolled in the population-based InCHIANTI study from 1998-2000, and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the 3 time points. Using a generalized estimating equation (GEE) approach, we determined if slow gait speed (< 0.8 meter/second) was associated with the biomarkers. Further investigation was conducted for interactions between high IL-6 (≥ 2.87 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 = 0.038). The odds ratio of slow gait speed for low 25(OH)D and high IL-6 was 1.63 (95% C.I.: 1.15, 2.32) compared to 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. Co-existing 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.

18.
J Natl Cancer Inst ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321426

RESUMO

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or phase-shift aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors." Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.

19.
JAMA Neurol ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31305918

RESUMO

Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aß42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective: To validate nEV biomarkers as AD predictors. Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aß42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aß42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31268512

RESUMO

Importance: Hearing impairment (HI) in midlife (45-65 years of age) may be associated with longitudinal neurodegeneration of temporal lobe structures, a biomarker of early Alzheimer disease. Objective: To evaluate the association of midlife HI with brain volume trajectories in later life (≥65 years of age). Design, Setting, and Participants: This prospective cohort study used data from the Baltimore Longitudinal Study of Aging to evaluate hearing from November 5, 1990, to October 3, 1994, and late-life volume change from July 10, 2008, to January 29, 2015, using magnetic resonance imaging (MRI) (mean follow-up time, 19.3 years). Data analysis was performed from September 22, 2017, to August 27, 2018. A total of 194 community-dwelling older adults who had midlife measures of peripheral hearing at a mean age of 54.5 years and late-life volume change of up to 6 years between the first and most recent MRI assessment were studied. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and bipolar disorder. Exposures: Hearing as measured with pure tone audiometry in each ear from November 5, 1990, to October 3, 1994, and late-life temporal lobe volume change measured by MRI. Main Outcomes and Measures: Linear mixed-effects models with random intercepts were used to examine the association of midlife hearing (pure tone average of 0.5-4 kHz tones in the better ear and each ear separately) with longitudinal late-life MRI-based measures of temporal lobe structures (hippocampus, entorhinal cortex, parahippocampal gyrus, and superior, middle, and inferior temporal gyri) in the left and right hemispheres, in addition to global and lobar regions, adjusting for baseline demographic characteristics (age, sex, subsequent cognitive impairment status, and educational level) and intracranial volume. Results: A total of 194 patients (mean [SD] age at hearing assessment, 54.5 [10.0] years; 106 [54.6%] female; 169 [87.1%] white) participated in the study. After Bonferroni correction, poorer midlife hearing in the better ear was associated with steeper late-life volumetric declines in the right temporal gray matter (ß = -0.113; 95% CI, -0.182 to -0.044), right hippocampus (ß = -0.008; 95% CI, -0.012 to -0.004), and left entorhinal cortex (ß = -0.009; 95% CI, -0.015 to -0.003). Poorer midlife hearing in the right ear was associated with steeper late-life volumetric declines in the right temporal gray matter (ß = -0.136; 95% CI, -0.197 to -0.075), right hippocampus (ß = -0.008; 95% CI, -0.012 to -0.004), and left entorhinal cortex (ß = -0.009; 95% CI, -0.015 to -0.003), whereas there were no associations between poorer midlife hearing in the left ear with late-life volume loss. Conclusions and Relevance: The findings suggest that midlife HI is a risk factor for temporal lobe volume loss. Poorer midlife hearing, particularly in the right ear, was associated with declines in hippocampus and entorhinal cortex.

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