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Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, we characterized the plasma proteomics profile of CVH and tested whether specific proteins mediated the associations between CVH and all-cause mortality in participants of the InCHIANTI study. Of the 1301 proteins tested, 92 proteins were associated with CVH (22 positively, 70 negatively). Proteins most strongly associated with CVH included leptin (LEP), fatty acid binding protein 3 (FABP3), Angiopoietin-2 (ANGPT2), and growth-differential factor 15 (GDF15). Of the 92 CVH-associated proteins, 33 proteins significantly mediated the associations between CVH and all-cause mortality, with percent mediation ranging from 5 to 30%. The most significant mediating proteins were GDF15 and insulin-like growth factor 2 (IGFBP2). Proteins associated with better CVH were enriched for proteins that reflect the suppression of the complement coagulation and GH/IGF pathways.

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.

Background: Higher mortality experienced by socially disadvantaged groups and/or racial/ethnic minorities is hypothesized to be, at least in part, due to an acceleration of the aging process. Using a new epigenetic aging measure, Levine DNAmAge, this study aimed to investigate whether epigenetic aging accounts for mortality disparities by race/ethnicity and education in a sample of U.S. postmenopausal women., Methods: 1834 participants from an ancillary study (BA23) in the Women's Health Initiative, a national study that recruited postmenopausal women (50-79 years) were included. Over the 22 years of follow-up, 551 women died, and 31,946 person-years were observed. Levine DNAmAge (unit in years) was calculated based on an equation that we previously developed in an independent sample, which incorporates methylation levels at 513 CpG sites., Results: As previously reported, non-Hispanic blacks and Hispanics were epigenetically older than non-Hispanic whites of the same chronological age. Similarly, those with less education had older epigenetic ages than expected in the full sample, as well as among non-Hispanic whites and Hispanics, but not among non-Hispanic blacks. Non-Hispanic blacks and those with low education exhibited the greatest risk of mortality. However, this association was partially attenuated when accounting for differences in DNAmAge. Furthermore, formal mediation analysis suggested that DNAmAge partially mediated the mortality increase among non-Hispanic blacks, compared to non-Hispanic whites (proportion mediated, 15.8%, P = 0.002), as well as the mortality increase for those with less than high school education, compared to college educated (proportion mediated, 11.6%, P < 2E-16)., Conclusions: Among a group of postmenopausal women, non-Hispanic blacks and those with less education exhibit higher epigenetic aging, which partially accounts for their shorter life expectancies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recent studies have shown contradictory associations between calcium levels and health outcomes. We suspected these conflicting results were the consequence of more general issues with how biomarkers are analyzed in epidemiological studies, particularly in the context of aging. To demonstrate the risks of typical analyses, we used three longitudinal aging cohort studies and their demographic subsets to analyze how calcium levels change with age and predict risk of mortality and frailty. We show that calcium levels either increase or decrease with age depending on the population, and positively or negatively predict frailty depending on the population and analysis; both age and frailty results showed substantial heterogeneity. Mortality analyses revealed few significant associations but were likely underpowered. Variation in population composition (demographics, diseases, diet, etc.) leads to contradictory findings in the literature for calcium and likely for other biomarkers. Epidemiological studies of biomarkers are particularly sensitive to population composition both because biomarkers generally have non-linear and often non-monotonic relationships with other key variables, notably age and health outcomes, and because there is strong interdependence among biomarkers, which are integrated into complex regulatory networks. Consequently, most biomarkers have multiple physiological roles and are implicated in multiple pathologies. We argue that epidemiological studies of aging using biomarkers must account for these factors, and suggest methods to do this., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the relationship between gait speed, recall memory, and mortality., Design: A cohort study (last follow-up December 2009)., Setting: Tuscany, Italy., Participants: Individual data from 1,014 community-dwelling older adults aged 60 years or older with baseline gait speed and recall memory measurements and follow-up for a median time of 9.10 (IQR 7.1;9.3) years. Participants were a mean (SD) age of 73.9 (7.3) years, and 55.8% women. Participants walking faster than 0.8 m/s were defined as fast walkers; good recall memory was defined as a score of 2 or 3 in the 3-word delayed recall section of the Mini-Mental State Examination., Measurements: All-cause mortality., Results: There were 302 deaths and the overall 100 person-year death rate was 3.77 (95% CI: 3.37-4.22). Both low gait speed and poor recall memory were associated with mortality when analysed separately (HR = 2.47; 95% CI: 1.87-3.27 and HR = 1.47; 95% CI: 1.16-1.87, respectively). When we grouped participants according to both recall and gait speed, death rates (100 person-years) progressively increased from those with both good gait speed and memory (2.0; 95% CI: 1.6-2.5), to those with fast walk but poor memory (3.4; 95% CI: 2.8-4.2), to those with slow walk and good memory (8.8; 95% CI: 6.4-12.1), to those with both slow walk and poor memory (13.0; 95% CI: 10.6-16.1). In multivariate analysis, poor memory significantly increases mortality risk among persons with fast gait speed (HR = 1.40; 95% CI: 1.04-1.89)., Conclusion: In older persons, gait speed and recall memory are independent predictors of expected survival. Information on memory function might better stratify mortality risk among persons with fast gait speed., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Background: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality., Methods: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; >50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index., Results: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 ± 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95%CI 2.86-3.79), 4-6 (OR 2.14, 95%CI 1.92-2.39), and 7-9 (OR 1.50, 95%CI 1.32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men., Conclusions: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs. The study protocol was published on PROSPERO (CRD42015024916).

Objectives: To evaluate the association, if any, between masticatory dysfunction (MD) and mortality in older adults., Design: The Invecchiare in Chianti (InCHIANTI) Study, a cohort study with 9-year follow-up., Setting: Tuscany, Italy., Participants: Individuals aged 65 and older (N = 1,155)., Measurements: MD was self-reported; Cox regression was used to assess the association between self-reported MD and 9-year all-cause mortality. This association was also evaluated after stratifying according to use of dentures. Analyses were adjusted for potential confounders, including demographic characteristics, lifestyle habits, comorbidities, nutrient intake, medications, and objective parameters., Results: Four hundred five (35%) participants reported MD. Over the 9-year follow-up, 475 (41%) subjects died. According to Cox regression analysis, self-reported MD was associated with higher mortality (relative risk (RR) = 1.23, 95% confidence interval (CI) = 1.02-1.48), after adjusting for potential confounders. In participants with self-reported MD, uncorrected edentulism was the condition associated with the greatest risk of mortality (RR = 2.10, 95% CI = 1.07-4.14); use of dentures seemed to blunt this association (RR = 1.12, 95% CI = 0.87-1.44)., Conclusion: Self-reported MD, chiefly when due to uncorrected edentulism, is associated with 9-year all-cause mortality in community-dwelling elderly adults. Further studies are needed to evaluate whether the timely correction of MD using adequate dentures can increase the survival of older adults., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Patterns of DNA methylation (DNAm) that track with aging have been identified. However, the relevance of these patterns for aging outcomes remains unclear. Longitudinal epigenome-wide DNAm information was obtained from the InCHIANTI study, a large representative European population. DNAm was evaluated using the Illumina HumanMethylation450 array on blood samples collected at baseline and 9-year follow-up: observations from 499 participants with paired longitudinal blood sample and information on differential blood count were included in analyses. A total of 56,579 markers were significantly associated with age in cross-sectional analysis of DNAm at year 9, 31,252 markers were changed significantly over the 9-year follow-up, and 16,987 markers were both cross-sectionally associated with age and significantly changed over time. Rates of change at 76 markers and year 9 level of DNAm at 88 markers were identified as strongly associated with mortality in Cox proportional hazard models adjusted for age and relevant covariates (mean follow-up time 4.4 years). Less than 0.05% of markers associated with age or that changed over time were also associated with mortality after adjusting for chronological age. Although the influence of DNAm on health and longevity remains unclear, these findings confirm that aging is associated cross-sectionally and longitudinally with robust and consistent patterns of methylation change., (Published by Oxford University Press on behalf of the Gerontological Society of America 2015.)

Background: We examined whether physical activity in early adulthood, late midlife, and old age as well as cumulative physical activity history are associated with changes in physical functioning and mortality in old age., Methods: Data are from participants aged 65 years or older enrolled in the InCHIANTI study who were followed up from 1998-2000 to 2007-2008 (n = 1,149). At baseline, participants recalled their physical activity levels at ages 20-40, 40-60, and in the previous year, and they were categorized as physically inactive, moderately active, and physically active. Physical performance was assessed with the Short Physical Performance Battery and self-reported mobility disability was evaluated at the 3-, 6- and 9-year follow-up. Mortality follow-up was assessed until the end of 2010., Results: Physical inactivity at baseline was associated with greater decline in Short Physical Performance Battery score (mean 9-year change: -2.72, 95% CI: -3.08, -2.35 vs -0.98, 95% -1.57, -0.39) and greater rate of incident mobility disability (hazard ratio 4.66, 95% CI 1.14-19.07) and mortality (hazard ratio 2.18, 95% CI 1.01-4.70) compared to physically active participants at baseline. Being physically active throughout adulthood was associated with smaller decline in physical performance as well as with lower risk of incident mobility disability and premature death compared with those who had been less active during their adult life., Conclusions: Higher cumulative physical activity over the life course was associated with less decline in physical performance and reduced rate of incident mobility disability and mortality in older ages., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms., Objective: To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans., Design: Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study ("Aging in the Chianti Region"), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older., Exposures: Twenty-four-hour urinary resveratrol metabolites., Main Outcomes and Measures: Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]) and prevalent and incident cancer and cardiovascular disease., Results: Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF, prevalent or incident cardiovascular disease, or cancer., Conclusions and Relevance: In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.

Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy. TUP concentrations were measured at enrolment (1998-2000) using the Folin-Ciocalteau assay after a solid-phase extraction. TDPs were also estimated at baseline throughout a validated food frequency questionnaire and using our database based on USDA and Phenol-Explorer databases. We modeled associations using Kaplan-Meier survival and Cox proportional hazards models, with adjustment for potential confounders. During the 12-y follow-up, 274 participants (34%) died. At enrollment, TUP excretion adjusted for age and sex tended to be greater in participants who survived [163 ± 62 mg gallic acid equivalents (GAE)/d)] than in those who died (143 ± 63 mg GAE/d) (P = 0.07). However, no significant differences were observed for TDPs. In the multivariable Cox model, participants in the highest tertile of TUP at enrolment had a lower mortality rate than those in the lowest tertile [HR = 0.70 (95% CI: 0.49-0.99); P-trend = 0.045], whereas no significant associations were found between TDP and overall mortality. TUP is an independent risk factor for mortality among community-dwelling older adults, suggesting that high dietary intake of polyphenols may be associated with longevity.

A combination of several metabolic and hormonal adaptations has been proposed to control aging. Little is known regarding the effects of multiple deregulations of these metabolic and hormonal systems in modulating frailty and mortality in hospitalized elderly patients. We measured 17 biological serum parameters from different metabolic/hormonal pathways in 594 hospitalized elderly patients followed up to 1 year who were stratified into three groups according to their multidimensional impairment, evaluated by a Comprehensive Geriatric Assessment (CGA)-based Multidimensional Prognostic Index (MPI). The mortality incidence rates were 7% at 1 month and 21% at 1 year. Our data show that frailty and mortality rate were positively associated with chronic inflammation and with a down-regulation of multiple endocrine factors. Of the 17 biomarkers examined, blood levels of IGF-1, triiodothyronine, C-reactive protein, erythrocyte sedimentation rate, white blood cell and lymphocyte counts, iron, albumin, total cholesterol, and LDL-c were significantly associated with both MPI severity grade and mortality. In multivariate Cox proportional hazard model, the following biomarkers most strongly predicted the risk of mortality (adjusted hazard ratio (HR) per 1 quintile increment in predictor distribution): IGF-1 HR = 0.71 (95% CI: 0.63-0.80), CRP HR = 1.48 (95% CI: 1.32-1.65), hemoglobin HR = 0.82 (95% CI: 0.73-0.92), and glucose HR = 1.17 (95% CI: 1.04-1.30). Multidimensional impairment assessed by MPI is associated with a distinctive metabolic 'signature'. The concomitant elevation of markers of inflammation, associated with a simultaneous reduction in multiple metabolic and hormonal factors, predicts mortality in hospitalized elderly patients., (© 2013 John Wiley & Sons Ltd and the Anatomical Society.)

Importance: The use of proton pump inhibitors (PPIs) has rapidly increased during the past several years. However, concern remains about risks associated with their long-term use in older populations., Objective: To investigate the relationship between the use of PPIs and the risk of death or the combined end point of death or rehospitalization in older patients discharged from acute care hospitals., Design: We investigated the relationship between PPI use and study outcomes using time-dependent Cox proportional hazards regression in patients 65 years or older discharged from acute care medical wards from April 1 to June 30, 2007., Setting: Eleven acute care medical wards., Participants: Four hundred ninety-one patients (mean [SD] age, 80.0 [5.9] years)., Main Outcome Measures: Mortality and the combined end point of death or rehospitalization. RESULTS The use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03-2.77]) but not with the combined end point (1.49 [0.98-2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22-7.16])., Conclusions and Relevance: In older patients discharged from acute care hospitals, the use of high-dose PPIs is associated with increased 1-year mortality. Randomized controlled studies including older frail patients are needed. In the meantime, physicians need to use caution and balance benefits and harms in long-term prescription of high-dose PPIs.

Objectives: To develop and validate a Multidimensional Prognostic Index (MPI) for mortality based on information collected by the Multidimensional Assessment Schedule (SVaMA), the recommended standard tool for multidimensional assessment of community-dwelling older subjects in seven Italian regions., Design: Prospective cohort study., Participants: Community-dwelling subjects older than 65 years who underwent an SVaMA evaluation from 2004 to 2010 in Padova Health District, Veneto, Italy., Measurements: The MPI-SVaMA was calculated as a weighted (weights were derived from multivariate Cox regressions) linear combination of the following nine domains: age, sex, main diagnosis, and six scores, ie, the Short Portable Mental Status Questionnaire, the Barthel index (contains two domains: activities of daily living and mobility), the Exton-Smith scale, the Nursing Care Needs, and the Social Network Support by a structured interview. Subjects were followed for a median of 2 years; those who had not died were followed for at least 1 year. The MPI-SVaMA score ranged from 0 to 1 and 3 grades of severity of the MPI-SVaMA were calculated on the basis of estimated cutoffs. Discriminatory power and calibration were further assessed., Results: A total of 12,020 subjects (mean age 81.84 ± 7.97 years) were included. Two random cohorts were selected: (1) a development cohort, ie, 7876 subjects (mean age 81.79 ± 8.05, %females: 63.1) and (2) a validation cohort, ie, 4144 subjects (mean age: 81.95 ± 7.83, %females: 63.7). The discriminatory power for mortality of MPI-SVaMA was 0.828 (95% CI 0.817-0.838) and 0.832 (95% CI 0.818-0.845) at 1 month and 0.791 (95% CI 0.784-0.798) and 0.792 (95% CI 0.783-0.802) at 1 year in development and validation cohorts, respectively. MPI-SVaMA results were well calibrated showing lower than 10% differences between predicted and observed mortality, both in development and validation cohorts., Conclusions: The MPI-SVaMA is an accurate and well-calibrated prognostic tool for mortality in community-dwelling older subjects, and can be used in clinical decision making., (Copyright © 2013 American Medical Directors Association, Inc. All rights reserved.)

Objectives: To examine the relationship between fruit and vegetable intake, physical activity, and all-cause mortality in older women., Design: Six Cox proportional hazards models examined independent and additive relationships between physical activity, carotenoids, and all-cause mortality. Additional models tested whether physical activity and carotenoids were conjointly related to mortality. Models were adjusted for age, education, and race and ethnicity., Setting: Baltimore, Maryland., Participants: Seven hundred thirteen women aged 70 to 79 participating in the Women's Health and Aging Studies., Measurements: Total serum carotenoids, a marker of fruit and vegetable intake, and physical activity were measured at baseline. Physical activity was measured according to kilocalorie expenditure., Results: During 5 years of follow-up, 82 (11.5%) participants died. Measured continuously, physical activity improved survival (HR = 0.52, 95% CI = 0.41-0.66, P < .001). The most active women were more likely to survive than the least physically active women (HR = 0.28, 95% CI = 0.13-0.59, P < .001). Continuous measures of carotenoids improved survival (HR = 0.67, 95% CI = 0.51-0.89, P = .01). Women in the highest tertile of total carotenoids were more likely to survive those in the lowest (HR = 0.50, 95% CI = 0.27-0.91, P = .03). When examined in the same model, continuous measures of physical activity (HR = 0.54, 95% CI = 0.42-0.68, P < .001) and carotenoids (HR = 0.76, 95% CI = 0.59-0.98, P = .04) predicted survival during follow-up., Conclusion: The combination of low total serum carotenoids and low physical activity, both modifiable risk factors, strongly predicted earlier mortality. These findings provide preliminary support that higher fruit and vegetable intake and exercise improve survival., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Evidence regarding the health benefits of carotenoids is controversial. Effects of serum carotenoids and their interactions on mortality have not been examined in a representative sample of US adults. The objective was to examine whether serum carotenoid concentrations predict mortality among US adults. The study consisted of adults aged ≥20 years enrolled in the Third National Health and Nutrition Examination Survey, 1988 to 1994, with measured serum carotenoids and mortality follow-up through 2006 (N = 13,293). Outcomes were all-cause, cardiovascular disease, and cancer mortality. In adjusted Cox proportional hazards models, participants in the lowest total carotenoid quartile (<1.01 μmol/L) had significantly higher all-cause mortality (mortality rate ratio, 1.38; 95% confidence interval, 1.15-1.65; P = .005) than those in the highest total carotenoid quartile (>1.75 μmol/L). For α-carotene, the highest quartile (>0.11 μmol/L) had the lowest all-cause mortality rates (P < .001). For lycopene, the middle 2 quartiles (0.29-0.58 μmol/L) had the lowest all-cause mortality rates (P = .047). Analyses with continuous carotenoids confirmed associations of serum total carotenoids, α-carotene, and lycopene with all-cause mortality (P < .001). In a random survival forest analysis, very low lycopene was the carotenoid most strongly predictive of all-cause mortality, followed by very low total carotenoids. α-Carotene/β-cryptoxanthin, α-carotene/lutein+zeaxanthin and lycopene/lutein+zeaxanthin interactions were significantly related to all-cause mortality (P < .05). Low α-carotene was the only carotenoid associated with cardiovascular disease mortality (P = .002). No carotenoids were significantly associated with cancer mortality. Very low serum total carotenoid, α-carotene, and lycopene concentrations may be risk factors for mortality, but carotenoids show interaction effects on mortality. Interventions of balanced carotenoid combinations are needed for confirmation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The purpose of this analysis was to characterize the natural history of weight change in the years prior to death among older persons and to examine how this pattern varies according to longevity and cause of death. Weight trajectories were analyzed by using data from 800 male decedents from the Baltimore Longitudinal Study of Aging (Maryland, 1958-2005) observed beginning an average of 19 years before death. A model including 3 distinct periods of weight change (weight stability/gain, mild weight loss, and accelerated weight loss before death) provided the best fit for all age-at-death groups. Approximately 9 years before death, the rate of weight loss increased to an average of 0.39 kg/year (P < 0.001) for all-cause mortality. For cancer deaths, weight loss accelerated significantly 3 years before death, regardless of age group. For cardiovascular deaths, the best-fitting inflection point increased with age, from 5 years for participants aged 60-69 years to 9-10 years before death for those aged 80 years or older. Results suggest that weight loss in older persons may begin earlier than previously believed. The duration of weight loss for noncancer deaths suggests that even distal changes in energy balance may be linked to risk of death.

Objectives: To examine whether performance in the Trail Making Test (TMT) predicts mobility impairment and mortality in older persons., Design: Prospective cohort study., Setting: Community-dwelling older persons enrolled in the Invecchiare in Chianti (InCHIANTI) Study., Participants: Five hundred eighty-three participants aged 65 and older and free of major cognitive impairment (Mini-Mental State Examination score >21) with baseline data on TMT performance. Of these, 427 performed the Short Physical Performance Battery (SPPB) for the assessment of lower extremity function at baseline and after 6 years. Of the initial 583 participants, 106 died during a 9-year follow-up., Measurements: The TMT Parts A and B (TMT-A and TMT-B) and SPPB were administered at baseline and 6-year follow-up. Impaired mobility was defined as an SPPB score less than 10. Vital status was ascertained over a 9-year follow-up., Results: InCHIANTI participants in the fourth quartile of the time to complete TMT-B minus time to complete TMT-A (TMT (B-A)) were significantly more likely to develop an SPPB score less than 10 during the 6-year follow-up than those in the first quartile (relative risk (RR)=2.4, 95% confidence interval (CI)=1.4-3.9, P=.001). After adjusting for potential confounders, these findings were substantially unchanged (RR=2.2, 95% CI=1.4-3.6, P=.001). Worse performance on the TMT was associated with significantly greater decline in SPPB score over the 6-year follow-up, after adjusting for age, sex, and baseline SPPB scores (beta=-0.01, standard error=0.003, P=.004). During the 9-year follow-up, 18.2% of the participants died. After adjustment for age and sex, the proportion of participants who died was higher in participants in the worst than the best performance quartile of TMT (B-A) scores (hazard ratio (HR)=1.7, 95% CI=1.0-2.9, P=.048). Results were similar in a parsimonious adjusted model (HR=1.8, 95% CI=1.0-3.2, P=.04)., Conclusion: Performance on the TMT is a strong, independent predictor of mobility impairment, accelerated decline in lower extremity function, and death in older adults living in the community. The TMT could be a useful addition to geriatric assessment.

Background: Red blood cell distribution width (RDW), a component of an electronic complete blood count, is a measure of heterogeneity in the size of circulating erythrocytes. In patients with symptomatic cardiovascular disease (CVD), RDW is associated with mortality. However, it has not been demonstrated that RDW is a predictor of mortality independent of nutritional deficiencies or in the general population., Methods: Red blood cell distribution width was measured in a national sample of 8175 community-dwelling adults 45 years or older who participated in the 1988-1994 National Health and Nutrition Examination Survey; mortality follow-up occurred through December 31, 2000. Deaths from all causes, CVD, cancer, and other causes were examined as a function of RDW., Results: Higher RDW values were strongly associated with an increased risk of death. Compared with the lowest quintile of RDW, the following were adjusted hazard ratios (HRs) for all-cause mortality (and 95% confidence intervals [CIs]): second quintile, HR, 1.1 (95% CI, 0.9-1.3); third quintile, HR, 1.2 (95% CI, 1.0-1.4); fourth quintile, HR, 1.4 (95% CI, 1.2-1.8); and fifth quintile, HR, 2.1 (95% CI, 1.7-2.6). For every 1% increment in RDW, all-cause mortality risk increased by 22% (HR, 1.22; 95% CI, 1.15-1.30; P < .001). Even when analyses were restricted to nonanemic participants or to those in the reference range of RDW (11%-15%) without iron, folate, or vitamin B(12) deficiency, RDW remained strongly associated with mortality. The prognostic effect of RDW was observed in both middle-aged and older adults for multiple causes of death., Conclusion: Red blood cell distribution width is a widely available test that is a strong predictor of mortality in the general population of adults 45 years or older.

Background: Sarcopenia, the age-related loss of muscle mass, may not be an isolated process but is associated with an increase in fat mass. The aim of this study was to estimate the mortality risk of sarcopenia in the presence or absence of obesity., Methods: Data are from 934 participants aged 65 years or older, enrolled in the "Invecchiare in Chianti" study, and followed for 6 years. At baseline, a peripheral quantitative computerized tomography (pQCT) scan was performed on all participants to evaluate the muscle density, and the muscular and fat cross-sectional areas of the calf. Walking speed was measured on a 7-m track. Cox proportional hazard models were performed to estimate the association of pQCT measures (per 1 standard deviation increase) with mortality., Results: Unadjusted analyses showed significant associations of muscle density (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.69-0.88), muscle area (HR 0.75, 95% CI 0.66-0.86), and fat area (HR 0.82, 95% CI 0.73-0.92) with mortality. After adjustment for potential confounders, no body composition parameter was significantly associated with mortality. Walking speed (used as a reference measure to verify whether the negative results were due to peculiarities of the study sample) confirmed its well-established association with mortality risk (HR 0.73, 95% CI 0.60-0.88). These results did not change after the analyses were stratified according to sarcopenia and body mass index groups, and restricted to participants with frailty or a high inflammatory profile., Conclusions: Calf skeletal muscle and fat mass are not significant risk factors for mortality in community-dwelling older adults. Walking speed confirmed to be a powerful predictor of health-related events.

Background: Plasma carotenoids are considered a valid biological marker for fruit and vegetable dietary intake. Recent studies show that low carotenoid levels are associated with a high risk of inflammation, cancer, and cardiovascular disease., Aim of the Study: To determine whether low plasma carotenoids are associated with increased mortality among older adults., Methods: Longitudinal study among 1,043 adults, 65 years and older, in the InCHIANTI study, a population-based cohort of adults living in the community in the Tuscany region, Italy., Results: Mean total carotenoid concentration was 1.80 micromol/l. During eight years of follow-up, 310 (29.7%) of participants died. Eight-year survival was lower in the lowest compared with the highest tertile of total serum carotenoids (P < 0.0001 by Mantel-Haenszel chi-square). In a multivariate Cox proportional hazards model adjusted for age, education, smoking, body mass index, energy intake, and chronic diseases, adults in the highest tertile of plasma carotenoids at enrollment had lower mortality compared to those in the lowest tertile (Hazards Ratio obtained by considering carotenoids level as an ordinal variable 0.81, 95%; CI 0.65-0.99; P for trend = 0.046)., Conclusions: Low plasma carotenoids are an independent risk factor for mortality among older adults living in the community.

Background: Findings from several studies suggested an association between oral health and several health outcomes including cardiovascular disease, aspiration pneumonia, malnutrition, poor quality of life, and mortality. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we tested the hypothesis that number of teeth is indicative of mortality risk independent of other confounders., Methods: Dentists conducted a standardized oral examination that included tooth count, tooth with coronal and cervical caries count, and gingival and periodontal index. Blood tests used in the analysis included fasting glucose, oral glucose tolerance test, serum low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, triglycerides, and white blood cell counts. Physical activity, skin fold thickness, body mass index and chronic diseases were also evaluated., Results: Of the 500 BLSA participants evaluated, 198 died an average of 130 (+/-75) months postdental evaluation, and 302 survivors were followed for a mean of 185 (+/-90) months. Based on multivariate Cox regression models, being edentulous or having than 20 teeth was independently associated with mortality., Conclusion: The results of this study support the notion that number of teeth is a significant and independent risk indicator for early mortality. These findings suggest that the improvement of oral health may have a positive impact on general health and may delay mortality.

Background: Despite longstanding controversies from animal studies on the relationship between basal metabolic rate (BMR) and longevity, whether BMR is a risk factor for mortality has never been tested in humans. We evaluate the longitudinal changes in BMR and the relationship between BMR and mortality in the Baltimore Longitudinal Study of Aging (BLSA) participants., Methods: BMR and medical information were collected at the study entry and approximately every 2 years in 1227 participants (972 men) over a 40-year follow-up. BMR, expressed as kcal/m(2)/h, was estimated from the basal O(2) consumption and CO(2) production measured by open-circuit method. Data on all-cause and specific-cause mortality were also obtained., Result: BMR declined with age at a rate that accelerated at older ages. Independent of age, participants who died had a higher BMR compared to those who survived. BMR was a significant risk factor for mortality independent of secular trends in mortality and other well-recognized risk factors for mortality, such as age, body mass index, smoking, white blood cell count, and diabetes. BMR was nonlinearly associated with mortality. The lowest mortality rate was found in the BMR range 31.3-33.9 kcal/m(2)/h. Participants with BMR in the range 33.9-36.4 kcal/m(2)/h and above the threshold of 36.4 kcal/m(2)/h experienced 28% (hazard ratio: 1.28; 95% confidence interval, 1.02-1.61) and 53% (hazard ratio: 1.53; 95% confidence interval, 1.19-1.96) higher mortality risk compared to participants with BMR 31.3-33.9 kcal/m(2)/h., Conclusion: We confirm previous findings of an age-related decline of BMR. In our study, a blunted age-related decline in BMR was associated with higher mortality, suggesting that such condition reflects poor health status.

Aims: We examined the relationship between plasma selenium levels at enrollment and all-cause mortality over a 6-year period among participants in the InCHIANTI study., Methods: 1042 men and women > or =65 years from the InCHIANTI study, a population- based study of older adults living in the Chianti region of Tuscany, a population-based cohort in Tuscany, Italy. Plasma selenium was measured at enrollment (1998-2000), and vital status was ascertained until May 2006., Results: During follow-up, 237 participants (22.7%) died. At enrollment, mean (SD) plasma selenium concentrations among participants who survived or died were 0.96 (0.14) and 0.87 (0.18) micromol/L (p<0.0001), respectively. The proportion of participants who died, from lowest to highest quartile of selenium, was 41.3, 27.0, 18.1 and 13.5% (p<0.0001 by Mantel-Haenszel chi-square). After adjusting for age, sex, education, and chronic diseases, adults in the lowest quartile of plasma selenium at enrollment had higher mortality compared with those in the highest quartile (Hazard Ratio (HR) 1.60, 95% Confidence Interval (CI) 1.04-2.47, p=0.034)., Conclusion: Low plasma selenium may be an independent predictor of mortality among older adults living in the community.

Our objective was to construct and validate a Multidimensional Prognostic Index (MPI) for 1-year mortality from a Comprehensive Geriatric Assessment (CGA) routinely carried out in elderly patients in a geriatric acute ward. The CGA included clinical, cognitive, functional, nutritional, and social parameters and was carried out using six standardized scales and information on medications and social support network, for a total of 63 items in eight domains. A MPI was developed from CGA data by aggregating the total scores of the eight domains and expressing it as a score from 0 to 1. Three grades of MPI were identified: low risk, 0.0-0.33; moderate risk, 0.34-0.66; and severe risk, 0.67-1.0. Using the proportional hazard models, we studied the predictive value of the MPI for all causes of mortality over a 12-month follow-up period. MPI was then validated in a different cohort of consecutively hospitalized patients. The development cohort included 838 and the validation cohort 857 elderly hospitalized patients. Of the patients in the two cohorts, 53.3 and 54.9% were classified in the low-risk group, respectively (MPI mean value, 0.18 +/- 0.09 and 0.18 +/- 0.09); 31.2 and 30.6% in the moderate-risk group (0.48 +/- 0.09 and 0.49 +/- 0.09); 15.4 and 14.2% in the severe-risk group (0.77 +/- 0.08 and 0.75 +/- 0.07). In both cohorts, higher MPI scores were significantly associated with older age (p = 0.0001), female sex (p = 0.0001), lower educational level (p = 0.0001), and higher mortality (p = 0.0001). In both cohorts, a close agreement was found between the estimated mortality and the observed mortality after both 6 months and 1 year of follow-up. The discrimination of the MPI was also good, with a ROC area of 0.751 (95%CI, 0.70-0.80) at 6 months and 0.751 (95%CI, 0.71-0.80) at 1 year of follow-up. We conclude that this MPI, calculated from information collected in a standardized CGA, accurately stratifies hospitalized elderly patients into groups at varying risk of mortality.

Objectives: To develop and validate mortality and hospitalization prognostic tools based upon information readily available to primary care physicians (PCPs)., Design: Population-based cohort study. Baseline predictors were patient demographics, a seven-item questionnaire on functional status and general health, use of five or more drugs, and previous hospitalization., Setting: Community-based study., Participants: Prognostic indexes were developed in 2,470 subjects and validated in 2,926 subjects, all community-dwelling, aged 65 and older, and randomly sampled from the rosters of 98 PCPs in Florence, Italy., Measurements: Fifteen-month mortality and hospitalization., Results: Two scores were derived from logistic regression models and used to stratify participants into four groups. With Model 1, based upon the seven-item questionnaire, mortality rate ranged from 0.8% in the lowest-risk group (0-1 point) to 9.4% in the highest risk group (> or = 3 points), and hospitalization rate ranged from 12.4% to 29.3%; area under the receiver operating characteristic curves (AUC) was 0.75 and 0.60, respectively. With Model 2, considering also drug use and previous hospitalization, mortality and hospitalization rates ranged from 0.3% to 8.2% and from 8.1% to 29.7%, for the lowest-risk to the highest-risk group; the AUC increased significantly only for hospitalization (0.67)., Conclusion: Prediction of death and hospitalization in older community-dwelling people can be easily obtained with two indexes using information promptly available to PCPs. These tools might be useful for guiding clinical care and targeting interventions to reduce the need for hospital care in older persons.

Objectives: We investigated the secular trend in white blood cell (WBC) count and the relationship between WBC count and mortality between 1958 and 2002., Background: The WBC count is a clinical marker of inflammation and a strong predictor of mortality. Limited data exist on the WBC count secular trend and the relationship between WBC and mortality., Methods: One thousand eighty-three women and 1,720 men were evaluated longitudinally in the Baltimore Longitudinal Study of Aging. Blood samples and medical information were collected at the study entry and every 2 years during follow-up visits. The WBC count and all-cause, cardiovascular, and cancer mortality were assessed., Results: A downward trend in WBC count was observed from 1958 to 2002. The secular downward trend was independent of age, gender, race, smoking, body mass index, and physical activity. The WBC count was nonlinearly associated with all-cause mortality and almost linearly associated with cardiovascular mortality. Participants with baseline WBC <3,500 cells/mm3 and WBC >6,000 cells/mm3 had higher mortality than those with 3,500 to 6,000 WBC/mm3. Within each WBC group, age-adjusted mortality rates declined in successive cohorts from the 1960s to the 1990s. Participants who died had higher WBC than those who survived, and the difference was statistically significant within 5 years before death., Conclusions: Our study provides evidence for a secular downward trend in WBC count over the period from 1958 to 2002. Higher WBC counts are associated with higher mortality in successive cohorts. We found no evidence that the decline of age-specific mortality rates that occurred from 1960 to 2000 was attributable to a secular downward trend in WBC.

Selenium and the carotenoids play an important role in antioxidant defenses and in the redox regulation involved in inflammation. We tested the hypothesis that low selenium and carotenoids predict mortality in older women living in the community. Women who were enrolled in the Women's Health and Aging Studies I and II in Baltimore, MD (n = 632; 70-79 y old) had serum selenium and carotenoids measured at baseline and were followed for mortality over 60 mo. Median (minimum, maximum) serum selenium and carotenoids were 1.53 (0.73, 2.51) micromol/L and 1.67 (0.13, 9.10) micromol/L; 14.1% of the women died. The 5 major causes of death were heart disease (32.6%), cancer (18.0%), stroke (9.0%), infection (6.7%), and chronic obstructive pulmonary disease (5.6%). Adjusting for age, education, smoking, BMI, poor appetite, and chronic diseases, higher serum selenium [hazard ratio (HR) 0.71, 95% CI 0.56-0.90/1 SD increase in log(e) selenium; P = 0.005] and higher serum total carotenoids (HR 0.77, 95% CI 0.64-0.84/1 SD increase in log(e) total carotenoids; P = 0.009) were associated with a lower risk of mortality. Women living in the community who have higher serum selenium and carotenoids are at a lower risk of death.

Increasing evidence demonstrates that inflammation is associated with many pathophysiologic processes and mortality in older adults. Increase in total white blood cell (WBC) counts is recognized as an important cellular marker of systemic inflammation. However, relationships of total WBC and individual differential counts with mortality in older adults, particularly in older women, have not been adequately evaluated. To address this important question, we obtained baseline total WBC and differential counts and 5-year all-cause mortality of 624 community-dwelling women age 65-101 in the Women's Health and Aging Study cohort, excluding those with WBC counts above the normal range. Using Kaplan-Meier survival and Cox proportional hazard regression analyses, and adjusting for age, race, body mass index, smoking, and education, we identified that baseline higher total WBC, higher neutrophil, or lower lymphocyte counts were independently associated with increased mortality. No significant associations of eosinophil, monocyte, or basophil counts with mortality were observed. These results suggest that beyond acute bacterial infection, changes in counts of baseline total WBC and its specific subpopulations predict increased mortality in older women. They provide a basis for further investigation into the role of leukocytes in age-related inflammation and its associated adverse outcomes in older adults.

Purpose: Our study assessed whether change in self-rated health is a stronger predictor of mortality than baseline self-rated health and the most recent self-rated health (prior to death or loss to follow-up) among disabled older women., Design and Methods: The Women's Health and Aging Study examined disabled older women at baseline and every 6 months for 3 years. During the follow-up period, 253 out of the 905 examined participants died. Cox regression models with time-dependent covariates were used., Results: After baseline characteristics were adjusted for, baseline self-rated health was not related to mortality. After covariates at the most recent observation and covariates measured only at baseline were controlled for, the most recent self-rated health was not associated with mortality either. After time-dependent covariates and covariates measured only at baseline were adjusted for, decline in self-rated health was significantly associated with increased mortality., Implications: Change in self-rated health is a stronger predictor of mortality than self-rated health at baseline and at the most recent observation. Older women with "fair" health are worse off if they are on a declining health trajectory than if their "fair" health is stable. Family caregivers and clinicians need to closely monitor change in self-rated health among disabled older women.

Objectives: To examine the associations between hemoglobin (Hb) concentration and (1) 5-year all-cause mortality and (2) serum erythropoietin (EPO), as the basis for the identification of data-driven thresholds, and to assess the clinical relevance of mildly low Hb., Design: Prospective study., Setting: Population based., Participants: Community-dwelling women aged 65 and older with moderate-to-severe disability--Women's Health and Aging Study I, Baltimore, Maryland, 1992-2000., Methods: Proportional hazards regression was used to model the relationship between baseline Hb (available for 686 subjects) and time to death. A generalized linear model was used to assess the cross-sectional association between Hb and EPO in 641 subjects., Results: A curvilinear slope of steady mortality decrease up to the Hb threshold of 13.9 g/dL was observed. Hb of 11 g/dL was independently associated with greater mortality than the World Health Organization (WHO) low-normal cutoff of Hb of 12 g/dL (hazard ratio (HR)=1.2, 95% confidence interval (CI)=1.1-1.4), whereas Hb of 14 g/dL was linked to 24% lower mortality (HR=0.76, 95% CI=0.63-0.92), after comprehensive adjustment for major health status and disease-burden indicators. A curvilinear, statistically significant slope of steady EPO decrease with increasing Hb up to the threshold of 14.3 g/dL was consistently observed., Conclusion: The meaningfully lower mortality risk with higher Hb levels provides empirical evidence against the notion that Hb currently perceived as mildly low is clinically benign. Furthermore, the mortality risk gradient observed even within the WHO normal Hb range suggests that Hb levels higher than what is currently recommended might offer clinical advantage. The relationship between Hb and EPO provided supporting physiological evidence for this hypothesis.

The physiology of age-related functional decline is poorly understood, but may involve hormones and inflammation. We hypothesized that older women with both low IGF-I and high IL-6 levels are at high risk for disability and death. We assessed walking speed and disability in 718 women enrolled in the Women's Health and Aging Study I, a 3-yr cohort study with 5-yr mortality follow-up. Women with IGF-I levels in the lowest quartile and IL-6 levels in the highest quartile had significantly greater limitation in walking and disability in mobility tasks and instrumental activities of daily living than those with neither risk factor (adjusted odds ratios, 10.77, 5.14, and 3.66). Women with both risk factors were at greater risk for death (adjusted relative risk, 2.10) as well as incident walking limitation, mobility disability, and disability in activities of daily living compared with those with high IGF-I and low IL-6 levels. The combination of low IGF-I and high IL-6 levels confers a high risk for progressive disability and death in older women, suggesting an aggregate effect of dysregulation in endocrine and immune systems. The joint effects of IGF-I and IL-6 may be important targets for treatments to prevent or minimize disability associated with aging.

Objectives: To examine the association between muscle strength and total and cause-specific mortality and the plausible contributing factors to this association, such as presence of diseases commonly underlying mortality, inflammation, nutritional deficiency, physical inactivity, smoking, and depression., Design: Prospective population-based cohort study with mortality surveillance over 5 years., Setting: Elderly women residing in the eastern half of Baltimore, Maryland, and part of Baltimore County., Participants: Nine hundred nineteen moderately to severely disabled women aged 65 to 101 who participated in handgrip strength testing at baseline as part of the Women's Health and Aging Study., Measurements: Cardiovascular disease (CVD), cancer, respiratory disease, other measures (not CVD, respiratory, or cancer), total mortality, handgrip strength, and interleukin-6., Results: Over the 5-year follow-up, 336 deaths occurred: 149 due to CVD, 59 due to cancer, 38 due to respiratory disease, and 90 due to other diseases. The unadjusted relative risk (RR) of CVD mortality was 3.21 (95% confidence interval (CI) = 2.00-5.14) in the lowest and 1.88 (95% CI = 1.11-3.21) in the middle compared with the highest tertile of handgrip strength. The unadjusted RR of respiratory mortality was 2.38 (95% CI = 1.09-5.20) and other mortality 2.59 (95% CI = 1.59-4.20) in the lowest versus the highest grip-strength tertile. Cancer mortality was not associated with grip strength. After adjusting for age, race, body height, and weight, the RR of CVD mortality decreased to 2.17 (95% CI = 1.26-3.73) in the lowest and 1.56 (95% CI = 0.89-2.71) in the middle, with the highest grip-strength tertile as the reference. Further adjustments for multiple diseases, physical inactivity, smoking, interleukin-6, C-reactive protein, serum albumin, unintentional weight loss, and depressive symptoms did not materially change the risk estimates. Similar results were observed for all-cause mortality., Conclusion: In older disabled women, handgrip strength was a powerful predictor of cause-specific and total mortality. Presence of chronic diseases commonly underlying death or the mechanisms behind decline in muscle strength in chronic disease, such as inflammation, poor nutritional status, disuse, and depression, all of which are independent predictors of mortality, did not explain the association. Handgrip strength, an indicator of overall muscle strength, may predict mortality through mechanisms other than those leading from disease to muscle impairment. Grip strength tests may help identify patients at increased risk of deterioration of health.

Objectives: Several peripheral blood markers of inflammation have demonstrated prognostic ability, but the value of combining multiple markers as a measure of inflammatory burden remains unknown. The objective of this study was to determine the prognostic value of combining four peripheral blood measures of inflammation in healthy older persons., Design: Inception cohort study with 7 years of follow-up., Setting: Three communities., Participants: Eight hundred seventy high-functioning subjects aged 70 to 79 who had serum albumin, cholesterol, interleukin (IL)-6, and C-reactive protein (CRP) levels measured at baseline., Measurements: Three- and 7-year mortality and Rosow- Breslau functional decline., Results: A summary score was created that assigned one point each for the following blood levels: albumin <3.8 g/dL, cholesterol <170 mg/dL (bottom decile), IL-6>3.8 pg/mL (top tertile), and CRP>2.65 mg/L (top tertile). By 3 years, 6% of subjects had died, and, by 7 years, 23% had died. In subjects with three or four markers of inflammation, the adjusted odds ratios (AORs) for 3- and 7-year mortality were 6.6 and 3.2, respectively, compared with those who had no abnormal markers. Subjects with one or two markers were at more moderate and statistically insignificant increased risk of 3- and 7-year mortality with AORs of 1.5 and 1.3, respectively. The risks for functional decline at 3- and 7-years were generally small (AOR = 1.1-1.9) and not statistically significant., Conclusions: In high-functioning older persons, a measure of inflammation can identify those at a much higher risk of mortality and a possibly higher risk of functional decline. Whether therapies directed at reducing inflammation can attenuate such risk remains to be determined.

We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.

BackgroundA person's rate of aging has important implications for his/her risk of death and disease; thus, quantifying aging using observable characteristics has important applications for clinical, basic, and observational research. Based on routine clinical chemistry biomarkers, we previously developed a novel aging measure, Phenotypic Age, representing the expected age within the population that corresponds to a person's estimated mortality risk. The aim of this study was to assess its applicability for differentiating risk for a variety of health outcomes within diverse subpopulations that include healthy and unhealthy groups, distinct age groups, and persons with various race/ethnic, socioeconomic, and health behavior characteristics.Methods and findingsPhenotypic Age was calculated based on a linear combination of chronological age and 9 multi-system clinical chemistry biomarkers in accordance with our previously established method. We also estimated Phenotypic Age Acceleration (PhenoAgeAccel), which represents Phenotypic Age after accounting for chronological age (i.e., whether a person appears older [positive value] or younger [negative value] than expected, physiologically). All analyses were conducted using NHANES IV (1999-2010, an independent sample from that originally used to develop the measure). Our analytic sample consisted of 11,432 adults aged 20-84 years and 185 oldest-old adults top-coded at age 85 years. We observed a total of 1,012 deaths, ascertained over 12.6 years of follow-up (based on National Death Index data through December 31, 2011). Proportional hazard models and receiver operating characteristic curves were used to evaluate all-cause and cause-specific mortality predictions. Overall, participants with more diseases had older Phenotypic Age. For instance, among young adults, those with 1 disease were 0.2 years older phenotypically than disease-free persons, and those with 2 or 3 diseases were about 0.6 years older phenotypically. After adjusting for chronological age and sex, Phenotypic Age was significantly associated with all-cause mortality and cause-specific mortality (with the exception of cerebrovascular disease mortality). Results for all-cause mortality were robust to stratifications by age, race/ethnicity, education, disease count, and health behaviors. Further, Phenotypic Age was associated with mortality among seemingly healthy participants-defined as those who reported being disease-free and who had normal BMI-as well as among oldest-old adults, even after adjustment for disease prevalence. The main limitation of this study was the lack of longitudinal data on Phenotypic Age and disease incidence.ConclusionsIn a nationally representative US adult population, Phenotypic Age was associated with mortality even after adjusting for chronological age. Overall, this association was robust across different stratifications, particularly by age, disease count, health behaviors, and cause of death. We also observed a strong association between Phenotypic Age and the disease count an individual had. These findings suggest that this new aging measure may serve as a useful tool to facilitate identification of at-risk individuals and evaluation of the efficacy of interventions, and may also facilitate investigation into potential biological mechanisms of aging. Nevertheless, further evaluation in other cohorts is needed.

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]

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p

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]

BackgroundAlthough gait speed slows with age, the rate of slowing varies greatly. To date, little is known about the trajectories of gait speed, their correlates, and their risk for mortality in older adults.MethodsGait speed during a 20-m walk was measured for a period of 8 years in initially well-functioning men and women aged 70-79 years participating in the Health, Aging and Body Composition study. We described the trajectories of gait speed and examined their correlates using a group-based mixture model. Also risk associated with different gait speed trajectories on all-cause mortality was estimated using a Cox-proportional hazard model.ResultsOf 2,364 participants (mean age, 73.5 ± 2.9 years; 52% women), we identified three gait speed trajectories: slow (n = 637), moderate (n = 1,209), and fast decline (n = 518). Those with fast decline slowed 0.030 m/s per year or 2.4% per year from baseline to the last follow-up visit. Women, blacks, and participants who were obese, had limited knee extensor strength, and had low physical activity were more likely to have fast decline than their counterparts. Participants with fast decline in gait speed had a 90% greater risk of mortality than those with slow decline.ConclusionDespite being well-functioning at baseline, a quarter of older adults experienced fast decline in gait speed, which was associated with an increased risk of mortality.