03095nas a2200397 4500008004100000022001400041245017000055210006900225260001300294300001000307490000700317520189000324653002102214653000902235653002202244653001502266653002802281653002802309653003502337653001102372653001102383653002502394653000902419653002602428653002402454653002102478653001802499100002202517700002402539700002102563700002102584700001802605700001802623700002002641856003602661 2010 eng d a1532-541500aCardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study.0 aCardiovascular disease is associated with greater incident dehyd c2010 Mar a421-60 v583 a
OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.
DESIGN: Longitudinal cohort study.
SETTING: Pittsburgh, Pennsylvania.
PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5% women, 16.5% African American).
MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.
RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95% confidence interval=1.03-2.05).
CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.
10aAge Distribution10aAged10aAged, 80 and over10aBiomarkers10aCardiovascular Diseases10aCross-Sectional Studies10aDehydroepiandrosterone Sulfate10aFemale10aHumans10aLongitudinal Studies10aMale10aMultivariate Analysis10aRegression Analysis10aSex Distribution10aUnited States1 aSanders, Jason, L1 aBoudreau, Robert, M1 aCappola, Anne, R1 aArnold, Alice, M1 aRobbins, John1 aCushman, Mary1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/116802962nas a2200313 4500008004100000022001400041245014300055210006900198260001300267300001100280490000700291520201600298653002202314653002802336653002002364653002002384653002802404653001102432653001802443653001102461653000902472100002202481700002402503700002002527700002302547700002202570700002002592856003602612 2011 eng d a1532-541500aMeasurement of organ structure and function enhances understanding of the physiological basis of frailty: the Cardiovascular Health Study.0 aMeasurement of organ structure and function enhances understandi c2011 Sep a1581-80 v593 aOBJECTIVES: To determine whether disease burden is associated with frailty independent of diagnosed chronic disease and whether physiological measurements provide greater understanding of the etiology of frailty.
DESIGN: Cross-sectional.
SETTING: Community.
PARTICIPANTS: Two thousand four hundred thirty-seven participants in the Cardiovascular Health Study, 1992/93 examination (mean age 74.8 ± 4.8, 43.4% male, 95.8% white).
MEASUREMENTS: Disease burden and frailty were tabulated using 10-point scales (0 = healthy, 10 = unhealthy). Disease burden was the sum of measurements characterizing the vasculature, brain, kidneys, lungs, and glucose metabolism. Frailty was assessed using the frailty index reported by Fried. Multivariate linear models were used to determine the association between disease burden (predictor) and frailty (outcome).
RESULTS: Unadjusted, 1-point-higher disease burden was associated with a 0.28-point-higher frailty score (P < .001). White matter grade, forced vital capacity, and cystatin-C were particularly strongly and significantly associated with frailty. Disease burden attenuated the association between frailty and age by 29%, and disease burden and age had similar associations with frailty. Disease burden attenuated the association between frailty and fibrinogen, Factor VIII, and C-reactive protein by 32%, 56%, and 83%, respectively. Frailty was associated with diagnosed depression, stroke, cognitive impairment, arthritis, and pulmonary disease but not coronary heart disease, diabetes mellitus, or kidney disease in the presence of a summary of disease burden. In the adjusted model, disease burden remained significantly associated with frailty (β = 0.11, P < .001).
CONCLUSION: Disease burden was independently and significantly associated with frailty. These results emphasize that typically unrecognized physiological changes may contribute significantly to frailty.
10aAged, 80 and over10aCardiovascular Diseases10aChronic Disease10aCost of Illness10aCross-Sectional Studies10aFemale10aFrail Elderly10aHumans10aMale1 aSanders, Jason, L1 aBoudreau, Robert, M1 aFried, Linda, P1 aWalston, Jeremy, D1 aHarris, Tamara, B1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/131802993nas a2200421 4500008004100000022001400041245012600055210006900181260001300250300001100263490000700274520177100281653002202052653000902074653002202083653002802105653003502133653002002168653001502188653004002203653001102243653001102254653001502265653000902280653000902289653001602298653002502314100002202339700002802361700002402389700002102413700001802434700002102452700002002473700002202493700002002515856003602535 2012 eng d a1758-535X00aLeukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.0 aLeukocyte telomere length is associated with noninvasively measu c2012 Apr a409-160 v673 aBACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).
METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4% male, 86.8% white, and 13.2% black).
RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = -132 [47] bp, p < .01), age (β [SE] = -107 [46], p = .02) or carotid thickness (β [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35%.
CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.
10aAfrican Americans10aAged10aAged, 80 and over10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aChronic Disease10aCystatin C10aEuropean Continental Ancestry Group10aFemale10aHumans10aLeukocytes10aLung10aMale10aMiddle Aged10aTelomere Homeostasis1 aSanders, Jason, L1 aFitzpatrick, Annette, L1 aBoudreau, Robert, M1 aArnold, Alice, M1 aAviv, Abraham1 aKimura, Masayuki1 aFried, Linda, F1 aHarris, Tamara, B1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/132803497nas a2200493 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520208000263653001602343653000902359653002202368653001002390653001502400653001602415653001402431653001902445653003502464653001102499653000902510653001802519653001102537653004902548653004902597653003302646653001802679653000902697653002902706653002802735653001702763100002202780700001902802700002102821700002202842700002102864700002002885700002402905700001802929700002002947856003602967 2014 eng d a1758-535X00aDo changes in circulating biomarkers track with each other and with functional changes in older adults?0 aDo changes in circulating biomarkers track with each other and w c2014 Feb a174-810 v693 aBACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults.
METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes.
RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04).
CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.
10aAdiponectin10aAged10aAged, 80 and over10aAging10aBiomarkers10aCholesterol10aCognition10aCohort Studies10aDehydroepiandrosterone Sulfate10aFemale10aGait10aHand Strength10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aInterleukin-610aMale10aNeuropsychological Tests10aPsychomotor Performance10aTime Factors1 aSanders, Jason, L1 aDing, Victoria1 aArnold, Alice, M1 aKaplan, Robert, C1 aCappola, Anne, R1 aKizer, Jorge, R1 aBoudreau, Robert, M1 aCushman, Mary1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/600003142nas a2200445 4500008004100000022001400041245009800055210006900153260001300222300001100235490000700246520191900253653000902172653001002181653002802191653001102219653003802230653001302268653002002281653001102301653001402312653000902326653001402335653002602349653001702375653001802392653001802410100002202428700002102450700002102471700002102492700002402513700002302537700002002560700002302580700001902603700001802622700002002640856003602660 2014 eng d a1758-535X00aHeritability of and mortality prediction with a longevity phenotype: the healthy aging index.0 aHeritability of and mortality prediction with a longevity phenot c2014 Apr a479-850 v693 aBACKGROUND: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.
METHODS: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.
RESULTS: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.
CONCLUSION: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
10aAged10aAging10aCardiovascular Diseases10aFemale10aGenetic Predisposition to Disease10aGenotype10aHealth Behavior10aHumans10aLongevity10aMale10aPhenotype10aRetrospective Studies10aRisk Factors10aSurvival Rate10aUnited States1 aSanders, Jason, L1 aMinster, Ryan, L1 aBarmada, Michael1 aMatteini, Amy, M1 aBoudreau, Robert, M1 aChristensen, Kaare1 aMayeux, Richard1 aBorecki, Ingrid, B1 aZhang, Qunyuan1 aPerls, Thomas1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/628002802nas a2200457 4500008004100000022001400041245006100055210006000116260001300176300001100189490000700200520158500207653000901792653002201801653002301823653003501846653001901881653001501900653001501915653002201930653002401952653001101976653001101987653001701998653002002015653000902035653001202044653002202056653001802078653002202096100002302118700001802141700002102159700002202180700001902202700002702221700002002248700002002268700002002288856003602308 2014 eng d a1532-541500aSubclinical vascular disease burden and longer survival.0 aSubclinical vascular disease burden and longer survival c2014 Sep a1692-80 v623 aOBJECTIVES: To determine the contribution of gradations of subclinical vascular disease (SVD) to the likelihood of longer survival and to determine what allows some individuals with SVD to live longer.
DESIGN: Cohort study.
SETTING: Cardiovascular Health Study.
PARTICIPANTS: Individuals born between June 30, 1918, and June 30, 1921 (N = 2,082; aged 70-75 at baseline (1992-93)).
MEASUREMENTS: A SVD index was scored as 0 for no abnormalities, 1 for mild abnormalities, and 2 for severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as 80 and younger, 81 to 84, 85 to 89, and 90 and older.
RESULTS: A 1-point lower SVD score was associated with 1.22 greater odds (95% confidence interval = 1.14-1.31) of longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction between kidney function, smoking, and C-reactive protein and SVD; the association between SVD and longer survival appeared to be modestly greater in persons with poor kidney function, inflammation, or a history of smoking.
CONCLUSION: A lower burden of SVD is associated with longer survival, independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and promote longer survival.
10aAged10aAged, 80 and over10aC-Reactive Protein10aCarotid Intima-Media Thickness10aCohort Studies10aCystatin C10aDepression10aDiabetes Mellitus10aElectrocardiography10aFemale10aHumans10aInflammation10aKidney Diseases10aMale10aSmoking10aSurvival Analysis10aUnited States10aVascular Diseases1 aOdden, Michelle, C1 aYee, Laura, M1 aArnold, Alice, M1 aSanders, Jason, L1 aHirsch, Calvin1 aDeFilippi, Christopher1 aKizer, Jorge, R1 aInzitari, Marco1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/658902703nas a2200445 4500008004100000022001400041245008300055210006900138260001300207300001100220490000700231520140200238653001001640653002201650653003501672653002001707653003401727653001101761653001401772653003601786653002801822100002101850700002201871700002001893700002501913700002101938700002101959700001901980700002401999700001702023700002302040700002102063700002402084700002402108700002302132700002102155700002502176700002002201856003602221 2015 ENG d a1758-535X00aGenome-Wide Association Study and Linkage Analysis of the Healthy Aging Index.0 aGenomeWide Association Study and Linkage Analysis of the Healthy c2015 Aug a1003-80 v703 aBACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.
METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.
RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.
CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.
10aAging10aApolipoproteins E10aForkhead Transcription Factors10aGenetic Linkage10aGenome-Wide Association Study10aHumans10aLongevity10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aMinster, Ryan, L1 aSanders, Jason, L1 aSingh, Jatinder1 aKammerer, Candace, M1 aBarmada, Michael1 aMatteini, Amy, M1 aZhang, Qunyuan1 aWojczynski, Mary, K1 aDaw, Warwick1 aBrody, Jennifer, A1 aArnold, Alice, M1 aLunetta, Kathryn, L1 aMurabito, Joanne, M1 aChristensen, Kaare1 aPerls, Thomas, T1 aProvince, Michael, A1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/670302886nas a2200445 4500008004100000022001400041245008300055210006900138260001300207300001100220490000700231520166800238653001601906653000901922653002201931653001001953653004301963653001902006653001102025653000902036653002502045653001202070653002902082653001102111653001102122653000902133653000902142653003202151653001702183100002102200700002202221700002102243700002402264700002202288700002502310700002102335700002802356700002002384856003602404 2015 eng d a1758-535X00aMultisystem physiologic impairments and changes in gait speed of older adults.0 aMultisystem physiologic impairments and changes in gait speed of c2015 Mar a319-240 v703 aBACKGROUND: Slowed gait is an important health indicator in older adults but a single identifiable cause is often lacking. We assessed whether a summary index measuring impairments across multiple physiologic systems was associated with slowed gait in older individuals.
METHODS: Data from the Cardiovascular Health Study (n = 3,010) were used to assess associations between baseline physiologic index (measuring vasculature, brain, kidneys, lungs, and glucose metabolism; range 0-10 with 0-2 points/system and lower score indicating higher function) and annual gait speed (m/s) over 6 years. Participants with complete data on the physiologic index and at least two gait speed measures were included. Mean gait speed and 95% confidence intervals (CI) by category of index were calculated using mixed effects models.
RESULTS: Those with scores of three or higher on the index had significantly slower gait speed at baseline compared to those with scores of 0-2 (7-10: mean speed = 0.83 m/s, 95% CI: 0.80, 0.84; 0-2: mean speed = 1.01 m/s, 95% CI: 0.99, 1.03). Those with higher indices also had faster decline in gait speed compared to those with lower scores after adjustment for demographic and health characteristics (7-10: change in speed = -0.020 m/s/year, 95% CI: -0.024, -0.016; 0-2: change in speed= -0.010 m/s/year, 95% CI: -0.014, -0.006).
CONCLUSIONS: Greater impairment across five organ systems was associated with slower gait speed and greater declines in gait speed over 6 years. Impairments accumulated over multiple physiologic systems may make older adults more vulnerable to slow gait speed.
10aAge Factors10aAged10aAged, 80 and over10aBrain10aCardiovascular Physiological Phenomena10aCohort Studies10aFemale10aGait10aGeriatric Assessment10aGlucose10aHealth Status Indicators10aHumans10aKidney10aLung10aMale10aSensitivity and Specificity10aTime Factors1 aRosso, Andrea, L1 aSanders, Jason, L1 aArnold, Alice, M1 aBoudreau, Robert, M1 aHirsch, Calvin, H1 aCarlson, Michelle, C1 aRosano, Caterina1 aKritchevsky, Stephen, B1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/659602603nas a2200265 4500008004100000022001400041245010000055210006900155260001300224300001100237490000700248520181100255100002202066700002102088700002202109700002402131700001302155700002402168700002002192700001902212700002202231700002802253700002002281856003602301 2016 eng d a1532-541500aEffects of Disease Burden and Functional Adaptation on Morbidity and Mortality on Older Adults.0 aEffects of Disease Burden and Functional Adaptation on Morbidity c2016 Jun a1242-90 v643 aOBJECTIVES: To ascertain whether older adults with extensive disease but relative vigor (adapters) shorten the period at the end of life in which they live with morbidity (compress morbidity).
DESIGN: Prospective, community-based cohort study in four U.S. cities.
SETTING: Cardiovascular Health Study.
PARTICIPANTS: Individuals aged 65 and older.
MEASUREMENTS: Participants were categorized into three groups according to extent of disease (assessed noninvasively), vigor, and frailty (expected agers (n = 3,528, extent of disease similar to vigor and frailty-reference group), adapters (n = 882, higher disease but vigorous), and prematurely frail (n = 855, lower disease but frail)) and compared according to years of able life (YAL), years of self-reported healthy life (YHL), and mortality using multivariable regression and survival analysis.
RESULTS: After adjustment, adapters had 0.97 (95% confidence interval (CI) = 0.60-1.33) more YAL and 0.54 (95% CI = 0.19-0.90) more YHL than expected agers, and those who were prematurely frail had -0.99 (95% CI = -1.36 to -0.62) fewer YAL and -0.53 (95% CI = -0.89 to -0.17) fewer YHL than expected agers. Adapters had 0.9 more and prematurely frail had 1.5 fewer years of total life than expected agers (P < .001). Adapters spent 55% of their remaining life able and healthy, those who were prematurely frail spent 37%, and of expected agers spent 47% (P < .001).
CONCLUSION: Despite similar levels of disease burden, older adults who were more vigorous appeared to compress morbidity and live longer. Older adults with higher frailty lengthened morbidity and had greater mortality. Adaptive factors may compress morbidity and decrease mortality.
1 aSanders, Jason, L1 aArnold, Alice, M1 aHirsch, Calvin, H1 aThielke, Stephen, M1 aKim, Dae1 aMukamal, Kenneth, J1 aKizer, Jorge, R1 aIx, Joachim, H1 aKaplan, Robert, C1 aKritchevsky, Stephen, B1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/713302489nas a2200193 4500008004100000022001400041245007900055210006900134260001500203520188200218100002002100700002202120700002002142700002402162700002302186700002902209700002102238856003602259 2016 eng d a1464-368500aTrajectories of function and biomarkers with age: the CHS All Stars Study.0 aTrajectories of function and biomarkers with age the CHS All Sta c2016 Jun 63 aBACKGROUND: Multimorbidity is a major driver of physical and cognitive impairment, but rates of decline are also related to ageing. We sought to determine trajectories of decline in a large cohort by disease status, and examined their correspondence with biomarkers of ageing processes including growth hormone, sex steroid, inflammation, visceral adiposity and kidney function pathways.
METHODS: We have followed the 5888 participants in the Cardiovascular Health Study (CHS) for healthy ageing and longevity since 1989-90. Gait speed, grip strength, modified mini-mental status examination (3MSE) and the digit symbol substitution test (DSST) were assessed annually to 1998-99 and again in 2005-06. Insulin-like growth hormone (IGF-1), dehydroepiandrosterone sulphate (DHEAS), interleukin-6 (IL-6), adiponectin and cystatin-C were assessed 3-5 times from stored samples. Health status was updated annually and dichotomized as healthy vs not healthy. Trajectories for each function measure and biomarker were estimated using generalized estimating equations as a function of age and health status using standardized values.
RESULTS: Trajectories of functional decline showed strong age acceleration late in life in healthy older men and women as well as in chronically ill older adults. Adiponectin, IL-6 and cystatin-C tracked with functional decline in all domains; cystatin-C was consistently associated with functional declines independent of other biomarkers. DHEAS was independently associated with grip strength and IL-6 with grip strength and gait speed trajectories.
CONCLUSIONS: Functional decline in late life appears to mark a fundamental ageing process in that it occurred and was accelerated in late life regardless of health status. Cystatin C was most consistently associated with these functional declines.
1 aNewman, Anne, B1 aSanders, Jason, L1 aKizer, Jorge, R1 aBoudreau, Robert, M1 aOdden, Michelle, C1 aHazzouri, Adina, Zeki Al1 aArnold, Alice, M uhttps://chs-nhlbi.org/node/712802424nas a2200217 4500008004100000022001400041245009400055210006900149260001600218520174800234100002201982700001802004700002202022700002202044700002302066700002002089700002002109700002002129700002102149856003602170 2017 eng d a1758-535X00aTrajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study.0 aTrajectories of IGFI Predict Mortality in Older Adults The Cardi c2017 Jul 233 aBackground: Disruption of insulin-like growth factor-I (IGF-I) increases health and life span in animal models, though this is unconfirmed in humans. If IGF-I stability indicates homeostasis, the absolute level of IGF-I may be less clinically relevant than maintaining an IGF-I setpoint.
Methods: Participants were 945 U.S. community-dwelling individuals aged ≥65 years enrolled in the Cardiovascular Health Study with IGF-I levels at 3-6 timepoints. We examined the association of baseline IGF-I level, trajectory slope, and variability around the trajectory with mortality.
Results: There were 633 deaths over median 11.3 years of follow-up. Lower IGF-I levels, declining or increasing slope, and increasing variability were each individually associated with higher mortality (all p < .001). In an adjusted model including all three trajectory parameters, baseline IGF-I levels <70 ng/mL (hazard ratio [HR] 1.58, 95% CI 1.28-1.96 relative to IGF-I levels of 170 ng/mL), steep declines and steep increases in trajectory slope (HR 2.22, 1.30-3.80 for a 15% decline; HR 1.40, 1.07-1.84 for a 10% decline; HR 1.80, 1.12-2.89 for a 15% increase; HR 1.31, 1.00-1.72 for a 10% increase, each vs no change), and variability ≥10% (HR 1.59, 1.09-2.32 for ≥ 30%; HR 1.36, 1.06-1.75 for 20%; and HR 1.17, 1.03-1.32 for 10% variability, each vs 0%) in IGF-I levels were independently associated with mortality.
Conclusions: In contrast to data from animal models, low IGF-I levels are associated with higher mortality in older humans. Irrespective of the actual IGF-I level, older individuals with stability of IGF-I levels have lower mortality than those whose IGF-I levels fluctuate over time.
1 aSanders, Jason, L1 aGuo, Wensheng1 aO'Meara, Ellen, S1 aKaplan, Robert, C1 aPollak, Michael, N1 aBartz, Traci, M1 aNewman, Anne, B1 aFried, Linda, P1 aCappola, Anne, R uhttps://chs-nhlbi.org/node/758402544nas a2200241 4500008004100000022001400041245011400055210006900169260001600238520177500254100002202029700002102051700002402072700002202096700002002118700002202138700002102160700001802181700001902199700002802218700002002246856003602266 2018 eng d a1758-535X00aAssociation of biomarker and physiologic indices with mortality in older adults: Cardiovascular Health Study.0 aAssociation of biomarker and physiologic indices with mortality c2018 Apr 123 aBackground: A goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers strongly and independently associated with mortality and which statistically attenuate chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it to a validated Physiologic Index (PI) in older adults.
Methods: The indices were constructed in the Cardiovascular Health Study, mean (SD) age 74.5 (5.1) years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor (IGF)-1, IGF binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N=2197) and validation (N=1124) samples. The PI included carotid intima-media thickness, pulmonary capacity, brain white matter grade, cystatin-C, and fasting glucose. Multivariable Cox proportional hazards models predicting death were calculated with 10 years of follow-up.
Results: In separate age-adjusted models, the hazard ratio (HR) for mortality per point of the BI was 1.30 (95% CI 1.25, 1.34) and the BI attenuated age by 25%. The HR for the PI was 1.28 (1.24, 1.33) (29% age attenuation). In the same model, the HR for the BI was 1.23 (1.18, 1.28) and for the PI was 1.22 (1.17, 1.26), and age was attenuated 42.5%. Associations persisted after further adjustment.
Conclusions: The BI and PI were significantly and independently associated with mortality. Both attenuated the age effect on mortality substantially. The indices may be feasible phenotypes for developing interventions hoping to alter the trajectory of aging.
1 aSanders, Jason, L1 aArnold, Alice, M1 aBoudreau, Robert, M1 aHirsch, Calvin, H1 aKizer, Jorge, R1 aKaplan, Robert, C1 aCappola, Anne, R1 aCushman, Mary1 aJacob, Mini, E1 aKritchevsky, Stephen, B1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/767104963nas a2201357 4500008004100000022001400041245010700055210006900162260001600231300000900247490000600256520112300262100001901385700001701404700002001421700002301441700002401464700001901488700002601507700002601533700002001559700002101579700001301600700002801613700001601641700002701657700001501684700001701699700002401716700001801740700002101758700002901779700002501808700001901833700001901852700002001871700001901891700001901910700002401929700001601953700002101969700001801990700001802008700002202026700002202048700001702070700002302087700002502110700002402135700001702159700002702176700002102203700002002224700002202244700001702266700002302283700002902306700002202335700002702357700001902384700002102403700002202424700002202446700002402468700002402492700002202516700002802538700002102566700002302587700002202610700002202632700003402654700001802688700001702706700001202723700002302735700002302758700002202781700001702803700001702820700002502837700002402862700002002886700002102906700002002927700002502947700002402972700001602996700002403012700001903036700002003055700002003075700002203095700002103117700001903138700002103157700002503178700001703203700001803220700001903238700001803257700001903275700002403294700002103318700002903339700002703368700002803395700001903423700002003442700002203462700002003484700001903504700002103523700002503544856003603569 2018 eng d a2041-172300aMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.0 aMultiethnic metaanalysis identifies ancestryspecific and crossan c2018 Jul 30 a29760 v93 aNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
1 aWyss, Annah, B1 aSofer, Tamar1 aLee, Mi, Kyeong1 aTerzikhan, Natalie1 aNguyen, Jennifer, N1 aLahousse, Lies1 aLatourelle, Jeanne, C1 aSmith, Albert, Vernon1 aBartz, Traci, M1 aFeitosa, Mary, F1 aGao, Wei1 aAhluwalia, Tarunveer, S1 aTang, Wenbo1 aOldmeadow, Christopher1 aDuan, Qing1 ade Jong, Kim1 aWojczynski, Mary, K1 aWang, Xin-Qun1 aNoordam, Raymond1 aHartwig, Fernando, Pires1 aJackson, Victoria, E1 aWang, Tianyuan1 aObeidat, Ma'en1 aHobbs, Brian, D1 aHuan, Tianxiao1 aGui, Hongsheng1 aParker, Margaret, M1 aHu, Donglei1 aMogil, Lauren, S1 aKichaev, Gleb1 aJin, Jianping1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aKalhan, Ravi1 aHeckbert, Susan, R1 aPaternoster, Lavinia1 aBurkart, Kristin, M1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aWilson, James, G1 aVonk, Judith, M1 aSanders, Jason, L1 aBarr, Graham1 ade Mutsert, Renée1 aMenezes, Ana, Maria Bapt1 aAdams, Hieab, H H1 avan den Berge, Maarten1 aJoehanes, Roby1 aLevin, Albert, M1 aLiberto, Jennifer1 aLauner, Lenore, J1 aMorrison, Alanna, C1 aSitlani, Colleen, M1 aCeledón, Juan, C1 aKritchevsky, Stephen, B1 aScott, Rodney, J1 aChristensen, Kaare1 aRotter, Jerome, I1 aBonten, Tobias, N1 aWehrmeister, Fernando, César1 aBossé, Yohan1 aXiao, Shujie1 aOh, Sam1 aFranceschini, Nora1 aBrody, Jennifer, A1 aKaplan, Robert, C1 aLohman, Kurt1 aMcEvoy, Mark1 aProvince, Michael, A1 aRosendaal, Frits, R1 aTaylor, Kent, D1 aNickle, David, C1 aWilliams, Keoki1 aBurchard, Esteban, G1 aWheeler, Heather, E1 aSin, Don, D1 aGudnason, Vilmundur1 aNorth, Kari, E1 aFornage, Myriam1 aPsaty, Bruce, M1 aMyers, Richard, H1 aO'Connor, George1 aHansen, Torben1 aLaurie, Cathy, C1 aCassano, Patricia, A1 aSung, Joohon1 aKim, Woo, Jin1 aAttia, John, R1 aLange, Leslie1 aBoezen, Marike1 aThyagarajan, Bharat1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aHorta, Bernardo, Lessa1 aUitterlinden, André, G1 aIm, Hae, Kyung1 aCho, Michael, H1 aBrusselle, Guy, G1 aGharib, Sina, A1 aDupuis, Josée1 aManichaikul, Ani1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/781904467nas a2200481 4500008004100000022001400041245009900055210006900154260001500223300001400238490000800252520309300260653000903353653002203362653001903384653001103403653002903414653002003443653001103463653000903474653001603483653001403499653003203513653004303545653002003588653001903608100002003627700002203647700002403669700002503693700001803718700002103736700001703757700002403774700001803798700002203816700002003838700002403858700002103882700002003903700002603923856003603949 2019 eng d a1538-359800aDiscriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality.0 aDiscriminative Accuracy of FEV1FVC Thresholds for COPDRelated Ho c2019 06 25 a2438-24470 v3213 aImportance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.
Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.
Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.
Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).
Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.
Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.
Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.
10aAged10aAged, 80 and over10aCohort Studies10aFemale10aForced Expiratory Volume10aHospitalization10aHumans10aMale10aMiddle Aged10aPrognosis10aProportional Hazards Models10aPulmonary Disease, Chronic Obstructive10aRisk Assessment10aVital Capacity1 aBhatt, Surya, P1 aBalte, Pallavi, P1 aSchwartz, Joseph, E1 aCassano, Patricia, A1 aCouper, David1 aJacobs, David, R1 aKalhan, Ravi1 aO'Connor, George, T1 aYende, Sachin1 aSanders, Jason, L1 aUmans, Jason, G1 aDransfield, Mark, T1 aChaves, Paulo, H1 aWhite, Wendy, B1 aOelsner, Elizabeth, C uhttps://chs-nhlbi.org/node/809702635nas a2200241 4500008004100000022001400041245006200055210006100117260001300178300001200191490000700203520196100210100002002171700002002191700002202211700002002233700001602253700002202269700002302291700002002314700002302334856003602357 2021 eng d a1942-008000aAssociation Between Myocardial Strain and Frailty in CHS.0 aAssociation Between Myocardial Strain and Frailty in CHS c2021 May ae0121160 v143 aBACKGROUND: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve.
METHODS: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having ≥3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography.
RESULTS: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95% CI, 1.07-1.61] per 1-SD lower strain; =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95% CI, 1.08-1.61] per 1-SD lower strain; =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95% CI, 0.96-1.89] =0.086) and 1.58 ([95% CI, 1.11-2.27] =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95% CI, 1.81-2.66]; <0.0001).
CONCLUSIONS: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.
1 aTan, Annabel, X1 aShah, Sanjiv, J1 aSanders, Jason, L1 aPsaty, Bruce, M1 aWu, Chenkai1 aGardin, Julius, M1 aPeralta, Carmen, A1 aNewman, Anne, B1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/879005260nas a2200553 4500008004100000022001400041245009600055210006900151260001500220300001400235490000800249520374200257653001003999653000904009653002204018653002804040653001104068653002904079653001104108653000904119653001804128653000904146653001604155653001504171653002604186653001504212653001804227653001904245100001804264700001904282700002404301700002004325700002504345700001804370700002404388700002404412700002004436700002104456700001704477700002504494700002104519700002404540700002204564700002304586700001704609700001804626700002604644856003604670 2021 eng d a1538-359800aAssociation Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.0 aAssociation Between Preserved Ratio Impaired Spirometry and Clin c2021 12 14 a2287-22980 v3263 aImportance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood.
Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults.
Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018).
Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted.
Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities.
Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]).
Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aFemale10aForced Expiratory Volume10aHumans10aLung10aLung Diseases10aMale10aMiddle Aged10aPrevalence10aRetrospective Studies10aSpirometry10aUnited States10aVital Capacity1 aWan, Emily, S1 aBalte, Pallavi1 aSchwartz, Joseph, E1 aBhatt, Surya, P1 aCassano, Patricia, A1 aCouper, David1 aDaviglus, Martha, L1 aDransfield, Mark, T1 aGharib, Sina, A1 aJacobs, David, R1 aKalhan, Ravi1 aLondon, Stephanie, J1 aNavas-Acien, Ana1 aO'Connor, George, T1 aSanders, Jason, L1 aSmith, Benjamin, M1 aWhite, Wendy1 aYende, Sachin1 aOelsner, Elizabeth, C uhttps://chs-nhlbi.org/node/911402778nas a2200385 4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520174600230653001001976653001101986653000901997653001802006653001102024653002302035653000902058653001502067653001802082100001802100700001902118700002302137700002702160700002002187700002202207700002002229700002202249700001602271700002202287700002402309700002302333856003602356 2022 eng d a1474-972600aPlasma proteomic signature of decline in gait speed and grip strength.0 aPlasma proteomic signature of decline in gait speed and grip str c2022 Dec ae137360 v213 aThe biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10 ), pleiotrophin (1.23 × 10 ), and TIMP-1 (5.97 × 10 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10 ), CDON (2.38 × 10 ), and SMOC1 (7.47 × 10 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.
10aAdult10aFemale10aGait10aHand Strength10aHumans10aIndependent Living10aMale10aProteomics10aWalking Speed1 aLiu, Xiaojuan1 aPan, Stephanie1 aXanthakis, Vanessa1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aAustin, Thomas, R1 aNewman, Anne, B1 aSanders, Jason, L1 aWu, Chenkai1 aTracy, Russell, P1 aGerszten, Robert, E1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/925503589nas a2200517 4500008004100000022001400041245007300055210006900128260001200197300001400209490000700223520217700230653001002407653001102417653002902428653001102457653000902468653000902477653001602486653002202502653004302524653001702567653001502584653001902599100002002618700002202638700002402660700002102684700002502705700002102730700001802751700002102769700001702790700001902807700002402826700002002850700002102870700002202891700002302913700001502936700002002951700002002971700001802991700002603009856003603035 2022 eng d a2325-662100aPooled Cohort Probability Score for Subclinical Airflow Obstruction.0 aPooled Cohort Probability Score for Subclinical Airflow Obstruct c2022 08 a1294-13040 v193 aEarly detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.
10aAdult10aFemale10aForced Expiratory Volume10aHumans10aLung10aMale10aMiddle Aged10aNutrition Surveys10aPulmonary Disease, Chronic Obstructive10aRisk Factors10aSpirometry10aVital Capacity1 aBhatt, Surya, P1 aBalte, Pallavi, P1 aSchwartz, Joseph, E1 aJaeger, Byron, C1 aCassano, Patricia, A1 aChaves, Paulo, H1 aCouper, David1 aJacobs, David, R1 aKalhan, Ravi1 aKaplan, Robert1 aLloyd-Jones, Donald1 aNewman, Anne, B1 aO'Connor, George1 aSanders, Jason, L1 aSmith, Benjamin, M1 aSun, Yifei1 aUmans, Jason, G1 aWhite, Wendy, B1 aYende, Sachin1 aOelsner, Elizabeth, C uhttps://chs-nhlbi.org/node/915602542nas a2200253 4500008004100000022001400041245011600055210006900171260001600240520174000256100001601996700002202012700002402034700002102058700002202079700002202101700002202123700001802145700002102163700002002184700002802204700002002232856003602252 2023 eng d a1758-535X00aAssociation of a blood-based aging biomarker index with death and chronic disease: Cardiovascular Health Study.0 aAssociation of a bloodbased aging biomarker index with death and c2023 Jul 193 aBACKGROUND: A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration.
METHODS: A Biomarker Index (BI) was constructed in the Cardiovascular Health Study (N=3197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up.
RESULTS: The hazard ratio (HR, 95% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7% and 22.0% in women and men, respectively.
CONCLUSIONS: BI was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging.
1 aZhang, Xiao1 aSanders, Jason, L1 aBoudreau, Robert, M1 aArnold, Alice, M1 aJustice, Jamie, N1 aEspeland, Mark, A1 aKuchel, George, A1 aBarzilai, Nir1 aKuller, Lewis, H1 aLopez, Oscar, L1 aKritchevsky, Stephen, B1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/9438