@article {1168, title = {Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study.}, journal = {J Am Geriatr Soc}, volume = {58}, year = {2010}, month = {2010 Mar}, pages = {421-6}, abstract = {

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.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cross-Sectional Studies, Dehydroepiandrosterone Sulfate, Female, Humans, Longitudinal Studies, Male, Multivariate Analysis, Regression Analysis, Sex Distribution, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2010.02724.x}, author = {Sanders, Jason L and Boudreau, Robert M and Cappola, Anne R and Arnold, Alice M and Robbins, John and Cushman, Mary and Newman, Anne B} } @article {1318, title = {Measurement of organ structure and function enhances understanding of the physiological basis of frailty: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {59}, year = {2011}, month = {2011 Sep}, pages = {1581-8}, abstract = {

OBJECTIVES: 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 {\textpm} 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.

}, keywords = {Aged, 80 and over, Cardiovascular Diseases, Chronic Disease, Cost of Illness, Cross-Sectional Studies, Female, Frail Elderly, Humans, Male}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2011.03557.x}, author = {Sanders, Jason L and Boudreau, Robert M and Fried, Linda P and Walston, Jeremy D and Harris, Tamara B and Newman, Anne B} } @article {1328, title = {Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {67}, year = {2012}, month = {2012 Apr}, pages = {409-16}, abstract = {

BACKGROUND: 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.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cardiovascular Diseases, Carotid Intima-Media Thickness, Chronic Disease, Cystatin C, European Continental Ancestry Group, Female, Humans, Leukocytes, Lung, Male, Middle Aged, Telomere Homeostasis}, issn = {1758-535X}, doi = {10.1093/gerona/glr173}, author = {Sanders, Jason L and Fitzpatrick, Annette L and Boudreau, Robert M and Arnold, Alice M and Aviv, Abraham and Kimura, Masayuki and Fried, Linda F and Harris, Tamara B and Newman, Anne B} } @article {6000, title = {Do changes in circulating biomarkers track with each other and with functional changes in older adults?}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {174-81}, abstract = {

BACKGROUND: 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.

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Aging, Biomarkers, Cholesterol, Cognition, Cohort Studies, Dehydroepiandrosterone Sulfate, Female, Gait, Hand Strength, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Interleukin-6, Male, Neuropsychological Tests, Psychomotor Performance, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt088}, author = {Sanders, Jason L and Ding, Victoria and Arnold, Alice M and Kaplan, Robert C and Cappola, Anne R and Kizer, Jorge R and Boudreau, Robert M and Cushman, Mary and Newman, Anne B} } @article {6280, title = {Heritability of and mortality prediction with a longevity phenotype: the healthy aging index.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Apr}, pages = {479-85}, abstract = {

BACKGROUND: 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{\textquoteright}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.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genotype, Health Behavior, Humans, Longevity, Male, Phenotype, Retrospective Studies, Risk Factors, Survival Rate, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt117}, author = {Sanders, Jason L and Minster, Ryan L and Barmada, M Michael and Matteini, Amy M and Boudreau, Robert M and Christensen, Kaare and Mayeux, Richard and Borecki, Ingrid B and Zhang, Qunyuan and Perls, Thomas and Newman, Anne B} } @article {6589, title = {Subclinical vascular disease burden and longer survival.}, journal = {J Am Geriatr Soc}, volume = {62}, year = {2014}, month = {2014 Sep}, pages = {1692-8}, abstract = {

OBJECTIVES: 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.

}, keywords = {Aged, Aged, 80 and over, C-Reactive Protein, Carotid Intima-Media Thickness, Cohort Studies, Cystatin C, Depression, Diabetes Mellitus, Electrocardiography, Female, Humans, Inflammation, Kidney Diseases, Male, Smoking, Survival Analysis, United States, Vascular Diseases}, issn = {1532-5415}, doi = {10.1111/jgs.13018}, author = {Odden, Michelle C and Yee, Laura M and Arnold, Alice M and Sanders, Jason L and Hirsch, Calvin and DeFilippi, Christopher and Kizer, Jorge R and Inzitari, Marco and Newman, Anne B} } @article {6703, title = {Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Aug}, pages = {1003-8}, abstract = {

BACKGROUND: 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.

}, keywords = {Aging, Apolipoproteins E, Forkhead Transcription Factors, Genetic Linkage, Genome-Wide Association Study, Humans, Longevity, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1758-535X}, doi = {10.1093/gerona/glv006}, author = {Minster, Ryan L and Sanders, Jason L and Singh, Jatinder and Kammerer, Candace M and Barmada, M Michael and Matteini, Amy M and Zhang, Qunyuan and Wojczynski, Mary K and Daw, E Warwick and Brody, Jennifer A and Arnold, Alice M and Lunetta, Kathryn L and Murabito, Joanne M and Christensen, Kaare and Perls, Thomas T and Province, Michael A and Newman, Anne B} } @article {6596, title = {Multisystem physiologic impairments and changes in gait speed of older adults.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Mar}, pages = {319-24}, abstract = {

BACKGROUND: 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.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Brain, Cardiovascular Physiological Phenomena, Cohort Studies, Female, Gait, Geriatric Assessment, Glucose, Health Status Indicators, Humans, Kidney, Lung, Male, Sensitivity and Specificity, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glu176}, author = {Rosso, Andrea L and Sanders, Jason L and Arnold, Alice M and Boudreau, Robert M and Hirsch, Calvin H and Carlson, Michelle C and Rosano, Caterina and Kritchevsky, Stephen B and Newman, Anne B} } @article {7133, title = {Effects of Disease Burden and Functional Adaptation on Morbidity and Mortality on Older Adults.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Jun}, pages = {1242-9}, abstract = {

OBJECTIVES: 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.

}, issn = {1532-5415}, doi = {10.1111/jgs.14163}, author = {Sanders, Jason L and Arnold, Alice M and Hirsch, Calvin H and Thielke, Stephen M and Kim, Dae and Mukamal, Kenneth J and Kizer, Jorge R and Ix, Joachim H and Kaplan, Robert C and Kritchevsky, Stephen B and Newman, Anne B} } @article {7128, title = {Trajectories of function and biomarkers with age: the CHS All Stars Study.}, journal = {Int J Epidemiol}, year = {2016}, month = {2016 Jun 6}, abstract = {

BACKGROUND: 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.

}, issn = {1464-3685}, doi = {10.1093/ije/dyw092}, author = {Newman, Anne B and Sanders, Jason L and Kizer, Jorge R and Boudreau, Robert M and Odden, Michelle C and Zeki Al Hazzouri, Adina and Arnold, Alice M} } @article {7584, title = {Trajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2017}, month = {2017 Jul 23}, abstract = {

Background: 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.

}, issn = {1758-535X}, doi = {10.1093/gerona/glx143}, author = {Sanders, Jason L and Guo, Wensheng and O{\textquoteright}Meara, Ellen S and Kaplan, Robert C and Pollak, Michael N and Bartz, Traci M and Newman, Anne B and Fried, Linda P and Cappola, Anne R} } @article {7671, title = {Association of biomarker and physiologic indices with mortality in older adults: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2018}, month = {2018 Apr 12}, abstract = {

Background: 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.

}, issn = {1758-535X}, doi = {10.1093/gerona/gly075}, author = {Sanders, Jason L and Arnold, Alice M and Boudreau, Robert M and Hirsch, Calvin H and Kizer, Jorge R and Kaplan, Robert C and Cappola, Anne R and Cushman, Mary and Jacob, Mini E and Kritchevsky, Stephen B and Newman, Anne B} } @article {7819, title = {Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 30}, pages = {2976}, abstract = {

Nearly 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.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-05369-0}, author = {Wyss, Annah B and Sofer, Tamar and Lee, Mi Kyeong and Terzikhan, Natalie and Nguyen, Jennifer N and Lahousse, Lies and Latourelle, Jeanne C and Smith, Albert Vernon and Bartz, Traci M and Feitosa, Mary F and Gao, Wei and Ahluwalia, Tarunveer S and Tang, Wenbo and Oldmeadow, Christopher and Duan, Qing and de Jong, Kim and Wojczynski, Mary K and Wang, Xin-Qun and Noordam, Raymond and Hartwig, Fernando Pires and Jackson, Victoria E and Wang, Tianyuan and Obeidat, Ma{\textquoteright}en and Hobbs, Brian D and Huan, Tianxiao and Gui, Hongsheng and Parker, Margaret M and Hu, Donglei and Mogil, Lauren S and Kichaev, Gleb and Jin, Jianping and Graff, Mariaelisa and Harris, Tamara B and Kalhan, Ravi and Heckbert, Susan R and Paternoster, Lavinia and Burkart, Kristin M and Liu, Yongmei and Holliday, Elizabeth G and Wilson, James G and Vonk, Judith M and Sanders, Jason L and Barr, R Graham and de Mutsert, Ren{\'e}e and Menezes, Ana Maria Baptista and Adams, Hieab H H and van den Berge, Maarten and Joehanes, Roby and Levin, Albert M and Liberto, Jennifer and Launer, Lenore J and Morrison, Alanna C and Sitlani, Colleen M and Celed{\'o}n, Juan C and Kritchevsky, Stephen B and Scott, Rodney J and Christensen, Kaare and Rotter, Jerome I and Bonten, Tobias N and Wehrmeister, Fernando C{\'e}sar and Boss{\'e}, Yohan and Xiao, Shujie and Oh, Sam and Franceschini, Nora and Brody, Jennifer A and Kaplan, Robert C and Lohman, Kurt and McEvoy, Mark and Province, Michael A and Rosendaal, Frits R and Taylor, Kent D and Nickle, David C and Williams, L Keoki and Burchard, Esteban G and Wheeler, Heather E and Sin, Don D and Gudnason, Vilmundur and North, Kari E and Fornage, Myriam and Psaty, Bruce M and Myers, Richard H and O{\textquoteright}Connor, George and Hansen, Torben and Laurie, Cathy C and Cassano, Patricia A and Sung, Joohon and Kim, Woo Jin and Attia, John R and Lange, Leslie and Boezen, H Marike and Thyagarajan, Bharat and Rich, Stephen S and Mook-Kanamori, Dennis O and Horta, Bernardo Lessa and Uitterlinden, Andr{\'e} G and Im, Hae Kyung and Cho, Michael H and Brusselle, Guy G and Gharib, Sina A and Dupuis, Jos{\'e}e and Manichaikul, Ani and London, Stephanie J} } @article {8097, title = {Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality.}, journal = {JAMA}, volume = {321}, year = {2019}, month = {2019 06 25}, pages = {2438-2447}, abstract = {

Importance: 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.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Female, Forced Expiratory Volume, Hospitalization, Humans, Male, Middle Aged, Prognosis, Proportional Hazards Models, Pulmonary Disease, Chronic Obstructive, Risk Assessment, Vital Capacity}, issn = {1538-3598}, doi = {10.1001/jama.2019.7233}, author = {Bhatt, Surya P and Balte, Pallavi P and Schwartz, Joseph E and Cassano, Patricia A and Couper, David and Jacobs, David R and Kalhan, Ravi and O{\textquoteright}Connor, George T and Yende, Sachin and Sanders, Jason L and Umans, Jason G and Dransfield, Mark T and Chaves, Paulo H and White, Wendy B and Oelsner, Elizabeth C} } @article {8790, title = {Association Between Myocardial Strain and Frailty in CHS.}, journal = {Circ Cardiovasc Imaging}, volume = {14}, year = {2021}, month = {2021 May}, pages = {e012116}, abstract = {

BACKGROUND: 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.

}, issn = {1942-0080}, doi = {10.1161/CIRCIMAGING.120.012116}, author = {Tan, Annabel X and Shah, Sanjiv J and Sanders, Jason L and Psaty, Bruce M and Wu, Chenkai and Gardin, Julius M and Peralta, Carmen A and Newman, Anne B and Odden, Michelle C} } @article {9114, title = {Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.}, journal = {JAMA}, volume = {326}, year = {2021}, month = {2021 12 14}, pages = {2287-2298}, abstract = {

Importance: 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.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Forced Expiratory Volume, Humans, Lung, Lung Diseases, Male, Middle Aged, Prevalence, Retrospective Studies, Spirometry, United States, Vital Capacity}, issn = {1538-3598}, doi = {10.1001/jama.2021.20939}, author = {Wan, Emily S and Balte, Pallavi and Schwartz, Joseph E and Bhatt, Surya P and Cassano, Patricia A and Couper, David and Daviglus, Martha L and Dransfield, Mark T and Gharib, Sina A and Jacobs, David R and Kalhan, Ravi and London, Stephanie J and Navas-Acien, Ana and O{\textquoteright}Connor, George T and Sanders, Jason L and Smith, Benjamin M and White, Wendy and Yende, Sachin and Oelsner, Elizabeth C} } @article {9255, title = {Plasma proteomic signature of decline in gait speed and grip strength.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Dec}, pages = {e13736}, abstract = {

The 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 {\texttimes} 10 ), pleiotrophin (1.23 {\texttimes} 10 ), and TIMP-1 (5.97 {\texttimes} 10 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 {\texttimes} 10 ), CDON (2.38 {\texttimes} 10 ), and SMOC1 (7.47 {\texttimes} 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.

}, keywords = {Adult, Female, Gait, Hand Strength, Humans, Independent Living, Male, Proteomics, Walking Speed}, issn = {1474-9726}, doi = {10.1111/acel.13736}, author = {Liu, Xiaojuan and Pan, Stephanie and Xanthakis, Vanessa and Vasan, Ramachandran S and Psaty, Bruce M and Austin, Thomas R and Newman, Anne B and Sanders, Jason L and Wu, Chenkai and Tracy, Russell P and Gerszten, Robert E and Odden, Michelle C} } @article {9156, title = {Pooled Cohort Probability Score for Subclinical Airflow Obstruction.}, journal = {Ann Am Thorac Soc}, volume = {19}, year = {2022}, month = {2022 08}, pages = {1294-1304}, abstract = {

Early 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.

}, keywords = {Adult, Female, Forced Expiratory Volume, Humans, Lung, Male, Middle Aged, Nutrition Surveys, Pulmonary Disease, Chronic Obstructive, Risk Factors, Spirometry, Vital Capacity}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.202109-1020OC}, author = {Bhatt, Surya P and Balte, Pallavi P and Schwartz, Joseph E and Jaeger, Byron C and Cassano, Patricia A and Chaves, Paulo H and Couper, David and Jacobs, David R and Kalhan, Ravi and Kaplan, Robert and Lloyd-Jones, Donald and Newman, Anne B and O{\textquoteright}Connor, George and Sanders, Jason L and Smith, Benjamin M and Sun, Yifei and Umans, Jason G and White, Wendy B and Yende, Sachin and Oelsner, Elizabeth C} } @article {9438, title = {Association of a blood-based aging biomarker index with death and chronic disease: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2023}, month = {2023 Jul 19}, abstract = {

BACKGROUND: 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.

}, issn = {1758-535X}, doi = {10.1093/gerona/glad172}, author = {Zhang, Xiao and Sanders, Jason L and Boudreau, Robert M and Arnold, Alice M and Justice, Jamie N and Espeland, Mark A and Kuchel, George A and Barzilai, Nir and Kuller, Lewis H and Lopez, Oscar L and Kritchevsky, Stephen B and Newman, Anne B} } @article {9640, title = {Plasma proteomic signature of human longevity.}, journal = {Aging Cell}, year = {2024}, month = {2024 Mar 05}, pages = {e14136}, abstract = {

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

}, issn = {1474-9726}, doi = {10.1111/acel.14136}, author = {Liu, Xiaojuan and Axelsson, Gisli Thor and Newman, Anne B and Psaty, Bruce M and Boudreau, Robert M and Wu, Chenkai and Arnold, Alice M and Aspelund, Thor and Austin, Thomas R and Gardin, Julius M and Siggeirsdottir, Kristin and Tracy, Russell P and Gerszten, Robert E and Launer, Lenore J and Jennings, Lori L and Gudnason, Vilmundur and Sanders, Jason L and Odden, Michelle C} }