Plasma proteomic signature of human longevity.

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.

Association of a Blood-Based Aging Biomarker Index With Death and Chronic Disease: Cardiovascular Health Study.

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 = 3 197), 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: Biomarker index 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.

Development of a Novel Accelerometry-Based Performance Fatigability Measure for Older Adults.

INTRODUCTION: Efforts to study performance fatigability have been limited because of measurement constrains. Accelerometry and advanced statistical methods may enable us to quantify performance fatigability more granularly via objective detection of performance decline. Thus, we developed the Pittsburgh Performance Fatigability Index (PPFI) using triaxial raw accelerations from wrist-worn accelerometer from two in-laboratory 400-m walks. METHODS: Sixty-three older adults from our cross-sectional study (mean age, 78 yr; 56% women; 88% White) completed fast-paced ( n = 59) and/or usual-paced 400-m walks ( n = 56) with valid accelerometer data. Participants wore ActiGraph GT3X+ accelerometers (The ActiGraph LLC, Pensacola, FL) on nondominant wrist during the walking task. Triaxial raw accelerations from accelerometers were used to compute PPFI, which quantifies percentage of area under the observed gait cadence-versus-time trajectory during a 400-m walk to a hypothetical area that would be produced if the participant sustained maximal cadence throughout the entire walk. RESULTS: Higher PPFI scores (higher score = greater fatigability) correlated with worse physical function, slower chair stands speed and gait speed, worse cardiorespiratory fitness and mobility, and lower leg peak power (| ρ | = 0.36-0.61 from fast-paced and | ρ | = 0.28-0.67 from usual-paced walks, all P < 0.05). PPFI scores from both walks remained associated with chair stands speed, gait speed, fitness, and mobility, after adjustment for sex, age, race, weight, height, and smoking status; PPFI scores from the fast-paced walk were associated with leg peak power. CONCLUSIONS: Our findings revealed that the objective PPFI is a sensitive measure of performance fatigability for older adults and can serve as a risk assessment tool or outcome measure in future studies and clinical practice.

Perceived physical fatigability improves after an exercise intervention among breast cancer survivors: a randomized clinical trial.

BACKGROUND: Among breast cancer populations, exercise interventions resulted in positive but relatively small improvements on fatigue, which may be due to insensitive measures of global fatigue. Perceived fatigability-whole-body tiredness anchored to standardized tasks/activities of a specific intensity and duration-may help to detect effective exercise interventions reducing fatigue in oncology. We examined whether perceived physical fatigability improved after an exercise intervention. METHODS: This single center randomized clinical trial of 49 breast cancer survivors was conducted from 2015 to 2017, among which 41 participants (22 = exercise, 19 = control) completed the trial and reported their perceived physical fatigability at the first (Visit 1) and the last visit (Visit 3) over 6-14 weeks. Perceived physical fatigability was measured using the 10-item, self-administered Pittsburgh Fatigability Scale (PFS) scored 0-50. The mean differences of perceived physical fatigability between Visit 3 and Visit 1 were computed and compared by intervention groups using two sample t test. RESULTS: Among the 41 women in the study (mean age 54.9 ± 9.8 years; 80% white), sociodemographic, clinical characteristics and baseline fatigue level were similar by intervention groups, except for antiestrogen use. Post-intervention changes (mean ∆ ± SE) of PFS Physical scores were greater in the exercise group (- 4.4 ± 1.4; - 22.5%) than the control group (0.2 ± 1.4; + 1.0%) (p = .022). CONCLUSION: The PFS captured a reduction in fatigue after the exercise intervention among breast cancer survivors. These findings aid mounting efforts to reduce fatigue in oncology by introducing a more sensitive instrument to measure perceived physical fatigability to better evaluate patient-reported outcomes in future cancer trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02770781.

Relationship between socioeconomic status, exposure to airborne pollutants, and chronic rhinosinusitis disease severity.

BACKGROUND: Air pollution directly interacts with airway mucosa, yet little is known about how pollutants affect upper airway inflammation. Studies have shown increased incidence of chronic rhinosinusitis (CRS), rhinitis, and asthma in areas with higher traffic pollution, and these neighborhoods are often associated with lower socioeconomic status (SES). The Area Deprivation Index (ADI) assesses neighborhood-level SES by zip code. The purpose of this study was to assess the relationship between SES and exposure to inhaled pollutants and CRS disease severity. METHODS: CRS patients with and without nasal polyps (CRSwNP and CRSsNP, respectively) were identified (total patients = 234; CRSwNP patients = 138; CRSsNP patients = 96). Pollutant concentrations, including particulate matter 2.5 (PM2.5 ), black carbon (BC), and nitrogen dioxide (NO2 ), were measured at 70 sites within the defined countywide sites and used to estimate patient exposures. SES was measured by ADI state deciles. Disease severity metrics included the modified Lund-Mackay score (LMS), the need for systemic steroids, and functional endoscopic sinus surgery (FESS). Associations were analyzed and identified using linear, logistic, and Poisson multivariable regression. RESULTS: The distribution of CRSsNP and CRSwNP patients across ADI state deciles was similar. ADI, however, was a predictor of exposure to airborne pollutants (PM2.5 , BC, and NO2 ) with a 1.39%, 2.39%, and 2.49% increase in PM2.5 , BC, and NO2 per increasing decile increment (p < 0.0001), respectively, which demonstrated a direct correlation between deprived neighborhoods and higher levels of exposure to PM2.5 , BC, and NO2 with an increase in pollutant levels per increase in ADI decile. Furthermore, ADI was a predictor for increased steroid treatment. CONCLUSION: Lower SES predicted higher exposure to air pollution and increased disease severity in patients with CRS as demonstrated by the increased need for steroid treatment.

Persistent polypharmacy and fall injury risk: the Health, Aging and Body Composition Study.

BACKGROUND: Older adults receive treatment for fall injuries in both inpatient and outpatient settings. The effect of persistent polypharmacy (i.e. using multiple medications over a long period) on fall injuries is understudied, particularly for outpatient injuries. We examined the association between persistent polypharmacy and treated fall injury risk from inpatient and outpatient settings in community-dwelling older adults. METHODS: The Health, Aging and Body Composition Study included 1764 community-dwelling adults (age 73.6 ± 2.9 years; 52% women; 38% black) with Medicare Fee-For-Service (FFS) claims at or within 6 months after 1998/99 clinic visit. Incident fall injuries (N = 545 in 4.6 ± 2.9 years) were defined as the initial claim with an ICD-9 fall E-code and non-fracture injury, or fracture code with/without a fall code from 1998/99 clinic visit to 12/31/08. Those without fall injury (N = 1219) were followed for 8.1 ± 2.6 years. Stepwise Cox models of fall injury risk with a time-varying variable for persistent polypharmacy (defined as ≥6 prescription medications at the two most recent consecutive clinic visits) were adjusted for demographics, lifestyle characteristics, chronic conditions, and functional ability. Sensitivity analyses explored if persistent polypharmacy both with and without fall risk increasing drugs (FRID) use were similarly associated with fall injury risk. RESULTS: Among 1764 participants, 636 (36%) had persistent polypharmacy over the follow-up period, and 1128 (64%) did not. Fall injury incidence was 38 per 1000 person-years. Persistent polypharmacy increased fall injury risk (hazard ratio [HR]: 1.31 [1.06, 1.63]) after adjusting for covariates. Persistent polypharmacy with FRID use was associated with a 48% increase in fall injury risk (95%CI: 1.10, 2.00) vs. those who had non-persistent polypharmacy without FRID use. Risks for persistent polypharmacy without FRID use (HR: 1.22 [0.93, 1.60]) and non-persistent polypharmacy with FRID use (HR: 1.08 [0.77, 1.51]) did not significantly increase compared to non-persistent polypharmacy without FRID use. CONCLUSIONS: Persistent polypharmacy, particularly combined with FRID use, was associated with increased risk for treated fall injuries from inpatient and outpatient settings. Clinicians may need to consider medication management for FRID and other fall prevention strategies in community-dwelling older adults with persistent polypharmacy to reduce fall injury risk.

Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study.

BACKGROUND: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation. METHODS: We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p < .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication. RESULTS: At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (-8.2%, 95% confidence interval: -14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p < .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p < .05). CONCLUSIONS: The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.

Association of air pollutants, airborne occupational exposures, and chronic rhinosinusitis disease severity.

BACKGROUND: Previous work has shown that chronic rhinosinusitis (CRS) severity may be associated with particulate matter 2.5 (PM2.5 ) and black carbon (BC) in CRS patients without nasal polyps (CRSsNP). Data regarding occupational exposures, however, are lacking. We assessed the impact of PM2.5 , BC, as well as occupational airborne exposure on CRS disease severity. METHODS: Patients with CRS with nasal polyps (CRSwNP), CRSsNP, and aspirin-exacerbated respiratory disease (AERD) were identified from an institutionwide database. Spatial modeling from 37 pollutant monitoring sites in Allegheny County was used to estimate exposures. Patient occupations using the 2010 Standard Occupation Classification (SOC10) and airborne occupation exposures to vapors, gases, dusts, fumes, fibers and mists (VGDFFiM) or diesel fumes were recorded. Disease severity was measured by modified Lund-Mackay score (LMS), systemic corticosteroid therapy, and incidence of functional endoscopic sinus surgery (FESS). RESULTS: Two hundred thirty-four patients were included (CRSwNP, n = 113; CRSsNP, n = 96; AERD, n = 25). The prevalence of AERD among those with CRSwNP was 18%. Patients exposed to VGDFFiM or diesel fumes required higher steroid doses vs nonexposed patients (p = 0.015 and p = 0.03, respectively); patients with VGDFFiM levels >5% were more likely to undergo FESS vs nonexposed patients (p = 0.0378). There was no difference in PM2.5 and BC with regard to disease severity and FESS between CRSwNP, CRSsNP, and AERD patients. Steroid use was significantly higher in CRSwNP and AERD vs CRSsNP (p = 0.001). LMS was significantly higher in AERD as compared with CRSwNP and CRSsNP (p = 0.001). CONCLUSION: Occupational airborne exposure to VGDFFiM correlated with increased prevalence of FESS and need for corticosteroids in CRS patients. There was no difference in PM2.5 and BC levels and disease severity outcome measures between CRS subtypes in this subset.

Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism.

Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.

Metabolites Associated with Vigor to Frailty Among Community-Dwelling Older Black Men.

Black versus white older Americans are more likely to experience frailty, a condition associated with adverse health outcomes. To reduce racial disparities in health, a complete understanding of the pathophysiology of frailty is needed. Metabolomics may further our understanding by characterizing differences in the body during a vigorous versus frail state. We sought to identify metabolites and biological pathways associated with vigor to frailty among 287 black men ages 70-81 from the Health, Aging, and Body Composition study. Using liquid chromatography-mass spectrometry, 350 metabolites were measured in overnight-fasting plasma. The Scale of Aging Vigor in Epidemiology (SAVE) measured vigor to frailty based on weight change, strength, energy, gait speed, and physical activity. Thirty-seven metabolites correlated with SAVE scores (p < 0.05), while adjusting for age and site. Fourteen metabolites remained significant after multiple comparisons adjustment (false discovery rate < 0.30). Lower values of tryptophan, methionine, tyrosine, asparagine, C14:0 sphingomyelin, and 1-methylnicotinamide, and higher values of glucoronate, N-carbamoyl-beta-alanine, isocitrate, creatinine, C4-OH carnitine, cystathionine, hydroxyphenylacetate, and putrescine were associated with frailer SAVE scores. Pathway analyses identified nitrogen metabolism, aminoacyl-tRNA biosynthesis, and the citric acid cycle. Future studies need to confirm these SAVE-associated metabolites and pathways that may indicate novel mechanisms involved in the frailty syndrome.

Association of Biomarker and Physiologic Indices With Mortality in Older Adults: Cardiovascular Health Study.

Background: A goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that strongly and independently associated with mortality and that statistically attenuated chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it with 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-1, insulin-like growth factor-binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N = 2,197) and validation (N = 1,124) 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 for mortality per point of the BI was 1.30 (95% confidence interval 1.25, 1.34) and the BI attenuated age by 25%. The hazard ratio for the PI was 1.28 (1.24, 1.33; 29% age attenuation). In the same model, the hazard ratio 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.

Mortality in Relation to Changes in a Healthy Aging Index: The Health, Aging, and Body Composition Study.

BACKGROUND: Baseline scores on a Healthy Aging Index (HAI), including five key physiologic domains, strongly predict health outcomes. This study aimed to characterize 9-year changes in a HAI and explore their relationship to subsequent mortality. METHODS: Data are from the Health, Aging, and Body Composition study of well-functioning adults aged 70-79 years. A HAI, which ranges from 0 to 10, was constructed at years 1 and 10 of the study including systolic blood pressure, forced expiratory volume, digit symbol substitution test, cystatin C, and fasting glucose. The relationships between the HAI at years 1 and 10 and the change between years and subsequent mortality until year 17 were estimated from Cox proportional hazards models. RESULTS: Two thousand two hundred sixty-four participants had complete data on a HAI at year 1, of these 1,122 had complete data at year 10. HAI scores tended to increase (i.e. get worse) over 9-year follow-up, from (mean [SD]) 4.3 (2.1) to 5.7 (2.1); mean within-person change 1.5 (1.6). After multivariable adjustment, HAI score was related to mortality from year 1 (hazard ratio [95% confidence interval] = 1.17 [1.13-1.21] per unit) and year 10 (1.20 [1.14-1.27] per unit). The change between years was also related to mortality (1.08 [1.02-1.15] per unit change). CONCLUSIONS: HAI scores tended to increase with advancing age and stratified mortality rates among participants remaining at year 10. The HAI may prove useful to understand changes in health with aging.

Racial Differences in Cause-Specific Mortality Between Community-Dwelling Older Black and White Adults.

OBJECTIVES: To understand which causes of death are higher in black than white community-dwelling older adults and determine whether differences in baseline risk factors explain racial differences in mortality. DESIGN: Longitudinal cohort study (Health, Aging, and Body Composition Study). SETTING: Pittsburgh, Pennsylvania; and Memphis, Tennessee. PARTICIPANTS: Black and white men and women aged 70 to 79 during recruitment (N=3,075; 48% men, 42% black) followed for a median of 13 years. MEASUREMENTS: A committee of physicians adjudicated cause of death, which was categorized as cardiovascular disease (CVD), stroke, cancer, dementia, pulmonary, infection, kidney, or other causes. Using competing risks regression, we examined whether known risk factors at baseline (demographic characteristics, smoking, body mass index, chronic diseases, physical function, cognition) could explain racial differences in cause-specific mortality risk. RESULTS: During follow-up, 1,991 (65%) participants died. Black participants died at higher rates from cancer (hazard ratio (HR)=1.36, 95% confidence interval (CI)=1.14-1.63), kidney disease (HR=2.09, 95% CI=1.16-3.74), stroke (HR=1.31, 95% CI=0.98-1.76); and CVD (HR=1.16, 95% CI=0.98-1.37). Poorer physical and cognitive performance at baseline among black participants explained most of the racial difference in risks of dying from kidney disease, stroke, and CVD but not cancer. When examining types of cancer deaths, black participants died at higher rates from multiple myeloma, pancreatic cancer, and prostate cancer, which baseline risk factors did not explain either. CONCLUSION: Factors contributing to poorer physical and cognitive performance in similarly aged black men and women could be targets to reduce excess mortality from CVD, stroke, and kidney disease. More work is needed to identify factors contributing to cancer mortality disparities.

Low blood pressure levels for fall injuries in older adults: the Health, Aging and Body Composition Study.

Fall injuries cause morbidity and mortality in older adults. We assessed if low blood pressure (BP) is associated with fall injuries, including sensitivity analyses stratified by antihypertensive medications, in community-dwelling adults from the Health, Aging and Body Composition Study (N = 1819; age 76.6 ± 2.9 years; 53% women; 37% black). Incident fall injuries (N = 570 in 3.8 ± 2.4 years) were the first Medicare claims event from clinic visit (7/00-6/01) to 12/31/08 with an ICD-9 fall code and non-fracture injury code, or fracture code with/without a fall code. Participants without fall injuries (N = 1249) were censored over 6.9 ± 2.1 years. Cox regression models for fall injuries with clinically relevant systolic BP (SBP; ≤ 120, ≤ 130, ≤ 140, > 150 mmHg) and diastolic BP (DBP; ≤ 60, ≤ 70, ≤ 80, > 90 mmHg) were adjusted for demographics, body mass index, lifestyle factors, comorbidity, and number and type of medications. Participants with versus without fall injuries had lower DBP (70.5 ± 11.2 vs. 71.8 ± 10.7 mmHg) and used more medications (3.8 ± 2.9 vs. 3.3 ± 2.7); all P < 0.01. In adjusted Cox regression, fall injury risk was increased for DBP ≤ 60 mmHg (HR = 1.25; 95% CI 1.02-1.53) and borderline for DBP ≤ 70 mmHg (HR = 1.16; 95% CI 0.98-1.37), but was attenuated by adjustment for number of medications (HR = 1.22; 95% CI 0.99-1.49 and HR = 1.12; 95% CI 0.95-1.32, respectively). Stratifying by antihypertensive medication, DBP ≤ 60 mmHg increased fall injury risk only among those without use (HR = 1.39; 95% CI 1.02-1.90). SBP was not associated with fall injury risk. Number of medications or underlying poor health may account for associations of low DBP and fall injuries.

A novel healthy blood pressure phenotype in the Long Life Family Study.

BACKGROUND: Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors. METHODS: We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32-88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between -1.5 and -0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP. RESULTS: Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components). CONCLUSION: In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity.

Air pollutants may be environmental risk factors in chronic rhinosinusitis disease progression.

BACKGROUND: Little is known about the role of environmental exposures in the pathophysiology of chronic rhinosinusitis (CRS). In this study, we measured the impact of air pollutants (particulate matter 2.5 [PM2.5 ] and black carbon [BC]) on CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP). METHODS: Spatial modeling from pollutant monitoring sites was used to estimate exposures surrounding residences for patients meeting inclusion criteria (total patients, n = 234; CRSsNP, n = 96; CRSwNP, n = 138). Disease severity outcome measures included modified Lund-Mackay score (LMS), systemic steroids, number of functional endoscopic sinus surgeries (FESS), and 22-item Sino-Nasal Outcome Test (SNOT-22) score. PM2.5 and BC exposures were correlated with outcome measures. RESULTS: Mean PM2.5 and BC findings were not significantly different between CRSwNP and CRSsNP patients or patients with and without asthma. Among those with CRSsNP, PM2.5 was significantly associated with undergoing FESS. For each unit increase in PM2.5 , there was a 1.89-fold increased risk in the proportion of CRSsNP patients who required further surgery (p = 0.015). This association was not identified in CRSwNP patients (p = 0.445). BC was also significantly associated with SNOT-22 score in the CRSsNP group. For each 0.1-unit increase in BC, there was a 7.97-unit increase in SNOT-22 (p = 0.008). A similar, although not significant, increase in SNOT-22 was found with increasing BC in the CRSwNP group (p = 0.728). CONCLUSION: Air pollutants correlate with CRS symptom severity that may be influenced by exposure levels, with a more pronounced impact on CRSsNP patients. This study is the first to demonstrate the possible role of inhalant pollutants in CRS phenotypes, addressing a critical knowledge gap in environmental risk factors for disease progression.

The association of air pollutants and allergic and nonallergic rhinitis in chronic rhinosinusitis.

BACKGROUND: There has been little investigation regarding air quality and rhinitis in the pathophysiology of upper airway disease. In this study, we assessed the impact of inhalant pollutants (particulate matter 2.5 [PM2.5 ] and black carbon [BC]) on allergic rhinitis and chronic rhinosinusitis (CRS) disease severity. METHODS: CRS patients with nasal polyps (CRSwNP) and without polyps (CRSsNP) were identified. Spatial modeling from pollutant monitoring sites was used to estimate exposures for patients meeting the inclusion criteria (total, n = 125; CRSsNP, n = 67; CRSsNP, n = 58). Skin-prick, intradermal dilutional, and in-vitro testing methods were utilized to determine aeroallergen sensitization. Disease severity indicators were measured by modified Lund-Mackay score (LMS), the 22-item Sino-Nasal Outcome Test (SNOT-22), systemic steroid therapy, and number of functional endoscopic sinus surgeries (FESS). RESULTS: Thirty-six percent (n = 45) of patients who described rhinitis symptoms demonstrated no reactivity to aeroallergen testing. Sixty-four percent (n = 80) tested positive for at least 1 allergen, with no differences found between CRSsNP and CRSwNP (62.1% vs 67.2%). There were significant differences in air pollutants between patients testing negative and positive for allergies (nonallergic vs allergic: PM2.5 , 11.32 vs 11.07 µg/m3 , p = 0.030; BC, 0.81 vs 0.76 absorbance, p =0.044). Nonallergic CRSwNP demonstrated higher PM2.5 compared with allergic counterparts (11.48 vs 11.09 µg/m3 , p = 0.032). A similar pattern was observed with BC (0.82 vs 0.75 absorbance, p = 0.017). In CRSsNP, BC correlated significantly with SNOT-22 (r = 0.55, p = 0.042). CONCLUSION: Our results suggest that small inhalant pollutants may contribute to nonallergic symptomatology in patients with and without nasal polyps. Regardless of allergy status, BC may play a role in CRS symptom severity.

Partial meniscectomy is associated with increased risk of incident radiographic osteoarthritis and worsening cartilage damage in the following year.

OBJECTIVES: To assess whether partial meniscectomy is associated with increased risk of radiographic osteoarthritis (ROA) and worsening cartilage damage in the following year. METHODS: We studied 355 knees from the Osteoarthritis Initiative that developed ROA (Kellgren-Lawrence grade ≥ 2), which were matched with control knees. The MR images were assessed using the semi-quantitative MOAKS system. Conditional logistic regression was applied to estimate risk of incident ROA. Logistic regression was used to assess the risk of worsening cartilage damage in knees with partial meniscectomy that developed ROA. RESULTS: In the group with incident ROA, 4.4 % underwent partial meniscectomy during the year prior to the case-defining visit, compared with none of the knees that did not develop ROA. All (n = 31) knees that had partial meniscectomy and 58.9 % (n = 165) of the knees with prevalent meniscal damage developed ROA (OR = 2.51, 95 % CI [1.73, 3.64]). In knees that developed ROA, partial meniscectomy was associated with an increased risk of worsening cartilage damage (OR = 4.51, 95 % CI [1.53, 13.33]). CONCLUSIONS: The probability of having had partial meniscectomy was higher in knees that developed ROA. When looking only at knees that developed ROA, partial meniscectomy was associated with greater risk of worsening cartilage damage. KEY POINTS: • Partial meniscectomy is a controversial treatment option for degenerative meniscal tears. • Partial meniscectomy is strongly associated with incident osteoarthritis within 1 year. • Partial meniscectomy is associated with increased risk of worsening cartilage damage.

Slow gait, white matter characteristics, and prior 10-year interleukin-6 levels in older adults.

OBJECTIVE: To examine the relationship between gait speed and prior 10 years interleukin-6 (IL-6) burden in older adults. We then assessed whether white matter characteristics influence this relationship. METHODS: In 179 community-dwelling older adults, gait speed was assessed on an automated walkway and serum IL-6 was assayed on ELISA. Concurrently, white matter characteristics were assessed on MRI by quantifying volume of white matter hyperintensities (WMH), a marker of small vessel disease, and normal-appearing white matter on fractional anisotropy (NAWM-FA), a marker of axonal integrity. IL-6 was assayed at regular intervals at gait assessment and over the prior 10 years and estimates of sustained 10-year IL-6 exposure and the rate of change in IL-6 over 10 years were obtained. Multivariate linear regressions were used to examine the relationships among sustained IL-6 exposure, rate of change in IL-6, gait speed, and white matter characteristics. RESULTS: In this sample (age 83 years, 58% female, 41% black, gait speed 0.9 m/s), higher sustained IL-6 levels, but not the rate of change in IL-6 or IL-6 at gait assessment, was significantly related to slower gait (ß = -0.27, p < 0.001) and to higher WMH (ß = 0.23, p = 0.002), but not NAWM-FA, withstanding covariate adjustments. WMH accounted for 30% attenuation in the relationship between higher sustained IL-6 levels and slower gait speed (p = 0.043) in the mediation analyses. CONCLUSIONS: Sustained exposure to high IL-6 over 10 years rather than the rate of change in IL-6 or an isolated high IL-6 level may adversely affect gait speed by influencing cerebral WMH.

Trajectories of function and biomarkers with age: the CHS All Stars Study.

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.