Prospective associations of plasma growth differentiation factor 15 with physical performance and cognitive functions in older adults

Background Growth differentiation factor 15 (GDF15) has been associated with several age-related disorders, but its associations with functional abilities in community-dwelling older adults are not well studied. Methods The study was a secondary analysis on 1096 community-dwelling older adults (aged 69 to 94 years) recruited from the Multidomain Alzheimer’s Preventive Trial. Plasma GDF15 was measured one year after participants’ enrolment. Annual data of physical performance (grip strength and short physical performance battery [SPPB]) and global cognitive functions (mini-mental state examination [MMSE] and a composite cognitive score) were measured for four years. Adjusted mixed-effects linear models were performed for cross-sectional and longitudinal association analyses. Results A higher GDF15 was cross-sectionally associated with a weaker grip strength (β = -1.1E-03, 95%CI [-2.0E-03, -1.5E-04]), a lower SPPB score (β = -3.1E-04, 95%CI [-5.4E-04, -9.0E-05]) and worse cognitive functions (β = -2.4E-04, 95%CI [-3.3E-04, -1.6E-04] for composite cognitive score; β = -4.0E-04, 95%CI [-6.4E-04, -1.6E-04] for MMSE). Participants with higher GDF15 demonstrated greater longitudinal declines in SPPB (β = -1.0E-04, 95%CI [-1.7E-04, -2.0E-05]) and composite cognitive score (β = -2.0E-05, 95%CI [-4.0E-05, -3.6E-06]). The optimal initial GDF15 cutoff values for identifying participants with minimal clinically significant decline after one year were 2189 pg/mL for SPPB (AUC: 0.580) and 2330 pg/mL for composite cognitive score (AUC: 0.587). Conclusions Plasma GDF15 is cross-sectionally and longitudinally associated with lower-limb physical performance and global cognitive function in older adults. Circulating GDF15 alone has limited capacity of discriminating older adults who will develop clinically significant functional declines.

Epigenetic Age Acceleration and Change in Frailty in MOBILIZE Boston

Age-associated changes in DNA methylation have been implicated as one mechanism to explain the development of frailty, however previous cross-sectional studies of epigenetic age acceleration (eAA) and frailty have had inconsistent findings. Few longitudinal studies have considered the association of eAA with change in frailty. We sought to determine the association between eAA and change in frailty in the MOBILIZE Boston cohort. Participants were assessed at two visits 12-18 months apart. Intrinsic, extrinsic, GrimAge, and PhenoAge eAA were assessed from whole blood DNA methylation at baseline using the Infinium 450k array. Frailty was assessed by a continuous frailty score based on the frailty phenotype and by frailty index (FI). Analysis was by correlation and linear regression with adjustment for age, sex, smoking status, and BMI. 395 participants with a frailty score and 431 with a FI had epigenetic and follow-up frailty measures. For the frailty score and FI cohorts, respectively, mean (SD) ages were 77.8 (5.49) and 77.9 (5.47), 232 (58.7%) and 257 (59.6%) were female. All participants with epigenetic data identified as white. Baseline frailty score was not correlated with intrinsic or extrinsic eAA, but was correlated with PhenoAge and, even after adjustment for covariates, GrimAge. Baseline FI was correlated with extrinsic, GrimAge, and PhenoAge eAA with and without adjustment. No eAA measure was associated with change in frailty, with or without adjustment. Our results suggest that no eAA measure was associated with change in frailty. Further studies should consider longer periods of follow-up and repeated eAA measurement.

Physical activity, body mass index, and blood progranulin in older adults: cross-sectional associations in the MAPT study

Physical activity (PA) has been shown to moderate the negative effects of obesity on pro-inflammatory cytokines but its relationship with the adipokine progranulin (PGRN) remains poorly investigated. This study aimed to examine the cross-sectional main and interactive associations of body mass index (BMI) and PA level with circulating PGRN in older adults. Five-hundred and twelve subjects aged 70 years and over involved in the Multidomain Alzheimer Prevention Trial (MAPT) Study who underwent plasma PGRN measurements (ng/ml) were included. Self –reported PA levels were assessed using questionnaires. People were classified into three BMI categories: normal weight, overweight or obesity. Further categorization using PA tertiles was used to define highly active, moderately active and low active individuals. Multiple linear regressions were performed in order to test the associations of BMI, PA level, and their interaction with PGRN levels. Multiple linear regressions adjusted by age, sex, diabetes mellitus status, total cholesterol, creatinine level and MAPT group demonstrated significant interactive associations of BMI status and continuous PA such that in people without obesity, higher PA levels were associated with lower PGRN concentrations, while an opposite pattern was found in individuals with obesity. In addition, continuous BMI was positively associated with circulating PGRN in highly active individuals but not in their less active peers. This cross-sectional study demonstrated reverse patterns in older adults with obesity compared to those without obesity regarding the relationships between PA and PGRN levels. Longitudinal and experimental investigations are required to understand the mechanisms that underlie the present findings.

Plasma angiopoietin-like protein 2 levels and mortality risk among younger-old Japanese people: a population-based case-cohort study

Aging is important medical and social problem. Excessive angiopoietin-like protein (ANGPTL)-2 signaling causes chronic tissue inflammation, promoting development and progression of aging-related diseases. Moreover, circulating ANGPTL2 levels reportedly predict risk of some aging-related diseases and subsequent death. However, there are as yet no reports of whether circulating ANGPTL2 levels predict vital prognosis in younger-old, community-dwelling populations. This study investigated associations between plasma ANGPTL2 levels and all-cause and specific-cause mortality in this population. The case-cohort study was abstracted from an on-going, age-specific prospective cohort study: the New Integrated Suburban Seniority Investigation Project. This project enrolled 3073 participants aged 64 years at the beginning of the investigation from 1996 through 2005. A sub-cohort of 714 randomly sampled participants plus 387 cases representing deceased participants followed through 2015 underwent survival analysis. Plasma ANGPTL2 concentrations were positively associated with >80% and 100% higher risk of all-cause mortality and cancer mortality, respectively, after adjustment for gender, smoking, alcohol consumption, walking time, sleep duration, caloric intake, medical status, disease history, BMI, and triglyceride, creatinine, uric acid, and high sensitivity C-reactive protein levels. More robust association between ANGPTL2 levels and all-cause and cancer mortality was seen in subjects with either frailties or with lifestyles of heavier drinking or current smoking. Elevated plasma ANGPTL2 levels are associated with high all-cause and cancer mortality in a community-dwelling sample of younger-old adults. These findings expand our knowledge of human aging and associated diseases.

Association of zinc intake with risk of impaired physical function and frailty among older adults

Background Zinc could be a target nutrient in the prevention of physical impairment and frailty in older adults due to its anti-inflammatory/antioxidant properties. However, prospective studies evaluating this inquiry are scarce. Thus, we aimed to assess the association between zinc intake and impaired lower-extremity function (ILEF) and frailty among community-dwelling older adults. Methods We examined 2,963 adults aged ≥60 years from the Seniors-ENRICA cohort. At baseline (2008–2010) and subsequent follow-up (2012), zinc intake (mg/d) was estimated with a validated computerized face-to-face diet history and adjusted for total energy intake. From 2012 to 2017, the occurrence of ILEF was ascertained with the Short Physical Performance Battery, and of frailty according to the Fried phenotype criteria. Analyses were conducted using Cox proportional hazard models adjusted for relevant confounders, including lifestyle, comorbidity, and dietary factors. Results During follow-up, we identified 515 incident cases of ILEF and 241 of frailty. Compared to participants in the lowest tertile of zinc intake (3.99–8.36 mg/d), those in the highest tertile (9.51–21.2 mg/d) had a lower risk of ILEF [fully-adjusted hazard ratio (95% confidence interval): 0.75 (0.58–0.97); p for trend: 0.03] and of frailty [0.63 (0.44–0.92); p for trend: 0.02]. No differences in the association were seen by strata of socio-demographic and lifestyle factors. Conclusions Higher zinc intake was prospectively associated with a lower risk of ILEF and frailty among older adults, suggesting that adequate zinc intake, that can be achieved through a healthy diet, may help preserve physical function and reduce the progression to frailty.

Interactions between weight loss and plasma neurodegenerative markers for determining cognitive decline among community-dwelling older adults

This study aimed to investigate the interaction between weight loss (WL) and plasma amyloid-β42/40 (Aβ42/40), neurofilament light chain (NfL), progranulin, and their association with cognitive decline over time among older adults. This 5-year observational approach included 470 participants from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8y (SD=4.5), 59.4% women. WL was defined as ≥5% decrease over the first year. Biomarkers were measured at 12 months. Cognitive function was assessed yearly from 12 months onwards by Mini-Mental State Examination (MMSE); Clinical Dementia Rating sum of boxes (CDR-SB); a composite score based on Category Naming Test, Digit Symbol Substitution Test, ten MMSE orientation items (MMSEO) and Free and total recall of the Free and Cued Selective Reminding test; and these tests individually. Twenty-seven participants (5.7%) presented WL. In adjusted analyses, combined WL+lower Aβ42/40 (≤0.103, lowest quartile) was related with more pronounced 4-year cognitive decline according to CDR-SB (p<0.0001) and MMSEO (p=0.021), compared to non-WL+higher Aβ42/40. WL+higher NfL (>94.55pg/mL, highest quartile) or progranulin (>38.4ng/mL, three higher quartiles) were related with higher cognitive decline according to CDR-SB, MMSE, MMSEO and composite score (all p<0.03), compared to non-WL+lower NfL or higher progranulin. Regrouping progranulin quartiles (Q1-Q3 vs. Q4) revealed higher cognitive decline among the WL+lower progranulin group compared to non-WL+lower progranulin. In conclusion, 1-year WL was associated with subsequent higher 4-year cognitive decline among older adults presenting low Aβ42/40 or high NfL. Future studies combining plasma biomarker assessments and body weight surveillance may be useful for identifying people at risk of cognitive impairment.

Relationship between five Epigenetic Clocks, Telomere Length and Functional Capacity assessed in Older Adults: Cross-sectional and Longitudinal Analyses

DNA methylation age acceleration (DNAmAA, derived from an epigenetic clock) and relative leukocyte telomere length (rLTL) are widely accepted biomarkers of aging. Nevertheless, it is still unclear which aspects of aging they represent best. Here we evaluated longitudinal associations between baseline rLTL and DNAmAA (estimated with 7-CpG clock) and functional assessments covering different domains of aging. Additionally, we made use of cross-sectional data on these assessments and examined their association with DNAmAA estimated by five different DNAm age measures. Two-wave longitudinal data was available for 1,083 participants of the Berlin Aging Study II (BASE-II) who were re-examined on average 7.4 years after baseline as part of the GendAge study. Functional outcomes were assessed with Fried’s frailty score, Tinetti mobility test, falls in the past 12 months (yes/no), Finger-floor distance, Mini Mental State Examination (MMSE), Center for Epidemiologic Studies Depression Scale (CES-D), Activities of Daily Living (ADL), Instrumented ADL (IADL) and Mini Nutritional Assessment (MNA). Overall, we found no evidence for an association between the molecular biomarkers measured at baseline, rLTL and DNAmAA (7-CpG clock), and functional assessments assessed at follow-up. Similarly, a cross-sectional analyses of follow-up data did also not show evidence for associations of the various DNAmAA measures (7-CpG clock, Horvath’s clock, Hannum’s clock PhenoAge, and GrimAge) with functional assessments. In conclusion, neither rLTL nor 7-CpG DNAmAA were able to predict impairment in the analyzed assessments over a ~7-year time-course. Similarly, DNAmAA estimated from five epigenetic clocks was not a good cross-sectional marker of health deterioration either.

Effect of FOXO3 and Air Pollution on Cognitive Function: A Longitudinal Cohort Study of Older Adults in China from 2000 to 2014

Forkhead Box O 3 (FOXO3) genotype is strongly associated with human longevity and may be protective against neurodegeneration. Air pollution is a risk factor for cognitive decline and dementia. We aimed to study the individual and combined effects of FOXO3 and air pollution on cognitive function in a large prospective cohort with up to 14 years of follow-up. We measured cognitive function and impairment using the Mini-Mental State Examination (MMSE). We used tagging SNPs rs2253310, rs2802292, and rs4946936 to identify the FOXO3 gene, of which roughly half of the population had the longevity associated polymorphism. We matched annual average fine particulate matter (PM2.5) concentrations within 1 km^2 grid. We conducted cross-sectional and longitudinal analyses using multivariable linear and logistic regression models and generalized estimating equation. At baseline, carriers of the longevity associated homozygous minor alleles of FOXO3 SNPs had a higher MMSE score than the carriers of homozygous major alleles. In the longitudinal follow-up, carriers of FOXO3 homozygous minor alleles had lower odds of cognitive impairment compared to non-carriers. Higher PM2.5 was associated with a lower MMSE score and higher odds of cognitive impairment. The positive effects of FOXO3 were the strongest in females, older people, and residents in areas with lower air pollution.

Free-living gait cadence measured by wearable accelerometer: a promising alternative to traditional measures of mobility for assessing fall risk

Background Wearable devices have become widespread in research applications, yet evidence on whether they are superior to structured clinic-based assessments is sparse. In this manuscript, we compare traditional, lab-based metrics of mobility with a novel accelerometry-based measure of free-living gait cadence for predicting fall rates. Methods Using negative binomial regression, we compared traditional in-clinic measures of mobility (6-minute gait cadence, speed, and distance, and 4-meter gait speed) with free-living gait cadence from wearable accelerometers in predicting fall rates. Accelerometry data were collected with wrist-worn Actigraphs (GT9X) over 7 days in 432 community-dwelling older adults (aged 77.29±5.46 yrs, 59.1% men, 80.2% White) participating in the Study to Understand Fall Reduction and Vitamin D in You (STURDY). Falls were ascertained using monthly calendars, quarterly contacts, and ad-hoc telephone reports. Accelerometry-based free-living gait cadence was estimated with the Adaptive Empirical Pattern Transformation algorithm. Results Across all participants, free-living cadence was significantly related to fall rates; every 10 steps/min. higher cadence was associated with a 13.2% lower fall rate (p=0.036). Clinic-based measures of mobility were not related to falls (p>0.05). Among higher-functioning participants (cadence ≥100 steps/min.), every 10 steps/min higher free-living cadence was associated with a 27.7% lower fall rate (p=0.01). In participants with slow baseline gait (gait speed <0.8 m/s), all metrics were significantly associated with fall rates. Conclusion Data collected from biosensors in the free-living environment may provide a more sensitive indicator of fall risk than in-clinic tests, especially among higher functioning older adults who may be more responsive to intervention.

Association between Mediterranean diet and functional status in older adults: a longitudinal study based on the Washington Heights Inwood Community Aging Project (WHICAP)

Background Current evidence on the association between Mediterranean diet (MeDi) intake and activities of daily living (ADL) is limited and inconsistent in older adults. Methods This study included 1696 participants aged ≥ 65 years in the Washington Heights-Inwood Community Aging Project (WHICAP) study. The MeDi score was calculated based on data collected from the Willett’s semi-quantitative food frequency questionnaire. The multivariable-adjusted Cox regression model was applied to examine the association of MeDi score with risks of disability in basic (BADL) and instrumental ADL (IADL), as well as the overall ADL (B-IADL). Results 832 participants with incident ADL disability were identified over a median follow-up of 5.39 years. The continuous MeDi score was significantly associated with decreased risk of disability in B-IADL (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.99, p = 0.018) in a model adjusted for age, sex, race/ethnicity, educational level, and dietary calories intake but was no longer significant after additionally adjusted for multiple comorbidities and physical activities (0.97 [0.93, 1.01], p = 0.121). The continuous MeDi score was significantly associated with decreased risk of disability in B-IADL (0.92 [0.85, 1.00], p = 0.043) and BADL (0.90 [0.82, 0.99], p = 0.030) in non-Hispanic Whites, but not in non-Hispanic Blacks and Hispanics (p > 0.05 for all). Conclusions Higher MeDi score was associated with decreased risk of ADL disability, particularly in non-Hispanic Whites.