Published papers

© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. Introduction: Mobility disability is a powerful indicator of poor health in older adults. The biological and pathophysiological mechanism underlying the development of mobility disability remains unknown. This study conducted a data-driven discovery phase investigation to identify plasma proteins that predict the incidence of mobility disability in community-dwelling older adults without mobility disability at baseline. Methods: We investigated 660 women and men, aged 71.9 ± 6.0 (60–94) years, who participated in the Invecchiare in Chianti, “Aging in the Chianti Area” study and completed the 400-m walk at fast pace (400-m walk) at enrollment. Median follow-up time was 8.57 [interquartile, 3.20–9.08] years. SOMAscan technology was used to measure 1,301 plasma proteins at enrollment. The incident of mobility disability was defined as inability to complete the 400-m walk. Protein-specific Cox proportional hazard model was adjusted for sex, age, and other important covariates. Results: Plasma levels of 75 proteins predicted mobility disability (p '.05). Significant proteins were enriched for the KEGG “PI3K-Akt signaling,” “phagosomes,” and “cytokine–cytokine receptor interaction” pathways. After multiple comparison adjustment, plasma cathepsin S (CTSS; hazard ratio [HR] 1.33, 95% CI: 1.17, 1.51, q = 0.007), growth/differentiation factor 15 (GDF15; HR: 1.45, 95% CI: 1.23, 1.72, q = 0.007), and thrombospondin-2 (THBS2; HR: 1.44, 95% CI: 1.22, 1.69, q = 0.007) remained significantly associated with high risk of losing mobility. Conclusion: CTSS, GDF15, and THBS2 are novel blood biomarkers associated with new mobility disability in community-dwelling individuals. Overall, our analysis suggests that cellular senescence and inflammation should be targeted for prevention of mobility disability.

Background and objective: Physical activity (PA) confers protection to individuals from the risk of death. However, in the very old, the dose-response relationship between PA and all-cause mortality and the possible biological mediators of this association are less known. We investigated whether PA predicts 6-year all-cause mortality and what biomarkers mediate the association. Design: Prospective cohort data from the Tokyo Oldest Old Survey on Total Health study. Setting: Community-dwelling population. Participants: A total of 441 women and men aged over 85 years. Measurements: Questionnaire-based PA was assessed at baseline and 3-year and 6-year follow-up visits. Survival status was confirmed up to the 6-year follow-up visit (153 deaths, 34.7%). Data of plasma albumin, cholinesterase, NT-proBNP, interleukin-6, cystatin C, and HbA1c levels were collected. For mediation analysis for survival analysis, we used the baseline PA and biomarkers with Weibull distribution accelerated failure time model and linear regression model adjusted for age, sex, body mass index, smoking, education level, and Mini-Mental State Examination. Results: A curvilinear relationship was observed in the association between baseline PA and all-cause mortality. Compared to the inactive (0 METs*h/week), light amount of PA was associated with a lower risk of mortality. Compared to the highest tertile of PA (11.2 METs*h/week), higher PA did not reduce the risk of death. Circulation levels of albumin and cholinesterase mediated the association between baseline PA and all-cause mortality (proportion mediated, 54%, both; p < 0.05). Conclusions: Compared to completely inactive, light PA reduces the risk of all-cause mortality in the very old population. Mediation analysis suggests that protein synthesis in the liver may mediate the association between PA and all-cause mortality. Further studies are needed to understand the underlying association between PA, nutrition, and death.

Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/ differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65–94 years; women, 52.4%; mean follow-up, 7.0 ± 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of “baseline GDF-15 × time” in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences.

Sarcopenia is one of the primary risk factors for various adverse health events in later life. However, its pathophysiology in the very old population remains unclear. Hence, this study aimed to examine whether plasma free amino acids (PFAAs) correlate with major sarcopenic phenotypes (i.e., muscle mass, muscle strength, and physical performance) in community-dwelling adults aged 85–89 years living in Japan. Cross-sectional data from the Kawasaki Aging Well-being Project were used. We included 133 adults aged 85–89 years. In this study, fasting blood was collected to measure 20 plasma PFAAs. Measures for the three major sarcopenic phenotypes included appendicular lean mass assessed by multifrequency bioimpedance, isometric handgrip strength, and gait speed from a 5 m walk at a usual pace. Furthermore, we used phenotype–specific elastic net regression models adjusted for age centered at 85 years, sex, body mass index, education level, smoking status, and drinking habit to identify significant PFAAs for each sarcopenic phenotype. Higher histidine and lower alanine levels were associated with poor gait speed, but no PFAAs correlated with muscle strength or mass. In conclusion, PFAAs such as plasma histidine and alanine are novel blood biomarkers associated with physical performance in community-dwelling adults aged 85 years or older.

Background: Muscle and bone are physiologically interconnected, but joint changes of muscle and bone with aging, and whether the muscle-bone changes are different by sex and by country has been little studied. We examined longitudinal associations of bone mineral density (BMD) and muscle mass or muscle strength in community-dwelling 65 years or older in the United States and Japan. Methods: The present analytic sample included 1129 women and men from the Baltimore Longitudinal Study of Aging (BLSA) (mean age, 74.5 ± 7.5 years; women, 49.8%) and 1998 women and men from the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) (mean age, 70.0 ± 4.5 years; women, 51.4%). Median follow-up was 4.6 (min-max, 0–15.4) years in the BLSA and 4.0 (min-max, 0–13.4) years in the NILS-LSA. We selected visits at which participants had BMD (whole body, pelvic, femoral neck, trochanter, and Ward's triangle BMDs) and muscle mass [appendicular lean mass, (ALM)] measured by DXA scan. In each bone site, we ran cohort-specific bivariate linear mixed-effects models adjusted for baseline age, sex, body height, body weight, fat mass, education year, and smoking status. Race was an additional adjustment in the BLSA. Additionally, we performed sex-specific analyses. Results: In the BLSA, the rate of change in ALM positively correlated with the rate of change in the whole body (rho = 0.30, P < 0.0001) and pelvic BMD (rho = 0.24, P < 0.0001), but not in trochanter, femoral neck, or Ward's triangle BMD (P > 0.05). In the NILS-LSA, ALM positively correlated with the rate of change in all bone sites (rho ranged from 0.20 to 0.71, P < 0.01). In women, ALM positively correlated with the rate of change in all bone sites in both cohorts (in the NILS-LSA, rho ranged from 0.35 to 0.91, P < 0.01; in the BLSA, rho ranged from 0.26 to 0.56, P < 0.05) except for femoral neck BMD in the BLSA. In men, ALM positively correlated with pelvic, trochanter, and Ward's triangle BMD in the NILS-LSA (rho ranged from 0.45 to 0.68, P < 0.0001), and whole body and trochanter BMD in the BLSA (both, rho = 0.20, P < 0.05). Conclusions: Muscle loss co-occurred with bone loss in both cohorts, but the association in the NILS-LSA tended to be stronger than in the BLSA, and the association was higher in women than in men, implying that the association may differ by sex and country.

© 2018 Purpose: Acceleration capacity affects physical function, but whether it differentially affects men versus women or weak versus strong individuals is less known. We investigated whether knee extension rate of velocity development (RVD, a measure of acceleration) is associated with walking performance independent of peak torque and whether the relationships differ in men versus women and in weak versus strong individuals. Methods: Relationships of RVD with walking performance were assessed in 326 women and 365 men aged 26–96 years enrolled in the Baltimore Longitudinal Study of Aging. Tests included knee extension peak torque and RVD assessed during a 180°·s−1 isokinetic strength test and four walking performance measures (usual-paced and fast-paced 6 m walks and 2.5 min usual-paced and 400 m fast-paced walks). Sex-stratified linear regression models were adjusted for age, race, height, appendicular lean mass, fat mass, peak torque, knee pain, and RVD*peak torque interaction. Results: In men, RVD was not independently associated with any walking performance measure (p > 0.05), and, for the 6 m-usual walk only, there was a significant RVD*peak torque interaction (p < 0.0001). In women, RVD was independently associated with usual-paced walks (p < 0.05) and there were significant RVD ∗ peak torque interactions for all measures. Strength-specific analyses indicated that RVD was most associated with performance among weaker individuals. Conclusion: RVD is associated with walking performance in women, but less in men, and is most related to performance when strength is low. Strategies to accomplish motor tasks may be sex-specific. Future studies are needed to understand the mechanisms underlying such sex differences.