A roadmap to build a phenotypic metric of ageing: insights from the Baltimore Longitudinal Study of Aging.

Over the past three decades, considerable effort has been dedicated to quantifying the pace of ageing yet identifying the most essential metrics of ageing remains challenging due to lack of comprehensive measurements and heterogeneity of the ageing processes. Most of the previously proposed metrics of ageing have been emerged from cross-sectional associations with chronological age and predictive accuracy of mortality, thus lacking a conceptual model of functional or phenotypic domains. Further, such models may be biased by selective attrition and are unable to address underlying biological constructs contributing to functional markers of age-related decline. Using longitudinal data from the Baltimore Longitudinal Study of Aging (BLSA), we propose a conceptual framework to identify metrics of ageing that may capture the hierarchical and temporal relationships between functional ageing, phenotypic ageing and biological ageing based on four hypothesized domains: body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity. We explored the longitudinal trajectories of key variables within these phenotypes using linear mixed-effects models and more than 10 years of data. Understanding the longitudinal trajectories across these domains in the BLSA provides a reference for researchers, informs future refinement of the phenotypic ageing framework and establishes a solid foundation for future models of biological ageing.

No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque.

BACKGROUND AND AIMS: Increased carotid artery intima-media thickness (IMT) and the presence of plaques have been shown to be predictors of cardiovascular disease. The cardiovascular risk in patients with overt thyroid diseases is related to increased risk of atherosclerosis, but there has been no clear evidence about subclinical disorders. We have assessed whether subclinical thyroid dysfunction is associated with arterial thickening and plaque. METHODS AND RESULTS: The SardiNIA study is a population-based survey on the Italian island of Sardinia. We reviewed data from 5815 subjects (aged 14-102 years), none of whom had overt hyperthyroidism or hypothyroidism or was taking thyroid medication. Serum thyrotropin (TSH), free thyroxine, together with carotid ultrasound IMT and the presence of common carotid plaques were analysed in all subjects. Possible association of IMT and carotid plaques with thyroid parameters was evaluated by univariate and multivariate analyses. IMT was significantly associated with age, sex, smoking, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol, pulse pressure (PP), history of arterial hypertension, diabetes, and previous cardiovascular events (p = 0.001 or lower, R(2) = 0.47). Carotid plaques were predicted by age, sex, LDL, PP, history of diabetes, previous cardiovascular events, and the use of statins (p = 0.029 or lower). Thyroid hormone was not predictive of carotid atherosclerosis when adjusted for confounders. CONCLUSION: Thyroid hormone is not associated with increased IMT or with the presence of carotid artery plaque. Our data do not support the idea that treating subclinical disorders might help to prevent arterial remodelling or carotid atherosclerosis.

The relationship between visceral adiposity and left ventricular diastolic function: results from the Baltimore Longitudinal Study of Aging.

BACKGROUND AND AIMS: It is unclear whether subcutaneous and visceral fat are differentially correlated to the decline in left ventricular (LV) diastolic function with aging. This study sought to examine the hypothesis that age-related changes in the regional fat distribution account for changes in LV diastolic function and to explore potential mediators of this association. METHODS AND RESULTS: In this cross-sectional study, we evaluated 843 participants of the Baltimore Longitudinal Study of Aging with echocardiogram, dual-energy X-ray absorptiometry (DEXA), abdominal computed tomography (CT) and blood tests performed at the same visit. LV diastolic function was assessed by parameters of LV relaxation (E/A ratio, Em and Em/Am ratio) and LV filling pressures (E/Em ratio). Total body fat was computed by DEXA, while visceral and subcutaneous fat were determined from abdominal CT. In multivariate models adjusted for demographics, cardiovascular risk factors, antihypertensive medications, physical activity and LV mass, both visceral and subcutaneous fat were associated with LV diastolic dysfunction. When both measures of adiposity were simultaneously included in the same model, only visceral fat was significantly associated with LV diastolic dysfunction. Triglycerides and sex-hormone binding globulin, but not adiponectin and leptin, were found to be significant mediators of the relationship between visceral fat and LV diastolic function, explaining 28-47% of the association. Bootstrapping analyses confirmed the significance of these findings. CONCLUSIONS: Increased visceral adiposity is associated with LV diastolic dysfunction, possibly through a metabolic pathway involving blood lipids and ectopic fat accumulation rather than adipokines.

Early contribution of arterial wave reflection to left ventricular relaxation abnormalities in a community-dwelling population of normotensive and untreated hypertensive men and women.

We examined the contribution of arterial wave reflection to early abnormalities in left ventricular relaxation, whether this association was modified by gender or hypertension and the role of reflected wave timing and amplitude. We studied a cohort of normotensive and untreated essential hypertensive Taiwanese participants (675 men, 601 women, mean age 52 years). Doppler flow and applanation tonometry were performed to assess carotid-femoral pulse wave velocity (PWV) and augmentation index (AI). Diastolic parameters including the ratio between the peak velocity of early and late diastolic mitral inflow (E/A), E-deceleration time and left atrial (LA) diameter were measured by echocardiography. In multivariate models predicting E/A, women were more likely to have lower E/A than men (ß=-0.08, P<0.001). AI was significantly associated with lower E/A in both men (ß=-0.09, P=0.005) and women (ß=-0.12, P<0.001) independent of PWV. Inclusion of AI in the overall model reduced the gender difference in E/A by 61% and rendered it nonsignificant. There was a significant interaction between AI and hypertension (P=0.02). The inverse association between AI and E/A was significant only in normotensive men and women, and only for the amplitude but not timing of the reflected wave. In conclusion, the contribution of wave reflection to left ventricular diastolic dysfunction was independent of arterial stiffness, more pronounced in normotensive individuals and explained a significant portion of the gender difference in diastolic function.