Biomarkers and Correlates of Aging

Abstract

The rapid aging of the global population, often accompanied by disabilities and various age-related diseases, is becoming a major public health burden (WHO 2015). Stimulating healthy aging is therefore of tremendous importance. However, substantial inter-individual variation in aging and aging-associated morbidity remain in individuals of the same chronological age, pointing towards markedly different rates of biological aging (Ben-Shlomo et al. 2014; Hamczyk et al. 2020; Medina-Lezama et al. 2018; Patel et al. 2015; Yusuf et al. 2020). The determinants of biological aging are largely unknown. Elucidation of the factors underlying interindividual differences in biological aging and delineation of their precise contributions are essential for the development of individualized approaches to promoting healthy aging. <br /> CVDs are the leading causes of morbidity and mortality worldwide (CollaboratorsGBDCoD 2017; North and Sinclair 2012). As with other age-related diseases, inter-individual variation in cardiovascular aging and associated morbidity in individuals of the same chronological age, points towards markedly different rates of biological aging (Ben-Shlomo et al. 2014; Hamczyk et al. 2020; Medina-Lezama et al. 2018; Patel et al. 2015; Yusuf et al. 2020). Whether and to what extent different cardiovascular risk factors and cardiovascular aging markers contribute to different rates of biological aging, estimated as DNAm age acceleration, remains largely unknown. Therefore, in study I, I examined whether classical cardiovascular risk factors involving multiple domains as well as novel quantitative markers of cardiovascular aging, including arterial stiffness, endothelial function and systemic hemodynamics, have consistent and independent effects on various epigenetic age accelerations across a wide age range in the general population. Using a population-based approach with extensive deep-(endo)phenotype data on nearly 3,500 participants aged 30 years and above (30 - 95 years old), we found that multiple cardiovascular risk factors, arterial stiffness and hemodynamics were consistently and independently associated with DNAm age acceleration estimators, and could contribute to different rates of biological aging. <br /> Lipid metabolites are essential components of biological membranes and signaling molecules, and the lipidome represents an individual's biological state (Hahn et al. 2017). Certain lipid profiles have been associated with human longevity and lifespan (Gonzalez-Covarrubias et al. 2013; Montoliu et al. 2014; Vaarhorst et al. 2011), yet systematic studies assessing which lipid species across different classes and compositions influence biological aging are lacking. The heterogeneous chemical structure of lipids poses challenges for their accurate quantification, and until now only a few lipid species have been investigated in relation to aging and age-related health outcomes. Therefore, in study II, I investigated 14 complex lipid classes, covering 964 molecular species and 267 one-fatty-acid-tail compositions, in relation to different rates of epigenetic aging – a proxy for biological aging – across the adult lifespan on the first 4181 participants of the Rhineland Study. We present the largest and most comprehensive study to date showing that across neutral lipids, phospholipids, and sphingolipids, different complex lipid species are associated with different rates of biological aging, with the effects mainly depending on lipid class and fatty acid chain length. These findings offer novel potential targets for promoting healthy aging. <br /> Telomeres are DNA-protein complexes located at the end of chromosomes and have been proposed as another hallmark of biological aging as they shorten with age and each cell division, thereby triggering cellular senescence (Blackburn et al. 2015; O'Sullivan and Karlseder 2010). Emerging evidence has suggested that telomere-triggered cellular senescence might contribute to the pathogenesis of endothelial and hemodynamic dysfunction (Maeda et al. 2019; Minamino et al. 2001; Minamino et al. 2002). However, cross-sectional studies have yielded conflicting results regarding the associations between LTL and vascular phenotypes, and the temporality of associations remains unclear. Therefore, in study III, I assessed the association of measured, genetically predicted LTL, and ΔLTL with vascular phenotypes, including endothelial function, hemodynamics, arterial stiffness, blood pressure, across the adult lifespan in a population-based study. Using a hypothesis-driven approach, we observed that both measured and genetically predicted LTL, as well as ΔLTL, were all consistently associated with endothelial function and hemodynamic traits, but not with markers of arterial stiffness. Importantly, the robust association between a validated PRS of LTL and different quantitative markers of cardiovascular function support a causal role for telomere shortening in the pathogenesis of endothelial and cardiac dysfunction. These findings implicate telomere-triggered cell senescence in the mechanistic pathways underlying cardiovascular dysfunction and CVDs. Additionally, ΔLTL was associated with endothelial function, cardiac index, and systemic vascular resistance index. This suggests that telomere shortening itself, rather than genetically or non-genetically determined, contributes to cardiovascular dysfunction (Werner et al. 2019; Yeh et al. 2019). <br /> In summary, in this thesis I presented novel evidence about the precise contributions of cardiovascular phenotypes and complex lipids to different rates of biological aging, and the role of telomere-triggered cell senescence in cardiovascular aging. In a progressively older world population, these findings could provide the basis for the development of more potent anti-aging approaches focused on biological aspect of the aging process.