Keywords

Telomere length
Leukocyte telomere length
Brain aging
Cognition
Brain MRI
White matter hyperintensities

1. Introduction

Brain aging is accompanied by typical functional changes manifesting as a global or domain-specific cognitive decline, particularly affecting domains of processing speed, memory, reasoning, and executive functions (Cole et al., 2019). At the molecular level, these cognitive impairments are associated with changes in neurotransmitter levels (Peters, 2006), synaptic losses, dendritic regression, and neuronal cell death (Mattson and Arumugam, 2018, Morrison and Baxter, 2012). At the macrostructural level, a decrease in grey and white matter volume, cortical thinning, ventricular enlargement, decrease in brain weight, and white matter damage are evident in aging (Cole et al., 2019, Peters, 2006). In epidemiological studies, magnetic resonance imaging (MRI) is used to detect and assess the extent of these macro- and microstructural changes as well as vascular lesions in the brain. As accelerated brain aging and its cerebrovascular and cognitive consequences represent a major cause of disability and death in the elderly (Debette et al., 2019), it is essential to understand the relevance of possible causal predictors such as telomere length in this process.

The ends of linear human chromosomes are protected by the nucleoprotein caps containing repeating TTAGGG hexamer sequences called telomeres. During mitosis, the inability of DNA polymerase to complete the replication of chromosomal ends causes telomere attrition (Blackburn et al., 2015). In an individual’s lifetime, telomere attrition mainly occurs during development due to a high number of cell divisions and aging due to a high level of oxidative stress (Blackburn et al., 2015). Leukocyte telomere length (LTL), measured easily in peripheral blood, is correlated with telomere length across most tissues and thus acts as a proxy of telomere length elsewhere in the body (Demanelis et al., 2020).

The role of telomere length and its attrition is widely studied in human aging and aging-related diseases. Many studies found that shorter LTL is associated with an increased risk of cardiovascular diseases (De Meyer et al., 2018, Haycock et al., 2014), Alzheimer’s disease (Blackburn et al., 2015, Forero et al., 2016), as well as all-cause mortality (Wang et al., 2018). In addition, Mendelian randomization studies provided evidence for a causal relationship between telomere length and Alzheimer’s disease (Zhan et al., 2015) and cardiovascular disease (Codd et al., 2013). However, the association is inconsistent with Parkinson’s disease (Rivero-Segura et al., 2020). In the Rotterdam study, shorter and longer LTL was associated with an increased risk of Alzheimer’s disease (Fani et al., 2020).

The role of telomeres in brain aging is still under-investigated. So far, data exist on age-related imaging correlates such as white matter abnormalities and measures of atrophy and clinical correlates of the aging brain with an emphasis on cognitive impairment. High diversity exists not only regarding phenotypical aging presentations but also regarding the study design, including methods used to measure LTL. Not surprisingly, the results of these studies vary widely and, in some cases, are even contradictory, particularly on cognitive function.

Here, we aim to summarize the current evidence on the role of telomere length in brain aging by systematically reviewing articles on the association of LTL with age-related structural and cognitive changes in the brain and by performing meta-analyses when enough data is available. We explicitly focus on observational studies, including cross-sectional and longitudinal designs in non-demented individuals. We only include studies using MRI to define structural brain changes and evaluate cognitive function in at least one cognitive domain. We considered articles published in English since 2005.

More at link.