Age‐related telomere attrition in the human putamen

Abstract

Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of “biological” age, is a known phenomenon and epidemiologically correlated with age‐related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post‐mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross‐sectional cortical brain samples so far indicated no attrition with age. Hence, age‐related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte‐rich spleen samples from 98 post‐mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region‐specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region‐ and age‐dependent expression pattern corresponded with region‐dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age‐related vulnerability of the nigro‐striatal network.

Comparative Application of Terminal Restriction Fragment Analysis Tools to Large-Scale Genomic Assays

“…However, when evaluating the telomere length in individual T-DNA mutants of candidate genes following extensive genomic screens, either program will be efficient in analyzing the telomere length. Although both the TeloTool and WALTER programs were developed by research groups primarily working with the model plant Arabidopsis thaliana [20,23], these programs have quickly gained popularity for telomere length analysis in many other classical and emerging plant models [35], as well as for the analysis of non-plant telomeres, including those in human cells, cancer cell lines, green algae, and Trypanosomes [17,24,25,[36][37][38]. Thus, our results may be relevant for telomere biology studies and the functional analysis of candidate genes in other systems, including large-scale genomic screens in other models and in humans.…”

“…Specifically, Mannherz and Agarwal (2023) [24] recently used WALTER to accurately measure the telomere length in 293T cells transduced with shRNA targeting the SAMHD1 gene. Similarly, WALTER is also suitable for the analysis of developmental changes in telomere length, including age-related telomere attrition in a human brain structure called the putamen [25]. The main features of the TeloTool and WALTER telomere length analysis methods are summarized in Supplemental Table S1.…”