Telomeres and age-related disease: how telomere biology informs clinical paradigms

Abstract

Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies.

Figure 1. Clinical manifestations of telomere disorders and their onset relative to tissue turnover rate.

Shown are representative images of diagnostic histopathology and radiographic studies in patients with telomere-mediated disease (A–D) and 5-ethynyl-2′-deoxyuridine (EdU) incorporation detected in corresponding mouse tissues (E–H). The estimated turnover rate of more than 90% of cells is indicated for each pair of images. (A) Photomicrograph of a bone marrow biopsy showing an acellular marrow replaced by adipose tissue with only remnants of hematopoiesis, taken from an individual with aplastic anemia. Image reproduced with permission from Annual Reviews of Genomics and Human Genetics (31). (B) Histopathology of a duodenal biopsy from a patient with telomere-mediated enteropathy shows profound villous atrophy. Image reproduced with permission from Aging Cell (53). (C) Abdominal CT scan image from a patient with liver cirrhosis, as evidenced by the nodular liver surface, the caudate lobe hypertrophy, and splenomegaly. (D) Lung windows of a chest CT scan from a carrier of the telomerase mutation show classic basilar honeycombing changes pathognomonic for IPF. (E) Flow cytometry plot of EdU incorporation in the bone marrow after a short (2-hour) pulse, showing that nearly one-third of the cells have undergone division. (F) Immunohistochemistry of intestinal section after a EdU pulse (5 days) shows that nearly all enteric epithelial cells are positively labeled (brown). (G) Brown staining shows EdU-labeled hepatocytes after EdU labeling (14 days). (H) Image of terminal bronchiole shows EdU-positive lung epithelial cells (red) identified by the Clara cell antigen (green) after 14 day label.

Figure 2. Model for understanding the mechanisms of telomere-mediated disease in high- and low-turnover tissues.

In high-turnover tissues (left), cell replication is the primary determinant of disease onset. In contrast, in low-turnover tissues (right), other genetic and acquired hits contribute to disease onset. In both cases, telomere dysfunction induces apoptosis and/or senescence. The senescence phenotype may be associated with gene expression changes, mitochondrial dysfunction, aberrant Ca²⁺ signaling, and the SASP.

Figure 3. Telomere syndromes have defined pathological ranges of telomere shortening.

Although short telomere length (TL) has been associated with numerous conditions, in some cases, the shortening reflects acquired replicative stress states rather than telomere-driven degenerative changes. (A) Putative dataset showing large effect size and short telomere length outside of the normal age-adjusted range. (B) Small and statistically significant change in telomere length in hypothetical dataset is less likely to reflect a telomere-mediated process.