The Role of Telomeres in Human Disease

Abstract

Telomere biology was first studied in maize, ciliates, yeast, and mice, and in recent decades, it has informed understanding of common disease mechanisms with broad implications for patient care. Short telomere syndromes are the most prevalent premature aging disorders, with prominent phenotypes affecting the lung and hematopoietic system. Less understood are a newly recognized group of cancer-prone syndromes that are associated with mutations that lengthen telomeres. A large body of new data from Mendelian genetics and epidemiology now provides an opportunity to reconsider paradigms related to the role of telomeres in human aging and cancer, and in some cases, the findings diverge from what was interpreted from model systems. For example, short telomeres have been considered potent drivers of genome instability, but age-associated solid tumors are rare in individuals with short telomere syndromes, and T cell immunodeficiency explains their spectrum. More commonly, short telomeres promote clonal hematopoiesis, including somatic reversion, providing a new leukemogenesis paradigm that is independent of genome instability. Long telomeres, on the other hand, which extend the cellular life span in vitro, are now appreciated to be the most common shared germline risk factor for cancer in population studies. Through this contemporary lens, I revisit here the role of telomeres in human aging, focusing on how short and long telomeres drive cancer evolution but through distinct mechanisms.

Keywords: aging; cancer; clonal hematopoiesis; genome instability; pulmonary fibrosis; telomerase.

Figure 1

Distinct pediatric and adult manifestations of short telomere syndromes and their increasing prevalence with age. Short telomere syndromes show a phenotype continuum that is determined by the severity of the telomere length defect relative to age. The colored lines indicate percentiles for telomere length, and the two boxes summarize the common presentations at the extremes of age. Each red circle represents a hypothetical short telomere syndrome patient. The red shaded region indicates the threshold where short telomere length is sufficient to provoke telomere-mediated disease. Abbreviations: AML, acute myeloid leukemia; CH, clonal hematopoiesis; MDS, myelodysplastic syndrome. Telomere length nomogram adapted from Reference .

Figure 2

Telomere and telomerase components reported to be mutated in Mendelian telomere syndromes, grouped by their function when known. The proteins encoded by the 12 short telomere syndrome genes are indicated by a subscript S. Proteins encoded by Coats plus syndrome genes are indicated by a subscript CP; note that POT1 mutations have been identified in only one patient, in the absence of segregation studies. Proteins encoded by genes identified as mutated in cancer-prone families based on their hypothesized function in telomere lengthening are indicated by a superscript L. RAP1 is encoded by TERF2IP, and TPP1 is encoded by TPP1, sometimes referred to as ACD. Figure adapted with permission from Reference .

Figure 3

Estimated prevalence of short telomere syndromes relative to other classic DNA repair syndromes. The estimate for short telomere syndromes is based on the prevalence of short telomere mutations in idiopathic pulmonary fibrosis. Estimates for the other syndromes are based on the prevalence of rare pathogenic mutations in the respective genes.

Figure 4

The short telomere threshold for disease, which is reached only in a subset of the human population. This scheme traces telomere shortening with age in two individuals (red circles), one with a telomere length near the median at birth and one with a telomere length in the lowest decile at birth. The threshold shown is based on data from short telomere syndrome patients (as also shown in Figure 1). Telomere length nomogram adapted from Reference .

Figure 5

Cancer prevalence and association with T cell immunodeficiency in short telomere syndromes. (a) Pie chart showing a 15% cancer prevalence in short telomere syndromes, broken down into hematologic (MDS/AML) and solid malignancies. (b) Overlap in the solid tumor spectrum with malignancies associated with T cell immunodeficiency, such as in AIDS. (c) Mechanisms of T cell immunodeficiency in short telomere syndromes, which are compounded throughout T cell development in humans and mice. Factors include depleted hematopoietic progenitors in bone marrow, increased T cell apoptosis in the thymus during development, and increased T cell apoptosis among mature T cells. Abbreviations: AIDS, acquired immunodeficiency syndrome; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.

Figure 6

Models for short telomere cancer risk in solid organs and in the bone marrow based on recently generated data. (a) Model for solid tumor evolution in short telomere syndromes. In this hypothesized mechanism of carcinogenesis, T cell immunodeficiency promotes defective immune surveillance to promote cancer risk, especially in squamous cell compartments. (b) Mechanisms of leukemogenesis. Acquired somatic reversion in adults with short telomere syndromes at high allele frequency averts the telomere crisis that leads to MDS or leukemogenesis. The latter model is based on data showing a higher prevalence and mutual exclusivity of somatic reversion mutations with cytogenetic abnormalities (based on Reference 82). Abbreviation: MDS, myelodysplastic syndrome.

Figure 7

Schema showing hypothesized long and short telomere syndrome patients (red circles) with telomeres at extremes of the normal range. The melanoma phenotype in patients with long telomeres contrasts with the melanocyte loss seen in the premature graying phenotype of the short telomere syndromes, demonstrating how the short telomere aging phenotype is tumor suppressive at this extreme. Telomere length nomogram adapted from Reference .