Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.
This Timeline article summarizes recent advances in the telomere and telomerase fields, expanding our understanding of their roles in aging and disease. Initially, telomeres were believed to protect chromosome ends and telomerase to be essential for replicating these ends in single-celled organisms. While this remains true, various aspects related to telomeres and telomerase have significantly progressed. These include the identification of key molecular components, implications for cellular replication limits, genetic disorders causing premature telomere shortening, potential therapeutic strategies targeting telomerase, and the influence of telomeres on gene expression regulation. The article highlights progress in these areas, while acknowledging remaining challenges and unanswered questions in the field.
Aging affects the immune system, especially T-cell responses. Some centenarians successfully avoid age-related diseases, while others require nursing care. Previous studies on centenarians examined resting cells and found differences in gene expression and proliferation between high-performing and low-performing individuals. High-performing centenarians also show longer telomeres and increased telomerase activity, which are potential biomarkers of aging.
Telomeres are repetitive DNA sequences at the ends of chromosomes and play a role in the spatial organization of the genome. They interact with interstitial telomeric sequences (ITS) and shelterin proteins, forming loops that influence gene expression in distant genomic regions. Short telomeres are associated with human laminopathies and telomeropathies. As telomeres shorten with age, these interactions may change and impact normal and pathological processes. Telomeres contribute to genome stability during early adulthood but are implicated in age-related diseases later in life.
Telomerase activity in resting T lymphocytes is low, but increases temporarily upon antigen presentation. It remains unclear if telomerase activation is necessary for T-cell proliferation or telomere maintenance. This study found that short-term T-cell proliferation does not require telomerase activation, and telomeres gradually shorten in a diverse T-cell population, even in the presence of telomerase. By examining telomerase activity at the single-cell level and monitoring changes in the shortest telomeres, it was observed that only a subset of CD28+ T-cells exhibit robust telomerase activity during stimulation, maintaining their telomere lengths. Further research on this T-cell subset may enhance our understanding of telomerase regulation and its role in immune cells.
The discovery of telomerase genes has established the link between telomere loss and aging, and telomerase activation and immortalization. Telomerase detection and inhibition have potential in cancer treatment, while controlled telomerase activation may benefit degenerative diseases. It is important to distinguish telomerase activation from cancer and avoid overestimating cancer risks in telomerase-based therapies. This review clarifies the differences between telomerase and oncogenes and explains the dual role of telomerase repression in tumor suppression early in life and tumor promotion later in life. Understanding these concepts helps guide therapeutic approaches for cancer and age-related tumorigenesis.