Telomeres and Ageing

Telomeres are repetitive DNA sequences capping the ends of chromosomes, protecting coding DNA from degradation and end-to-end fusion.

With each cell division the terminal end of the chromosome is not fully replicated, so the telomere progressively shortens (the end-replication problem).

Telomere shortening is a specific type of genomic damage, and telomere attrition is one of the primary hallmarks of ageing.

Telomerase adds DNA bases back onto telomeres. Transfecting its catalytic component into senescent cells lengthens telomeres, extends replicative lifespan, and restores a "young" pattern of gene expression.

Hayflick limit — human fibroblasts in culture stop dividing after about 50 doublings. The classic example of programmed ageing.

When telomeres are exhausted the cell can no longer proliferate — this is replicative senescence.

Replicative lifespan in vitro correlates inversely with donor age.

Key exam concept: telomere shortening protects the cell against uncontrolled division and abnormal growth — at the expense of ageing. It is fundamentally an anti-cancer (tumour-suppressor) mechanism.

Cells fall into three groups by replicative capacity: Continuously replicating — epidermal, gastrointestinal, haematopoietic (telomere biology matters most here)

In non-replicating tissues, telomere shortening is not the mechanism — cell loss causes a permanent deficit instead (e.g. dopaminergic neuron loss affecting gait and balance).

Lung ageing: decreased telomerase activity plus replicative senescence plus rising pro-inflammatory cytokines produce low-grade chronic pulmonary inflammation — "lung inflammageing" (Table 42.1).

Telomere-triggered senescence produces the SASP — matrix metalloproteases and pro-inflammatory cytokines that spread senescence and drive inflammageing.

Senescence is not only telomeric — it is also triggered by non-telomeric DNA damage and excessive mitogenic signalling via p16INK4a.

Stem cell exhaustion is an integrative consequence of telomere shortening together with DNA damage, epigenetic alterations, senescence and mitochondrial dysfunction.

Telomere shortening occurs during normal ageing in mice and humans, and experimentally altering telomere loss changes lifespan in mice.

A meta-analysis of 25 studies showed telomere attrition predicts all-cause mortality.

Critical exam point — telomere length is NOT currently accepted as a biomarker of biological age. Longitudinal studies show erratic changes over time, probably due to measurement error.

In the oldest old, no relationship was found between telomere length and mortality. However, healthy centenarians had significantly longer telomeres than unhealthy centenarians — telomere length reflects health and function rather than exceptional longevity.

Telomerase inhibitors are potent potential anticancer agents, because most cancers reactivate telomerase to achieve immortality.

Werner syndrome (DNA helicase mutation) is the classical progeroid illustration of genomic instability; the telomere syndromes are a separate recognised group of premature-ageing disorders.

How far telomere shortening explains in-vivo human ageing remains unknown — it explains finite cell life in culture better than whole-organism ageing.

Telomere attrition retained as a core hallmark. Telomere attrition remains one of the twelve hallmarks of ageing in the updated framework. (Cell 2023)

The telomere–cancer paradox confirmed by Mendelian randomisation. In a two-sample MR study using East Asian cohorts, longer telomere length per 1-SD increase due to germline variants was associated with higher risk of site-specific cancer, strongest for thyroid cancer (OR 2.49). Separate MR analysis found significant associations with primary lymphoid malignancy (OR 1.52), Hodgkin lymphoma (OR 1.64), non-Hodgkin lymphoma (OR 1.70) and B-cell lymphoma (OR 1.57). MR in breast disease found longer telomeres increase risk of breast cancer, benign neoplasms and breast inflammation, with no reverse causation. Take-home: short telomeres cause degenerative disease; long telomeres permit malignancy. Telomere length is a double-edged sword. (Cancer Epidemiol Biomarkers Prev 2025; Aging 2024)

Telomere Biology Disorders — a real adult diagnosis. TBDs are inherited bone marrow failure syndromes caused by pathogenic germline variants in telomere-related genes, with a heterogeneous phenotype including bone marrow failure, pulmonary and liver disease, and predisposition to haematologic and solid malignancies. Genes to remember: TERT, TERC, DKC1, RTEL1. Trial inclusion requires age-adjusted telomere length ≤1st percentile and/or identified mutations plus one cytopenia and/or pulmonary fibrosis.

Danazol — first drug shown to preserve telomeres in humans. Long-term results of a prospective phase 1/2 study showed danazol improved haematologic parameters and stabilised telomere attrition in TBD. Patients received danazol 800 mg daily for two years, with telomere attrition as the primary biologic endpoint and flow-FISH for serial measurement. Androgens are thought to work by enhancing telomerase activity and reducing the rate of telomere attrition. (Blood Advances 2026)

Ex vivo telomere elongation of stem cells. Clinical use of ZSCAN4 for telomere elongation in haematopoietic stem cells has been reported, forming the basis of the EXG34217 trial in TBD with bone marrow failure — the first attempt at directly lengthening human telomeres therapeutically. (NEJM Evidence 2025)

"Telomere shortening protects against uncontrolled cell division at the expense of ageing."

"Telomere length is not currently accepted as a marker of biological age because longitudinal change is erratic and measurement-error prone."