Telomere Attrition Module

Module telomere_attrition 2 disorders Pathograph 3

A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed telomere attrition: the progressive shortening of the protective telomere end-complexes of chromosomes with successive cell divisions and age. Because conventional DNA polymerases cannot fully replicate chromosome ends, telomeres shorten with each division unless maintained by telomerase; in most somatic tissues telomerase is limiting, so telomeres erode over the lifespan. Critically short or uncapped telomeres can no longer fulfil their protective function and are sensed as DNA double-strand breaks, triggering a persistent DNA-damage response that drives replicative senescence and blocks further division. The resulting failure to replenish tissues underlies telomere syndromes and contributes to age-related disease and mortality. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific lesion (e.g. telomerase-complex or shelterin mutations in the short-telomere/telomere-syndrome disorders) while preserving the conserved attrition -> DNA-damage/senescence -> tissue-failure chain.

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Pathophysiology Nodes

3 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "telomere_attrition#Telomere-Initiated DNA Damage and Replicative Senescence"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context. This module is the aging-facing complement of the cancer-facing enabling_replicative_immortality module: this one models telomere ATTRITION driving senescence in normal/aging cells, whereas enabling_replicative_immortality models telomere-maintenance REACTIVATION that lets tumor cells escape that barrier. It also feeds cellular_senescence (telomere attrition is one of the senescence-inducing stresses). Key conformance target: "telomere_attrition#Telomere-Initiated DNA Damage and Replicative Senescence".

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Used By Disorder Entries

Hutchinson-Gilford Progeria Syndrome via Telomere shortening → Progressive Telomere Attrition

Idiopathic Pulmonary Fibrosis via Alveolar epithelial telomere attrition → Telomere-Initiated DNA Damage and Replicative Senescence

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Pathograph

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Pathophysiology

Progressive Telomere Attrition

trigger

Because conventional DNA replication cannot fully copy the ends of linear chromosomes (the end-replication problem) and somatic telomerase is limiting, telomeres lose repeat sequence with each cell division and shorten progressively with age. This cumulative loss of telomeric DNA is the initiating lesion of the hallmark; age-related and premature-aging syndromes are characterized by short telomeres.

Telomere Maintenance GO:0000723 DECREASED

Used by disorders

Hutchinson-Gilford Progeria Syndrome as Telomere shortening

Downstream

Telomere-Initiated DNA Damage and Replicative Senescence

Telomere-Initiated DNA Damage and Replicative Senescence

central effector

When telomeres become critically short or uncapped they can no longer protect chromosome ends, which are then sensed as DNA double-strand breaks. The resulting persistent DNA-damage-response signaling enforces replicative senescence - an essentially permanent proliferative arrest. This is the conserved central effector that disease-specific telomere lesions converge upon, and the point at which telomere attrition feeds the cellular senescence module.

DNA Damage Response GO:0006974 INCREASED Replicative Senescence GO:0090399 INCREASED

Used by disorders

Idiopathic Pulmonary Fibrosis as Alveolar epithelial telomere attrition

Downstream

Tissue Replenishment Failure and Age-Related Disease