How GLTD impacts ageing and age-related diseases like Alzheimer’s

Jun 7, 2024

Gene-length-dependent transcription decline (GLTD) in ageing organisms results in longer genes showing decreased expression. This decline, linked to DNA damage and polymerase stalling, contributes to ageing and age-related diseases like Alzheimer’s. Targeting GLTD offers potential therapeutic avenues for enhancing healthspan and longevity.

March 2024 – Trends in Genetics


Key takeaways


  • Longer genes show decreased expression in ageing due to gene-length-dependent transcription decline (GLTD): GLTD is a phenomenon where the expression of longer genes diminishes more rapidly than shorter ones as organisms age. This systematic reduction in gene expression affects various cell types and tissues, indicating a widespread impact on the biological ageing process
  • GLTD is linked to DNA damage and polymerase stalling, contributing significantly to the ageing process: DNA damage accumulates over time, causing RNA polymerase, the enzyme responsible for gene transcription, to stall more frequently on longer genes. This stalling impedes the transcription process, leading to reduced expression of these genes, which in turn contributes to cellular ageing and functional decline
  • GLTD is also observed in age-related diseases like Alzheimer’s, highlighting its impact on healthspan: Age-related diseases, particularly neurodegenerative disorders such as Alzheimer’s, exhibit pronounced GLTD, especially in long synaptic genes located at chromosomal fragile sites. This vulnerability to DNA damage in key neural genes underscores the role of GLTD in the progression of such diseases, affecting cognitive function and overall healthspan


By understanding and potentially reversing GLTD, therapeutic strategies could be developed to mitigate its effects. Approaches like improving DNA repair mechanisms, reducing DNA damage, or modulating transcription processes could help maintain gene expression levels, thereby enhancing longevity and reducing the incidence or severity of age-related diseases


Read the article at: Soheili-Nezhad, Sourena, et al. “Time is Ticking Faster for Long Genes in Aging.Trends in Genetics, vol. 40, no. 4, April 2024, pp. 299-309. Elsevier, doi:10.1016/j.tig.2024.01.009.