Recent studies of aging organisms have identified a systematic phenomenon, characterized by a negative correlation between gene length and their expression in various cell types, species, and diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) and suggest that it may represent a bottleneck in the transcription machinery and thereby significantly contribute to aging as an etiological factor. We review potential links between GLTD and key aging processes such as DNA damage and explore their potential in identifying disease modification targets. Notably, in Alzheimer’s disease, GLTD spotlights extremely long synaptic genes at chromosomal fragile sites (CFSs) and their vulnerability to postmitotic DNA damage. We suggest that GLTD is an integral element of biological aging.