Available online 9 March 2023, 103483

Age-related changes in gene expression have long been examined to understand the biology of aging. The hallmarks of aging are biological processes known to be associated with aging, but whether there is a unifying driver of these attributes, is not well understood. With the advent of technology over the last few years, it is quite clear that aging leads to global decline in transcription. In this Perspective, we highlight a new study in Nature Genetics that aimed to determine why global transcription rate reduces with age and how this phenomenon is the driver that interconnects multiple hallmarks of aging. This study recognizes that age-related accumulation of DNA damage, particularly transcription-blocking lesions, stalls RNA polymerase. This phenomenon affects longer genes leading to a gradual loss of transcription and skewing the transcriptome. In order to design a successful aging intervention, future work will be needed to test how some promising therapies in pre-clinical trials target affect transcriptional rate.

AUG is funded through NIH-R01HL161106, U54AG075931; National Academy of Medicine (Catalyst grant); AFAR-Hevolution; and RK Mellon Foundation. We thank Heather Makar for help with editing figures.

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