Downregulation of transposable elements extends lifespan in Caenorhabditis elegans

Abstract

Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in the soma also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control.

Expression of Most Retrotransposons in Human Blood Correlates with Biological Aging

“…8). This observed trend is in line with previous reports of demethylation of RTE with age in gene-poor regions 5,21,23,33 .…”

“…The role of RTEs in aging has been studied extensively but not in a systematic manner with large, non-cancerous human cohorts across RTE categories before this study. Current understanding of the relationship between RTEs and aging are largely conducted in vitro or in model organisms 7,9,33,35 that might not apply to human due to intraspecies differences 36 . Moreover, the link of RTEs to aging in non-cancerous human cohorts has not been studied systematically in large cohorts.…”

Genome-wide analysis of transcription-coupled repair reveals novel transcription events inCaenorhabditis elegans

“…Notably, XR-seq exhibits sensitivity comparable to that of capped RNA-seq in detecting annotated intergenic enhancer RNAs (eRNAs) and long intergenic non-coding RNAs (lincRNAs), but is superior at detecting intergenic Piwi-interacting RNAs (piRNAs). In C. elegans, piRNAs are transcribed from >15,000 discrete genomic loci by RNAPII, resulting in 28-nt short-capped piRNA precursors that play key roles in germline development, genome integrity, and other biological processes [66][67][68][69]. The majority of piRNAs are localized to two ~3 Mb cluster regions on chromosome IV [70], and we found 2,090 annotated piRNAs and 1,341 unannotated intergenic regions unique to xpc-1 XR-seq on this chromosome.…”

Somatic mutation as an explanation for epigenetic aging

“…Aging has also been associated with other major types of molecular changes beyond DNA mutations 20,21 , leading to debate as to which of these aging "hallmarks" are fundamental causes [22][23][24][25] . In particular, much recent attention has been given to associations of age with DNA methylation, a dynamic epigenetic mark found primarily at CG dinucleotides (CpG sites) throughout the genome 26 .…”