The role of retrotransposable elements in ageing and age-associated diseases

Abstract

The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as 'junk DNA' and 'molecular parasites'. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.

Fig. 1 |. L1 life cycle.

L1s are transcribed by host RNA polymerase II. The mRNAs are translated (green ribosome) into ORF1 (brown) and ORF2 (pink) proteins. Multiple trimers of ORF1 and one ORF2 bind the mRNA in cis to form RNPs. SINEs (Alu) hijack ORF2 in trans to form their own RNPs. RNPs interact with the DNA replication machinery to retrotranspose into the genome. How L1 cDNA is produced in non-replicating cells is not clear.

Fig. 2 |. Retrotransposition mechanisms.

a, Non-LTR elements. L1 structure: 5’UTR with internal promoters, purple; ORF0, pink; ORF1, green; ORF2, orange; EN, endonuclease domain of ORF2; RT, reverse transcriptase domain of ORF2; 3’UTR with polyadenylation signals (pA), blue; TSD, target site duplications. The steps (1–6) of TPRT are illustrated. b, LTR elements. HERV structure: LTRs with internal promoters, pink; PBS, tRNA primer binding site; Gag (capsid protein), green; Pro (protease), grey-blue; Pol (polymerase), brown; Env (envelope protein), grey-green. Many HERVs lack Env. Pol has domains with RT, ribonuclease H (RNase) and integrase (IN) activities.

Fig. 3 |. Surveillance of retrotransposons.

Heterochromatin, dark blue; euchromatin, light blue; retrotransposons, red lines. a, Young condition. Transcriptional regulators (KZFPs, RB, SIRT6, HUSH, YY1) target retrotransposon elements (repeating arrows) in the genome. SIRT6 and KZFPs both recruit (white arrows) the co-repressor KAP1. AGO and PIWI are targeted to nascent retrotransposon transcripts by siRNAs or piRNAs (red lines). Collectively these effectors recruit DNMTs and repressive HMTs to promote heterochromatin formation. Retrotransposon transcripts (dashed black lines) are also degraded by argonaute slicer complexes. b, Aged condition. Surveillance by regulators such as RB and SIRT6 is diminished, resulting in decreased KAP1 recruitment and reduced DNA methylation and repressive heterochromatin modification at retrotransposons. This allows the binding of transcriptional activators (FOXA1).

Fig. 4 |. Retrotransposons as agents of aging and disease.

a, Overview of retrotransposon–aging interactions. Defense mechanisms are weakened with age, allowing the deprepression of retrotransposons (inner layer). The direct molecular consequences of retrotransposon activity (middle layer) drive several cellular and tissue-level processes (outer layer) which collectively promote aging. b, Specific retrotransposon–disease interactions. L1 transcription and integration are shown inside the nucleus (double circle), translation in cytoplasm, and reverse transcription in both compartments. DNA strands are shown in blue and RNA strands in red. Diseases are abbreviated in capital red letters (terms not defined in text: CD, cardiovascular diseases; ND, neurodegenerative diseases; OA, osteoarthritis; PD, Parkinson’s disease; RA, rheumatoid arthritis). Arrows: activating effects; lines ending in bars: inhibitory interactions; dashed arrows/question marks: hypothetical or uncertain processes.