Exploring the Relationship of Transposable Elements and Ageing: Causes and Consequences

Abstract

Ageing is a gradual biological process marked by a decline in physiological function, increasing susceptibility to disease, and mortality. Transposable elements (TEs) are repetitive DNA sequences capable of moving within the genome and thus potentially inducing mutations and disrupting normal cellular functions. Their mobile nature contributes to genomic variation, as transposition events can alter gene expression, chromosome structure, and the epigenetic landscape. To mitigate TE-induced damage, cells rely on epigenetic mechanisms, such as DNA methylation, histone modifications, and small RNAs, to repress TE activity. However, these silencing mechanisms become less effective with age, leading to increased TE activation. This review explores the dual role of TEs as both a cause and consequence of ageing, suggesting a complex relationship between TEs and the ageing process.

Keywords: age-related diseases; chromatin; long-lived organisms; senescence; transposable elements.

Fig. 1.

Schematic representation of the main regulatory mechanisms of TE activity. a) The small-interfering RNA (siRNA) pathway: double-stranded RNA (dsRNA) is cleaved by Dicer into siRNAs, which are loaded into Argonaute (AGO) proteins to form the RNA-induced silencing complex (RISC). This complex guides the cleavage of complementary TE transcripts. b) The Piwi-interacting RNA (piRNA) pathway: piRNAs, transcribed from piRNA clusters, bind to PIWI proteins, guiding them to TE loci where they induce repressive chromatin modifications, silencing TEs at the transcriptional level. Additionally, piRNAs can target TE transcripts for post-transcriptional cleavage via the Argonaute protein Aubergine (AUB), triggering the “ping-pong loop” to amplify piRNA production. c) Transcriptional regulation through chromatin modification: TEs can be silenced at the DNA level by heterochromatinization, mediated by DNA methylation and histone modifications such as deacetylation and methylation.

Fig. 2.

Age-related activation of LINE1 elements due to SIRT6 depletion and its impact on genome stability and inflammation. In young/wild-type mouse cells, LINE1 elements are kept in a repressed state due to the regulatory role of SIRT6. SIRT6 ensures that the 5′ UTR region of LINE1 is packaged into transcriptionally inactive heterochromatin with the coordination of other factors such as KAP1 and HP1a. However, in old and senescent cells or in SIRT6 knockout mice, LINE1 elements become increasingly active. This activation is partly due to the inability to maintain the LINE1 5′ UTR in a stable heterochromatic state. As cells age, SIRT6 is depleted from the LINE1 5′ UTR, as it relocates to sites of DNA damage to facilitate DNA repair. The reduced presence of SIRT6 at the LINE1 5′ UTR weakens the silencing mechanisms, leading to the activation of LINE1 elements. The LINE1 transcripts can assemble into active ribonucleoprotein (RNP) complexes, which, upon transport to the nucleus, enhance LINE1 transposition and lead to DNA damage. Moreover, the cytoplasmic accumulation of LINE1 cDNA triggers a type I interferon (IRF) response, leading to pathological inflammation. Notably, inhibiting LINE1 replication with nucleoside reverse-transcriptase inhibitors (NRTIs) in aged mice significantly improved both mice health and lifespan.

Fig. 3.

Schematic representation of the toxic Y effect. The heterogametic sex (XY or ZW chromosomes, right) harbours a higher abundance of TE sequences (red) compared to the homogametic sex (XX or ZZ chromosomes, left). These TEs are typically silenced by epigenetic mechanisms (yellow lollipops). However, in aged individuals, these silencing mechanisms may weaken, leading to the activation of TEs. Because the Y or W chromosomes are TE-rich, more TEs may become active in one sex than the other, potentially contributing to sex differences in ageing and reduced lifespan.

Fig. 4.

Schematic representation of the mechanism underlying the difference in longevity between royal and worker castes in termites. In termites, the queen and king greatly outlive the workers. Analysis of TE expression in young and old samples of either cast revealed an increase in TE transcripts only in old workers, likely due to a piRNA pathway downregulation. Indeed, the downregulation of piRNA pathway effectors, such as aub1, zuc, qin and csul, in older workers results in decreased TE control, which subsequently leads to an increase in TE expression.

Fig. 5.

TE activity as a cause and consequence of ageing. TEs are typically repressed by epigenetic mechanisms (represented as yellow lollipops). With ageing, the breakdown of these regulatory mechanisms leads to their deregulation, resulting in increased expression and occasional transposition. This elevated TE activity can contribute to DNA damage, cell death, and cellular senescence, as well as cognitive and motor dysfunction, ultimately raising disease risk and potentially accelerating age-related decline.