Tightening the connection between transposable element mobilization and aging

Abstract

The process of senescence is typically accompanied by a gradual (or not so gradual) loss of the capacity to maintain homeostasis that, in turn, is thought to underlie the promotion of the reduced function and disease states that typically accompany old age. Although there are multiple factors that likely contribute to this process, a relatively recent observation has been the association of a decline in maintenance of repressive heterochromatin and aging. Studies in organisms as diverse as yeast, worms, flies, mice, and human cell culture have documented a decline in repressive heterochromatin with senescence, and genetic interventions have indicated that maintaining repressive heterochromatin might be beneficial for increasing healthy life span (1, 2).How then might this loss of repressive heterochromatin lead to an age-related decline in physiological function? A recent suspect is the mobilization of transposable elements (TEs), and the retrotransposon hypothesis of aging has been garnering increased attention as of late for explaining the association between loss of repressive heterochromatin and aging. According to this hypothesis, retrotransposable elements (RTEs) and other TEs lie relatively dormant in somatic cells, where they are most often confined to heterochromatin domains. With age, these domains tend to lose their capacity to maintain condensation, perhaps due to changes in redox state and/or genotoxic stress, and the resident RTEs become activated. Increased expression of RTEs promotes transposition and increased mutagenesis, which, in turn, would compromise cell function and thus contribute to aging. On the surface, this hypothesis appears quite attractive. It has been shown that there is a decline in repressive heterochromatin with age and that TEs become active and mobile in aging somatic cells (3). In PNAS, Wood et al. (4) take a large step forward toward showing a causal relationship between TE mobilization and aging; specifically, they show that interventions that maintain or result in more repressive, youthful chromatin suppress age-related TE activity and extend life span.Previously, Jiang et al. (5) had shown that with age, there is a loss of silencing of reporter genes residing in heterochromatin regions of the fly. In the present study, Wood et al. (4) conducted a series of RNA-sequencing studies in the Drosophila model showing that among a set of 250 native genes known to reside in heterochromatin, many have age-associated increases in RNA expression in both head tissues (mostly brain) and fat body (the Drosophila equivalent of the liver and adipose tissue). Moreover, these increases in expression paralleled those increases observed for the expression of RTEs, the predominant residents of heterochromatin regions. Of course, this remains a simple correlation. To examine whether this correlation may represent a causal relationship, Wood et al. (4) first demonstrated that the normal age-related increase in TE activation is repressed or even reversed in response to caloric restriction, a re...

Disturbance of floral colour pattern by activation of an endogenous pararetrovirus, petunia vein clearing virus, in aged petunia plants

“…In young animals, transposons are completely repressed both transcriptionally and post-transcriptionally by RNA silencing pathways. As animals age, these genetic surveillance mechanisms break down and become less effective, leading to the loss of heterochromatin structure, and transposon mobilization (activation) (Wood and Helfand, 2013;Orr, 2016). Our observation that an endogenous pararetrovirus, PVCV, is activated as plants age may be a phenomenon similar to the age-dependent activation of transposons in animals (Wood and Helfand, 2013;Orr, 2016).…”

“…In animals such as Caenorhabditis elegans, Drosophila melanogaster, and mammals, there is a connection between activation of transposons and ageing (Wood and Helfand, 2013;Orr, 2016;Wood et al, 2016). In young animals, transposons are completely repressed both transcriptionally and post-transcriptionally by RNA silencing pathways.…”

Activation of transposable elements and genetic instability during long-term culture of the human fungal pathogen Candida albicans

“…In our experimental conditions, increased TE activity (increased TE copy number) was more related to culture duration (90 days) than initial stimulation with stress stimuli as stress stimuli did not potentate TE activity compared to control conditions after 90 days of long-term culture (this study). In general, this observation may reflect age-related changes in TE activity and associated mechanisms, namely the loss of histones or heterochromatin or aberrant RNAi pathway (Hu et al 2014; Orr 2016; Drinnenberg et al 2009). However, more studies are needed to reveal the molecular basis of long-term culture-mediated changes in TE activity in C. albicans .…”

Roles of Topoisomerases in Heterochromatin, Aging, and Diseases

“…For example, Top3β -KO mice display reduced lifespan [6]. It is known that loss of heterochromatin and de-silencing of transposons could be a driver for aging [20,90]. Thus, the impaired function of Top3β in heterochromatin and transposon silencing may contribute to the aging phenotype in the knockout mice.…”