Today’s open access paper is a companion piece to a recent discussion of repetitive element activity as a potential biomarker of biological aging. In today’s paper, the authors note that a number of interventions that modestly slow aging in mice also reduce the activity of repetitive elements in the genome. Many forms of repetitive element are the remnants of ancient viruses, sequences that are capable of copying themselves into new locations in the genome, but are normally suppressed. A fair amount of attention has been given to retrotransposons, one category of repetitive elements, in the context of aging in recent years, but all repetitive elements appear to become more active with age. The systems responsible for repressing their activity begin to run awry, for reasons that are incompletely understood.
Haphazard copying of repetitive elements is a form of stochastic mutational DNA damage, capable of randomly disrupting the blueprint of specific genes. This can result in the manufacture of broken proteins or the loss of expression of functional proteins. A higher pace of mutational damage raises the risk of cancer through an unlucky combination of mutations, but is thought to also lead to the disruption of tissue function more generally. In most cases mutational damage to the nuclear genome will occur in unused genes, or to genes that have little importance. Where it does disrupt important genes, it usually occurs in somatic cells that do not replicate widely and have a limited life span. In order for this sort of damage to cause significant downstream effects, it must occur in stem cells or progenitor cells that can spread it widely throughout tissue. This is known as somatic mosaicism, and certainly does occur, but it is still unclear as to how large a detrimental effect it produces, in comparison to other issues in aging.
Healthy aging interventions reduce non-coding repetitive element transcripts
Advances in transcriptomics (e.g., RNA-seq) have led to important insight on many genes and pathways linked with ‘the hallmarks of aging‘ and broader health outcomes. However, most of these studies have focused on coding sequences – a small fraction of the genome. Non-coding, repetitive elements (RE, more than 60% of the genome) have been particularly neglected as ‘junk DNA‘, despite growing evidence that they have many important biological functions. RE include DNA transposons, retrotransposons, tandem repeats, satellites and terminal repeats. A major fraction of RE, mainly DNA transposons and retrotransposons, are transposable elements (TE) with the ability to propagate, multiply, and change genomic position.
Most RE/TE are in genomic regions that are chromatinized and suppressed (inactive), but recent reports show that certain TE become active during aging, perhaps due to reduced chromatin architecture/stability (e.g., histone dysregulation). Activation of these specific TE may contribute to aging by causing genomic and/or cellular damage/stress (e.g., inflammation). However, we recently reported that aging is associated with a progressive, global increase in transcripts from most RE (not only TE) in model organisms and humans. This global dysregulation of RE may have an important, more general role in aging, as RE transcripts have been linked with other key hallmarks of aging including oxidative stress and cellular senescence. In fact, it has been suggested that RE dysregulation itself may be an important hallmark of aging. If so, a logical prediction would be that interventions that increase health/lifespan and reduce hallmarks of aging (e.g., calorie restriction [CR], select pharmacological agents and exercise) should also suppress RE/TE.
Here, we analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-α-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and age-accelerating treatments increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Thus, RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.