In Search of Regulators of Transposon Activity
Transposable elements, or transposons, are DNA sequences in the genome capable of hijacking transcriptional machinery to copy themselves into new locations, breaking other genes. They are thought to be largely the remnant of ancient viral infections, but are also potentially important contributors to evolutionary change. Transposons are effectively suppressed in youth, but this suppression breaks down with age, as the various epigenetic systems that manage packaging of nuclear DNA and access of transcriptional machinery to specific locations on the genome become dysregulated. One of the lines of research related to this is the search for regulators of transposon activity, trying to find ways to effectively turn off transposon activity in older people.
Transposons, genes that can relocate to different parts of the genome, are repressed earlier in life but get more active with age and are associated with age-related disease and decline. A new study highlights how transposons - commonly called "jumping genes" because of their ability to move to different parts of the genome - are associated with age-related disease and decline, as well as how additional genes governing transposon expression may one day be therapeutic targets for aging. Transposons make up approximately 45% percent of human DNA, and their activity is largely repressed in younger, healthy cells. However, with age, these genes are expressed more and become more mobile, correlating with various age-related declines in function
Researchers focused on long interspersed element 1 (LINE-1), a family of transposons that collectively make up about 17% of the human genome. Previous studies have shown that, like other transposons, LINE-1 also appears to be expressed more with age and in aging-related disease. The researchers worked with human cells in vitro to see how overexpression of the suspected regulatory genes affected the activity of LINE-1. Engineering cells to overexpress two of the genes, IL16 and STARD5, markedly increased overall LINE-1 expression. In addition, treating normal cells with a short-term exposure to IL16 protein also induced higher expression of LINE-1. "These are new validated regulators of transposable element activity, and they are potential targets for aging."
Regulating jumping genes is a new job description for both of these genes, but their potential connections to aging make sense. STARD5 is involved in moving cholesterol within cells and is upregulated in response to stress in the endoplasmic reticulum (ER) - an organelle involved in protein synthesis and lipid metabolism. "Aging is often accompanied by changes that can promote ER stress. Given its role, it's possible that STARD5 is involved in age-related alterations," Bravo said. "Interestingly, we observed that upregulating STARD5 led to an upregulation of IL16, suggesting that there may be a synergy between the two in activating transposons."
IL16 is mainly known for its role in regulating immune responses to infection, though they found that its blood levels increase with age. Connections between jumping gene activity and immune responses aren't far-fetched - evolutionary biology research has indicated that transposons are descendants of ancient viruses that took up residence in cells. In addition, chronic low-grade inflammation is one of the signs of biological aging, which could be tied to immune responses to transposon expression.