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Stanford Study Suggests Link Between Epigenetics and Aging in Worms

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Histone methylation appears to be involved in life span in the worm model organism Caenorhabditis elegans, according to a paper appearing in the early, online edition of Nature today.

Using RNA interference, Stanford University researchers found that knocking down the expression of specific genes increased C. elegans life span by as much as 30 percent. Among the genes with the largest effect: ash-2, which codes for a methyltransferase enzyme in a complex that methylates histone H3. That, in turn, points to interplay between such epigenetic marks and longevity.

"[A]n epigenetic change can affect the life span of an organism," senior author Anne Brunet, a genetics and cancer biology researcher at Stanford, said in a statement.

But, she emphasized, this effect was only observed when worms' reproductive bits were operational. Sterile C. elegans did not exhibit the same increase in life span in the absence of ash-2.

"It makes a sort of sense that the reproductive system would be involved in life span, since that is really the only 'immortal' part of an organism," she said.

Brunet and her team used RNAi to systematically knock down methyltransferase genes in C. elegans. Because past studies hint that longevity and fertility may be inter-related, the researchers decided to initially work with fertile worms rather than the sterile worms that are often used in research.

Using this approach, the researchers found both known and previously unidentified genes whose knockdown increased worm longevity. Of these, ash-2 — a gene coding for a methyltransferase in the so-called ASH-2 trithorax complex that trimethylates histone H3 at lysine 4 — stood out as having the most marked effect.

In the absence of ash-2, the team detected decreased methylation in worm larvae combined with life span increases of as much as 31 percent compared to control worms.

Knocking down other members of the same complex — including wdr-5 and set-2 — also produced longer-lived worms, as did set-9, set-15, and set-4 knockdown.

On the other hand, when the researchers curbed the expression of a histone H3K4me3 demethylase gene called rbr-2, they found that methylation was enhanced and worms' life span was some 15 to 25 percent shorter than that of wild type worms.

The longevity effects detected also appeared to be connected to reproductive processes: when the team knocked down ash-2 in sterile worms they did not see increased life span. In contrast, the production of mature eggs appeared to play into worm life extension.

In addition, the team's subsequent experiments revealed that ash-2 tends to be highly expressed in both germline cells and newly formed eggs. And knocking down the methyltransferase ash-2 or over-expressing the demethylase rbr-2 in germline cells alone could produce significant life span increases in the worms.

When they looked at genes whose expression was altered during ash-2 knockdown, the researchers identified between 220 and 847 differentially expressed genes, depending on the stage of worm development examined. Again, they noted, many of these genes appear to be specifically regulated in germline cells.

Together the findings suggest reproductive and epigenetic patterns may both contribute to life span in C. elegans — though the precise mechanism behind this interaction is yet unclear.

The team reportedly plans to do future studies to not only assess the apparent epigenetic aspects of this process but also to explore how methylation patterns shift in C. elegans over time and under various environmental conditions.

"[W]e show that members of an H3K4me3 methyltransferase complex have a pivotal role in the regulation of longevity in C. elegans," the team concluded. "The finding that aging can be regulated epigenetically raises the intriguing possibility that aspects of the aging process could be reversed."

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