How long we live may be a function not only of our genetics and the environment, but of our ancestors’ epigenetics as well, a study published today (October 19) in Nature suggests. The researchers found that epigenetic modifications that extended lifespan in worms can be passed down across multiple generations.
Transgenerational epigenetic inheritance has been reported for a variety of traits across a number of species—the color of flowers in plants, eye color in Drosophila, and fur color in mice are all known to be epigenetically inherited, for example. But “this is the first time this has been linked to longevity,” said molecular geneticist William Kelly, who researches chromatin organization and germline maintenance at Emory University but who was not involved in the study.
How longevity is genetically regulated has been studied extensively in the model organism Caenorhabditis elegans over the past three decades. A landmark study published in 1993, for example, reported that mutations in genes tied to the insulin pathway can double of the C. elegans lifespan.
More recently, Anne Brunet, an associate professor of genetics at the Stanford School of Medicine, found that mutations in a chromatin-modifying complex also significantly increased lifespan in C. elegans. The complex, known as the histone H3 lysine 4 trimethylation (H3K4me3) complex, is responsible for methylating a chromatin packaging protein called histone H3. This methylation is often associated with the increased expression of genes in the vicinity.
When Brunet and her colleagues knocked down members of the H3K4me3 complex—such as the WDR-5 and SET-2—they extended C. elegans life by up to 30 percent, suggesting that the epigenetic changes regulated by the complex controlled genes related to lifespan.
“Basically we think that the reason why those worms live longer is because they have less of this H3K4 mark at specific loci in the genome,” Brunet explained. “That probably results in changes in the expression of some genes,” such as those that regulate the aging process, she added.
The possibility that such changes could affect longevity, in addition to the observation that the H3K4me3 complex could act on the germline, led Brunet's graduate student at the time Eric Greer (now a post-doc at Harvard Medical School) to wonder whether the complex’s effects could be epigenetically inherited across multiple generations.
To test this, he mated long-lived worms with deleterious mutations in either WDR-5 or SET-2 with normal, wildtype individuals, and selected the progeny that had a wildtype genetic makeup—i.e., those worms that had not inherited the mutation. This allowed the researchers to effectively eliminate the genetic mutation and look for any lingering H3K4 methylation marks on the genome.
To their “extreme surprise,” the researchers observed that lifespan was still being extended by 25 to 30 percent in the third generation of worms descended from the mutated worm, even though they were genetically identical to wildtype individuals who lived a normal length of time. (Similar results were obtained with a third component of the H3K4me3 complex called ASH-2, although researchers had to employ a different methodology due to the lack of viable ASH-2 mutant worms.) The results suggest that there is indeed an epigenetic, rather than genetic, component of the lifespan extension that can be passed from parent to offspring.
Gene expression analyses further confirmed that the worms that descended from the mutant-wildtype cross exhibited an altered gene expression profile similar to the original mutant parent, even though they had a wildtype genetic makeup. Thus, it seems that some of the faulty epigenetic programming from the mutant worms were not being reset in the germline, and were being passed on to subsequent generations as a result.
A significant number of genes with altered expression were involved in metabolism, a process that is intimately related to aging. “If you screw around with metabolism you screw around with longevity,” Kelly said.
Curiously, no lifespan extension was observed in the fourth generation of wildtype worms descended from the mutants. “We would have expected maybe that the effect would gradually wane, but in fact it seems to be disappearing in a more abrupt manner,” Brunet explained. “We don’t know why that is, but maybe there is a threshold type of epigenetic mechanism.”
Currently, Brunet’s team is focusing on understanding the functions of the differentially expressed genes, many of which have not been studied before, and how they relate to aging.
“It is well known that aging is regulated by genes that we inherit from our parents, and it is also well known that aging is regulated by the environment,” Brunet said. “But maybe aging is also regulated by what our parents and grandparents did during their lifespan.”
E.L. Greer et. al., "Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans," Nature, doi:10.1038/nature10572, 2011.