BioEd Online

The nematodes in geneticist Anne Brunet's lab at Stanford University in California have given their offspring the ultimate inheritance: a familial propensity towards long life. But curiously, the worms have done so without bequeathing a legacy of auspicious DNA sequences.

Instead, the worms have revealed an unexpected way to pass on longevity: through the inheritance of 'epigenetic' chemical marks. These do not change the DNA sequence but instead affect gene expression when they are attached to complexes of DNA and protein called histones. Brunet and her colleagues report the results online today in Nature¹.

"It's a new principle in terms of understanding where variation in longevity comes from," says geneticist David Gems of University College London, who was not involved in the study.

Changes in the expression of several genes have been credited with boosting lifespan in the nematode Caenorhabditis elegans. The worm is beloved among researchers who study ageing, in part because of its short lifespan of 2–3 weeks.

Methyl marker

One way to alter gene expression is by adding or subtracting chemical marks known as methyl groups to DNA and histones. Brunet's team had previously shown that nematodes live up to 30% longer when they bear mutations that affect a complex of proteins involved in adding methyl groups to a histone called H3 at a specific location².

Now the team reports that this longer lifespan can be passed on to the worms' offspring for three generations after the mutations have been bred out of their genome. Brunet and her team have not yet looked to see if the physical signs of ageing — which in worms includes sluggishness and reduced fertility — are also affected.

It is the first time, Brunet says, that longevity has been demonstrated to be handed down through epigenetic inheritance.

There are other examples in which epigenetic inheritance plays a part — such as eye colour in fruitflies and floral symmetry and colour in plants — but the process remains a mystery. Epigenetic marks are thought to be wiped clean in eggs and sperm, so how are they replaced at the right locations in the next generation?

"This is the big question in epigenetics," says Renato Paro, an epigeneticist at the Swiss Federal Institute of Technology Zürich in Basel. "We would all like to know."

It may be that the sites of epigenetic modifications are somehow labelled, perhaps with a molecule of RNA or a metabolite. Brunet says that her lab is on the hunt for such a signpost.

Dilution effect?

Whatever the mechanism, it does not last forever. By the fourth generation after the mutations have been bred out of Brunet's worms, their lifespan shrinks back to normal. It is possible, says Paro, that whatever marker may have guided methylation over the previous three generations became diluted with each successive brood.

The key question, says Gems, is whether the same epigenetic inheritance of longevity can occur in other animals. Brunet's lab is testing this in mice and in African killifish, some species of which have a lifespan of only 12 weeks.

"The worry of course is that maybe this is just some worm thing," says Gems, who notes that the nematode lifespan seems to be particularly susceptible to changes in individual genes. Ageing in other animals has sometimes proved to be more complex, he explains. "But it's a starting point that should motivate people to look into this further."