Researchers learn how mutations extend life span

In the sense that organisms existing today are connected through a chain of life – through their parents, grandparents, and other ancestors – almost a billion years back to the first animals of the pre-Cambrian era, an animal’s reproductive cells can be considered to be immortal. These germline cells generate their offspring’s somatic cells – other cells involved in all aspects of growth, metabolism, and behavior, which have a set life span – and new germline cells that continue on, generation after generation. 

Now, in a dramatic finding, researchers from the Massachusetts General Hospital (MGH) Department of Molecular Biology have found that certain genetic mutations known to extend the life span of the C. elegans roundworm induce “mortal” somatic cells to express some of the genes that allow the “immortality” of reproductive germline cells. Their report will appear in the journal Nature and is receiving advance online release.

“C. elegans mutants with extreme longevity accomplish this feat, in part, by adopting genetic programs normally restricted to the germline into somatic cells,” says Sean Curran, research fellow in genetics at MGH Molecular Biology and the study’s lead author. “We know that germline cells are more stable than somatic cells – they live longer and are more resistant to stresses that damage other cells – and understanding the molecular pathways involved in that stability may someday allow us to devise therapies protective against age-related decline in other tissues.”

Curran is a research fellow in the laboratory of MGH investigator Gary Ruvkun, whose work focuses on the development, longevity, and metabolism of C. elegans, a tiny worm broadly used as a model for studying basic biological systems. Ruvkun and other researchers discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the life span of C. elegans, and that similar mutations in the corresponding pathways also dramatically extend mammalian life span.

Longevity-associated mutations have been shown to lead to enhanced immune response – including increased control of gene expression through RNA interference (RNAi) – in somatic cells.  Since it is known that RNAi is among the mechanisms underlying germline cells’ enhanced resistance to pathogens and other stresses, the researchers examined whether the reactivation of germline genetic programs was involved in the extended life span of C. elegans mutants.

A series of experiments demonstrated that worms with increased longevity induced by mutations in the insulin-like signaling pathway did exhibit somatic cell expression of genes usually active only in germline cells. The mutant worms also were protected from stresses that damaged the DNA of nonmutant worms.

The researchers also found that inactivating germline-expressed genes in the mutant worms eliminated the increased life span and that longevity-associated mutations in two genes from a different metabolic pathway – one involved with detoxification and stress response – also increased the expression of germline markers.

“The idea that somatic cells can reacquire genetic pathways usually restricted to germline cells is fascinating, and since germline protection is seen across species, the activity of these genes may play a role in controlling mammalian life span,” says Ruvkun, senior author of the Nature paper. “Understanding the mechanisms involved in this transformation could help us develop new ways to repair and even regenerate key cells and tissues.” 

A professor of genetics at Harvard Medical School, Ruvkun was a co-recipient of the 2008 Lasker Award for Basic Medical Research for his role in discovering that tiny molecules of RNA can control the activity of critical genes.

Co-authors of the Nature paper are Xiaoyun Wu and Christian Riedel of MGH Molecular Biology. The study was supported by grants from the National Institutes of Health, the National Institute on Aging, the European Molecular Biology Organization, and the Human Frontier Science Program.