Worms that miss out on longevity genes from generations past can still reap their benefits, according to a study published online October 19 in Nature. Anne Brunet and colleagues at Stanford University in Palo Alto, California, found that genetically normal worms lived as many days as long-lived grandparents that had mutations in a methylation complex that moderates the Caenorhabditis elegans lifespan. The work bolsters the notion that extended lifespan arises not only from certain gene mutations, but also from epigenetic changes that may linger long after the mutations disappear through intercrossing. However, it remains unclear whether the findings apply to mammals.

As a graduate student in Brunet’s lab, lead author Eric Greer, who is now a postdoc with coauthor Yang Shi at Harvard Medical School—identified the histone H3 lysine 4 trimethylation (H3K4me3) complex in a genomewide RNA interference screen for chromatin regulators that influence worm lifespan. By loosening or condensing the packages of DNA and protein in eukaryotic nuclei, chromatin regulators can control expression of genes important for aging. The Stanford scientists found that worms lacking specific components of the H3K4me3 trimethylation complex live 25 to 30 percent longer than wild-type counterparts (Greer et al., 2010). Worms unable to form sex cells, or lacking the H3K4me3 demethylase RBR-2, did not get this longevity boost. Greer then asked a “heretical” question, Brunet told ARF. “What if those chromatin regulators act not only to regulate lifespan in the parents, but also change the chromatin in an epigenetic manner to impact the lifespan of their descendants?”

Though epigenetic changes are typically reset during meiosis, Greer’s hunch had some precedence. Examples of epigenetic inheritance for traits such as flower symmetry, fly stress response, and mammalian coat color dot the literature. Plus, research showed chromatin modifiers to be important regulators of lifespan in worms and flies.

Greer and colleagues wanted to see if longevity conferred by deficiency of individual trimethylation complex components (ASH-2, WDR-5, or SET-2) could carry through to subsequent generations. For WDR-5 and SET-2, they mated wild-type worms with loss-of-function homozygous mutants, then self-crossed the first-generation (F1) heterozygote offspring. Next-generation (F2) worms were genotyped once they laid progeny, and lifespan was measured in subsequent generations. The researchers found that the subset of F3 and F4 descendants with +/+ genotype lived 20-30 percent longer than genetically identical worms resulting from an initial cross of pure wild-type parents. The longer life paralleled that of pure F3 mutants (i.e., WDR-5 or SET-2 loss-of-function homozygotes). Using RNAi to knock down ASH-2 in the parental generation, the researchers saw similar lifespan benefits in the F2 and F3 generations, even though ASH-2 messenger RNA and protein levels had risen back to normal levels.

Similar to the lifespan extension brought on by loss-of-function mutations in the H3K4me3 complex (Greer et al., 2010), the epigenetic longevity effects did not show up in worms lacking a functional germline, or missing the RBR-2 demethylase. In addition, the epigenetic changes seemed fairly specific to H3K4me3 modifiers. Knockdown of other longevity genes (e.g., AGE-1, DOD-23, CCO-1, CYC-1, ASM-3) in parent worms had no impact on the lifespan of subsequent generations.

Although genetically wild-type progeny of mutant worms lived longer than control offspring of pure wild-type parents, their overall H3K4me3 activity was normal, as judged by Western blot and immunocytochemistry. However, the two groups of worms differed at the level of individual genes. For a subset of genes, expression patterns in long-lived, genetically normal worms were the same as in mutant ancestors, and different from expression patterns in normal worms living normal lifespan. This suggests that the H3K4me3 complex exerts epigenetic control over longevity by affecting gene expression at certain loci. The present study did not assess trimethylation status at individual genes.

Curiously, the longevity effect hung around for several generations, then suddenly vanished—for example, F3 and F4 lived 20 percent longer than normal worms, but F5 reverted to normal. Based on these data, Brunet speculates that epigenetic marks may get diluted with each generation until they fall below a threshold that determines whether the animal will exceed the normal lifespan. To explore this possible dosage effect, it would be helpful to see whether heterozygotes exhibit an intermediate longevity phenotype as compared to their wild-type and homozygous mutant siblings, noted Elizabeth Gjoneska of MIT (see full comment below). Gjoneska is a postdoctoral fellow in Li-Huei Tsai’s lab, which studies the role of another epigenetic modifier, histone deacetylase, in memory (see ARF related news story on Guan et al., 2009).

On the whole, Chris Link of the University of Colorado, Boulder, finds the results convincing. “The paper does a good job showing there really is this transgenerational epigenetic longevity effect in worms,” he told ARF. However, he added, “it’s a stretch to know how likely the phenomenon applies to people.” The longevity effect requires the germline, suggesting that the germline communicates with the rest of the worm’s body (soma) to influence lifespan, Link said. This seems plausible, because worms “contribute a lot of energy toward making eggs,” he noted. On the other hand, “people spend most of their resources raising progeny, so communication between the germline and body may not be so important,” Link speculated.

At this point, scientists do not know whether ASH-2, WDR-5, and SET-2 orthologs regulate lifespan in mammals. Brunet and colleagues plan to test this in mice. They are also using whole-genome approaches to work out the molecular basis of the H3K4me3 longevity effect. Given recent rodent studies showing that parental diet alone can lead to metabolic dysfunction in the progeny (Carone et al., 2010; Ng et al., 2010), Brunet’s lab is interested in exploring whether the transgenerational lifespan effect could be transmitted through epigenetic changes triggered environmentally, as well as through specific gene mutations.

In the meantime, the paper adds to the growing demonstration of inherited epigenetic effects, and “may get at the issue of missing heritability,” Link said, referring to the disconnect between estimated and actual genetic contribution in many complex disorders. In Alzheimer’s disease, twin studies suggest a heritability between 60 and 80 percent (see Gatz et al., 2006). However, known risk genes explain only one-third to one-half of that, noted Lars Bertram of the Max-Planck Institute for Molecular Genetics in Berlin, Germany, who heads the team of curators for the AlzGene database. While other risk genes may await discovery, another possible explanation is that heritability does not solely derive from genes, Link suggested, but also on inherited epigenetic marks not revealed by conventional sequencing or whole-genome analysis methods. Last year, the National Institute on Aging organized a workshop to explore the role epigenetic regulation may play in AD (see ARF conference series).—Esther Landhuis


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Comments on News and Primary Papers

  1. What if the elixir of life is encoded in the epigenome and longevity is transmitted in a hereditary fashion? The study by Greer and colleagues certainly seems to indicate that this concept holds true, and provides the first example of transgenerational epigenetic inheritance of a complex trait such as longevity. Given that plastic chromatin-mediated changes in gene expression are required throughout the lifespan, it is not surprising that epigenetic mechanisms, such as post-translational histone modifications that specifically alter chromatin structure, can control the capacity of the organism to adapt. Indeed, a number of chromatin modifiers have already been linked to aging. According to Greer et al., long-term hereditary epigenetic memory of longevity may also be mediated through post-translational modifications of chromatin, thus biologically embedding and transmitting lifespan information from parents to offspring. Importantly, the authors identified components of the methylation machinery responsible for regulating one of the more stable chromatin modifications, histone H3K4me3, as underlying long-term heritable transmission of longevity information.

    The authors suggest that the mechanism by which H3K4 methylation machinery regulates lifespan inheritance is associated with epigenetic changes in gene expression. However, as heritable global changes in H3K4me3 levels were not observed, it would be interesting to examine, on a genomewide level, heritable local changes in H3K4me3 levels and how they correlate to the corresponding gene expression changes. It is also very intriguing that lifespan extension can only be inherited for a limited number of generations, suggesting a potential dosage effect. In that context, an interesting question is whether heterozygotes exhibit intermediate longevity phenotype as compared to their wild-type and homozygous mutant siblings. Whether hereditary lifespan is indeed regulated via H3K4me3 or indirectly, possibly through other, non-histone targets of the methylation complex, transgenerational epigenetic inheritance of longevity is certainly an exciting concept. One may hope that lessons learned from C. elegans will translate to mammalian models.

    View all comments by Elizabeth Gjoneska


News Citations

  1. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified
  2. Bethesda: Dawn of the Epigenetics Era

Paper Citations

  1. . Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. 2010 Jul 15;466(7304):383-7. PubMed.
  2. . HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009 May 7;459(7243):55-60. PubMed.
  3. . Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010 Dec 23;143(7):1084-96. PubMed.
  4. . Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 2010 Oct 21;467(7318):963-6. PubMed.
  5. . Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006 Feb;63(2):168-74. PubMed.

External Citations

  1. epigenetic
  2. AlzGene

Further Reading


  1. . Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. 2010 Jul 15;466(7304):383-7. PubMed.
  2. . Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010 Dec 23;143(7):1084-96. PubMed.
  3. . Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 2010 Oct 21;467(7318):963-6. PubMed.

Primary Papers

  1. . Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011 Nov 17;479(7373):365-71. PubMed.