Epigenetic regulation of aging in C. elegans
Aging can be delayed by environmental interventions, such as changes in dietary intake, and several aging phenotypes can be reversed by circulating factors from young individuals. Interestingly, these environmental interventions have long-lasting effects on aging phenotypes even after they have been stopped, raising the possibility that epigenetic modifications that stably affect chromatin states mediate long-term organismal changes that delay or reverse aging. We asked if enzymatic complexes that affect chromatin states regulate lifespan by performing a targeted RNAi screen in fertile C. elegans (Greer et al., 2010). We identified a complex that trimethylates histone H3 at lysine 4 (H3K4me3), called the COMPASS complex, as a key regulator of worm lifespan. Deficiencies in members of this COMPASS complex, including ASH-2, WDR-5, and the H3K4 methyltransferase SET-2, all extend lifespan. Conversely, loss of function of the H3K4me3 demethylase RBR-2 leads to shorter lifespan, consistent with the idea that an increase in H3K4 trimethylation – a mark associated with active chromatin – promotes aging. Intriguingly, this COMPASS complex acts in germline cells to regulate the lifespan of the whole organism (Greer et al., 2010). These findings are exciting because they identify a crucial role for histone methylation in aging and reveal a communication between the ‘immortal’ germline and the ‘mortal’ soma for the regulation of lifespan. We have extended our exploration of epigenetic regulation of aging to histone marks associated with repressed chromatin. We discovered that deficiency in UTX-1, a demethylase for the repressive H3K27me3 mark, extends worm lifespan, but, unlike H3K4me3 regulators, it does so independently of the germline (Maures et al., 2011). The H3K27me3 mark significantly drops in somatic cells during normal aging (Maures et al., 2011), suggesting that repressive H3K27me3 levels allow somatic maintenance during aging.
A tantalizing question is whether epigenetic regulation of lifespan could extend to subsequent generations. We discovered that deficiencies of members of the H3K4me3 complex (ASH-2, WDR-5 or SET-2) only in the parental generation affect lifespan of subsequent generations of descendants that not longer have the initial mutation (Greer et al., 2011) (Fig. 2). Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with heritable changes in gene expression. Our study provides the first example of epigenetic inheritance of lifespan. This result is intriguing in light of the observed transgenerational inheritance of metabolic traits in many species (Carone et al., 2010; Dunn and Bale, 2011; Padmanabhan et al., 2013; Painter et al., 2008) and could have a transformative impact on how the field approaches complex traits.
Another powerful stimulus is the presence of the opposite sex. In species ranging from worms to primates, lifespan in the laboratory is almost always assessed in conditions where males and females are kept separate. We have discovered that in C. elegans, the presence of males shortens the lifespan of the opposite sex (hermaphrodites) and accelerates aging. Interestingly, this ‘male-induced demise’ can be triggered by conditioned media from males, indicating that a secreted factor, such as a pheromone, can elicit the demise of the opposite sex. Indeed, pheromone signaling is necessary for male-induced demise (Maures et al., 2014). Male-induced demise also occurred in distantly related nematode species, suggesting an evolutionary conserved process whereby males may induce the disposal of the opposite sex once progeny are born, perhaps to save resources for the next generation or prevent competition from other males (Maures et al., 2014). These results are exciting because they point to a conserved ‘non-organismal autonomous’ regulation of aging. We are interested in understanding how aging is influenced by other individuals.
Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro, GS, Han S, Banko MR, Gozani O and Brunet A (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature, 466: 383-387. Abstract PDF
Maures TJ, Greer EL, Hauswirth AG, and Brunet A (2011). H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent, manner. Aging Cell, 10: 980-990. Abstract PDF
Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y and Brunet A (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature, 479: 365-371. Abstract PDF