**5.** *set-18* **gene involvement in ageing and lifespan regulation**

*C. elegans set-18* gene was identified as a histone H3K36 dimethyltransferase. The deletion of *set-18* increased lifespan and oxidative stress resistance depending on the *daf-16* activity in the insulin/IGF pathway. Muscle-specific expression of *set-18* increased in aged worms, resulting in elevation of global H3K36me2 and inhibition of *daf-16a* expression and, consequently, decreased longevity. These results suggest that H3K36me2 and H3K36me3 modification have distinct functions in regulating ageing [11].

The FOXO family of transcription factors are highly conserved key converging points of several longevity pathways. *C. elegans* has a single FOXO orthologue, *daf-16*, and mutants with *daf-16* deficiency exhibit shortened lifespan compared with wild-type animals. Very recent studies showed that *daf-16* functions downstream of a histone modifier to influence lifespan. *daf-16* lifespan epistasis analyses suggest that the *set-18* gene works through *daf-16* to modulate lifespan. As *daf-16* transcript levels are not affected by *set-18* status in worms and that *set-18* regulates global histone modifications, an interesting possibility is that *set-18* acts as a cofactor of *daf-16* in target gene regulation *via* changes in local chromatin accessibility.

However, it is also possible that like UTX-1, *set-18* modulates the lifespan by regulating the expression of components of daf-16-dependent longevity pathways. Several well-known longevity pathways impinge on *daf-16*, including the *daf-2*/insulin pathway (insulin and IGF-1 signalling), the germline pathway, and the energetic metabolism pathway. Lifespan and oxidative stress tolerance are promoted by the FOXO *daf-16* and suppressed by its upstream IIS pathway genes such as the exclusive insulin-like growth factor receptor *daf-2* [32, 33].

The insulin and IGF-1 signalling (IIS) pathway are so highly conserved to modulate ageing and longevity. The IIS pathway is a signal transduction cascade that consists of insulin-like peptides (ILPs), an insulin/IGF-1 receptor (*daf-2*), a phosphoinositide 3-kinase (AGE-1/AAP-1/PI3K), serine/threonine kinases (PDK-1, AKT-1 and AKT-2) and the pivotal downstream forkhead box O transcription factor (*daf-16*) in *C. elegans*. This cascade in turn phosphorylates the FOXO/*daf-16* and prevents it from entering the nucleus to trigger anti-ageing genes, such as the genes conferring resistance to heat, oxidative stress resistance and DNA damage [24–27] as presented in **Figure 3**. *daf-16*/FOXO receives phosphorylation from the direct upstream AKT

*Epigenetic Modifications Involved in Ageing Process: The Role of Histone Methylation… DOI: http://dx.doi.org/10.5772/intechopen.100476*

**Figure 3.** *Possible action of set-18.*

kinases mediated signal transduction response to insulin or IGF and is subsequently sequestered in the cytoplasm by 14-3-3 proteins [34–36], which antagonises FOXO and negatively regulates the longevity [27, 32].
