## 5 Plant Compounds and Longevity
The mechanism of action implies a reduction in the total production of ROS, quantified with dichlorodihydrofluorescein diacetate (H2 DCF-DA), showing a lower accumulation of lipids and an activation of stress-inducible genes derived from an upregulation of the transcription factor DAF-16 and the downstream genes _lsp-16.2_ and _sod-3_. Mutants for DAF-16 and for the cytochrome b subunit of mitochondrial complex II (_mev-1_ strain), which lead to an overproduction of superoxide anions, did not respond to 4-HEG supplementation, suggesting that 4-HEG reduces oxidative stress but also needs an endogenous detoxification pathway in order to reduce it. The longevity-promoting activity of another plant used in Indian medicine, namely, _Withania somifera_ root extract, was also investigated in _C. elegans_[176]. The extract, which is considered as a traditional healthy long-life supplement did not exert significant effects on wild-type worms. Another interesting investigation analyzed the effects of _Viscum album coloration_ (Korean mistletoe) extract on _C. elegans_ and _Drosophila melanogaster_ lifespan [177]. The treatment with the extract significantly extended longevity in both species, without altering feeding or reproduction. Korean mistletoe extract, when administered together with full diet, increased the expression of sirtuin 2 (SIRT2), a target gene of dietary restriction, suggesting an effect as a dietary restriction mimetic. _Rosmarinus officinalis_ ethanolic extract was also investigated as longevity agent in on _C. elegans_[178]. The treatment with _R. officinalis_ extended _C. elegans_ longevity in an insulin/insulin growth factor (IGF) signaling pathway-dependent manner, leading to the activation of a conserved phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) cascade, which, in turn, caused the phosphorylation of the DAF-16/FOXO, heat shock factor (HSF)-1, and skinhead 1 (SKN-1/Nrf2) transcription factors. The extract also increased the resistance against oxidative and thermal stress by reducing the production of ROS and protecting against oxidative damage, suggesting that _R. officinalis_ modulates signaling pathways essential for defensive processes. Blueberry extract (_Vaccinium_ spp.) increased the lifespan of _C. elegans_ in a dose-dependent manner, reduced lipofuscin accumulation and ROS production, increased the activity of SOD, and diminished the levels of malondialdehyde(MDA). In addition, the extract increased stress tolerance by inducing the expression of genes related to antioxidant defense, including _cat-1, sod-3, daf-16, mev-1, sdn-1, mek-1_, and _nhr-8_[179]. The use of RNAi to inhibit the transcription factor DAF-16 reduced lifespan and reduced the expression of the _sod-3_. In another study, the isoprenylated aurone damaurone D was tested for its longevity-promoting effect in _C. elegans_[180]. Similar to other studies, the compound increased the lifespan of wild-type nematodes, reduced ROS production, increased CAT and SOD activity, increased _sod-3_ gene expression, and also improved stress tolerance under oxidative, thermal, and osmotic stress via the upregulation of _lsp-16.2_ and _sod-3_. The mechanism of action seems to involve genes related to the insulin/IGF signaling pathway, _daf-2, age-1_, and _daf-16_, evidenced by gene-specific mutant studies. In addition, damaurone D supplementation augmented the translocation of _daf-16_ to the nucleus, inducing the expression of genes involved in extending lifespan and protecting from oxidative damage. _Betula utilis_ ethanolic extract, a medicinal plant from the Himalayan area,increased the lifespan of the worms under normal conditions, but also under oxidative and thermal stress, reducing ROS production and lipofuscin accumulation in a process mediated by the insulin/IGF signaling pathway and also by _sir-2.1_ gene expression [181]. _B. utilis_ extract also induced the nuclear translocation of daf-16 and the subsequent gene expression of _sod-3_ and _gst-4_.