## 5 Plant Compounds and Longevity
In addition, the extract exerted neuroprotective effects, reducing amyloid-\(\beta\)-induced paralysis and reducing \(\alpha\)-synuclein aggregation in a CL4176 transgenic strain. Other studies have analyzed the longevity-promoting effects of some plants using _Drosophila melanogaster_ (common fruit fly) in an animal model. [PERSON] et al. [182] investigated the effects of the isoflavone prunetin on lifespan in _D. melanogaster_. A diet supplemented with prunetin was shown to extend life expectancy by three days in males and induce the expression of the longevity gene sirutin 1, which is associated with AMP-activated protein kinase (AMPK) activation. The authors suggest that prunetin, as an isoflavone, may feminize male flies, thus affecting their health and lifespan. Moreover, _Rel_ gene expression (_Rel_ is a member of the NF-\(\kappa\)B family), was significantly upregulated in male fly midguts after prunetin treatment with respect to the controls. The authors suggested that prunetin may improve resistance against microbiological stressors derived from food, promoting health and longevity. In another study, the administration of a methanol extract from the fruits of _Platanus orientalis_, which are rich in polyphenols, reduced ROS production, recovered proteasome activity associated to aging, and increased median and maximum longevity in _D. melanogaster_[183]. The administration of purified tilioside, a major glycosidic flavonoid from _Platanus orientalis_, also exerted similar results to those observed with the methanolic extract, also enhancing lysosomal-cathepsin activity. Tiliroside treatment reduced the production of ROS and increased the expression of protective genes such as _hsp70_ and _trxT_, which are derived from the activation of antioxidant response elements. The authors indicate that the activation of the AMPK pathway could explain the upregulation of autophagy and lysosomal-cathepsins. Finally, tiliroside was also capable to delay the progression of cellular senescence in human fibroblasts (specifically, the IMR90 cell line). _Ilex parasquariensis_, known as yerba mate, significantly extended the lifespan of flies, modulating the expression of antioxidant enzymes and increasing tolerance to stressful situations [184]. Two interesting investigations analyzed the anti-aging effects of plant extracts on neurodegenerative disease models. In the first study, grape skin extract improved flight muscle function, extending lifespan in a _D. melanogaster_ model of PD [185]. Among the mechanisms of action were the activation of autophagy, the preservation of mitochondrial function, and the reduction of aberrant mitochondrial aggregates. Autophagy activation was evidenced by a reduction in the autophagy receptor p62 and the conversion of LC3-I to LC3-II. In the second study, an extract of _Rhodiola rosea_ was tested in a [PERSON]'s disease model of _D. melanogaster_[186]. The extract improved locomotion and lifespan. The mechanism of action here is associated with the activation of autophagy, in part by the inhibition of the mTOR pathway, which would counteract the negative effects of [PERSON] mutant proteins. The flavonoid 4,4'-dimethoxyychalcone, found in the plant _Angelica keiskei koidzumi_, with longevity- and health-promoting effects, which is traditionally used in Asian folk medicine, was also reported to prolong the median lifespan of _C. elegans_ and _D. melanogaster_[187]. Moreover, the flavonoid prevented senescence in highly confluent human cells (HeLa cervical carcinoma, U2 OS osteosarcoma, and H4 neuroblastoma cells) through the induction of a pro-autophagic response, increasing the formation of autophagosomes and autophagic flux. The mechanism of action of 4,4'-dimethoxyychalcone involves specific GATA transcription factors, specifically, the GATA transcription factor Gln3. The flavonoid can interfere with the autophagy-repressive activity of Gln3, resulting in increased autophagic flux and cytoprotection in a process independent of TORC1 activity.