Identification of natural compounds that promote proteasome activation and confer lifespan extension

The proteasome is the major cellular proteolytic machinery responsible for the degradation of both normal and damaged proteins shown to be down-regulated during senescence. On the contrary, its activation confers lifespan extension and maintenance of the young morphology for longer in human primary fibroblasts. Furthermore, it represents one of the main secondary antioxidant mechanisms. In this study, extracts derived from plants of the Greek flora (such as Punica granatum, Rosa damascena, Quercus sp., Hedera helix, Origanum dictamnus, Liquiritieae glabra, Myrtus communis) were studied in order to identify natural compounds that promote proteasome activation. We have identified 3 compounds (flavonol and triterpenic type) that promote the following characteristics to cultures of HFL-1 primary human fibroblasts: a) proteasome activation up to 2-folds accompanied by increased amounts of functional proteasome, b) increased resistance and survival to oxidative challenges, c) decreased intracellular oxidative load and levels of reactive oxygen species (ROS) and, d) as a natural consequence of the above mentioned characteristics, delay of the appearance of the senescent morphology and lifespan extension. Moreover, when these compounds were supplemented to senescent fibroblasts, a rejuvenating effect was observed. Besides, since tyrosinase, a known proteasome substrate, plays a pivotal role in the melanin pigment biosynthetic pathway which is mainly responible for the age spots, the whitening properties of these compounds were tested and revealed. These data demonstrate the beneficial effect of natural compounds in human fibroblasts undergoing replicative senescence, while, this study provides new insights towards enhancement of cellular antioxidant mechanisms by natural compounds.