Isolation of natural products with anti-ageing activity from the fruits of Platanus orientalis.

BACKGROUND: Ageing is defined as the time-dependent decline of functional capacity and stress resistance resulting in increased morbidity and mortality. HYPOTHESIS/PURPOSE: Reportedly, these effects can be delayed by mild genetic or pharmacological activation of the main modules of the proteostasis network. STUDY DESIGN-METHODS: By employing advanced phytochemical methods we isolated natural products from the fruits of Platanus orientalis and studied (via a bio-guided approach) their effects in Drosophila flies, as well as in normal human fibroblasts. RESULTS: We report herein that dietary administration in Drosophila flies of a phenolics-enriched methanol extract from the fruits of Platanus orientalis exerted antioxidant effects; activated proteostatic mechanisms and mildly extended flies' longevity. We then isolated the two major compounds of the extract, namely Platanoside and Tiliroside and found that enrichment of the total extract with these compounds decreased oxidative stress and (in the case of the Tiliroside enriched extract) activated proteostatic mechanisms. Administration of purified Tiliroside in flies activated proteostatic genes, enhanced proteasome and lysosomal-cathepsin activities and decreased tissues' oxidative load; moreover, it delayed the rate of age-related decrease in flies' locomotion activity and increased flies' longevity. Notably, Tiliroside also activated proteasome in normal human fibroblasts and delayed progression of cellular senescence indicating that it may also impact on human cells rate of senescence. CONCLUSION: Our presented findings highlight the potential anti-ageing activity of naturals products derived from the fruits of P. orientalis.

The Indirubin Derivative 6-Bromoindirubin-3'-Oxime Activates Proteostatic Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effects.

AIMS: Organismal aging can be delayed by mutations that either activate stress responses or reduce the nutrient-sensing pathway signaling; thus, by using Drosophila melanogaster as an in vivo experimental screening platform, we searched for compounds that modulate these pathways. RESULTS: We noted that oral administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 6-bromoindirubin-3'-oxime (6BIO) in Drosophila flies extended healthy life span. 6BIO is not metabolized in fly tissues, modulated bioenergetic pathways, decreased lipid and glucose tissue load, activated antioxidant and proteostatic modules, and enhanced resistance to stressors. Mechanistically, we found that the effects on the stress-responsive pathways were largely dependent on the activity of the transcription factor nuclear factor erythroid 2-related factor (Nrf-2). Genetic inhibition of Gsk-3 largely phenocopied the 6BIO-mediated effects, while high levels of Gsk-3 expression and/or kinase activity suppressed proteostatic modules and reduced flies' longevity; these effects were partially rescued by 6BIO. Also, 6BIO was found to partially reduce the 3-phosphoinositide-dependent protein kinase-1 (Pdpk1) activity, a major effector of the insulin/insulin-like growth factor-1 cell signaling pathways. INNOVATION: 6BIO exerts the unique property of increasing stress tolerance and in parallel partially suppressing the nutrient-sensing pathway signaling. CONCLUSION: Our findings suggest that the 6BIO scaffold can be used for the development of novel antiaging compounds. Antioxid. Redox Signal. 27, 1027-1047.