Induction of cellular stress responses by phytochemicals for nutritional applications toward anti-aging intervention

Abstract

Human lifespan has increased significantly in developed and developing countries, raising considerably the percentage of elderly people. Aging is an important risk factor for the development of age-related diseases and is associated with decreased cellular antioxidant defenses and impaired stress responses, reducing the ability of cells to cope with stress. Epidemiological studies indicate a direct relationship between fruit and vegetable intake and increased longevity as well as decreased mortality from chronic age-related diseases, such as cardiovascular diseases and cancer. Antioxidant phytochemicals are proposed as bioactive compounds. However, due to their low bioavailability after intestinal absorption, plant bioactive compounds are likely to act not as direct antioxidants but rather through the modulation of proteins, gene expression and cell signaling pathways. As xenobiotics, we hypothesize that, by imposing mild stress on human cells, antioxidant phytochemicals may afford anti-aging properties through induction of stress responses and cellular antioxidant defenses. Our group, under the scope of the undergoing NaturAge project, is currently investigating this hypothesis, namely the ability of some plant extracts and isolated phytochemicals to induce antioxidant defenses through Nrf2/ARE signaling. That, by making use of biochemical and molecular tools, will be associated with possible anti-aging effects using normal human skin fibroblasts undergoing aging in vitro. Recently, we have shown the ability of the polyphenol curcumin to induce cellular antioxidant defenses through induction of a stress response in normal human skin fibroblasts, affording protection from a further oxidant challenge with tert-BOOH [1]. Curcumin incubation for 24h induced heme oxygenase-1 (HO-1) protein levels, GST activity, GSH levels and GSH/GSSG ratio. These effects were preceded by induction of oxidative stress as shown by increased levels of ROS and DNA damage, and impairment of the cells’ GSH redox state. The induction of antioxidant defenses in human fibroblasts was shown to be redox and PI3K/Akt dependent [1]. Replicative senescent cells possessed higher constitutive HO-1 levels, and induction of HO-1 by curcumin was considerably impaired. In conclusion, the induction of stress responses by curcumin in human skin fibroblasts, which resulted in protection against a subsequent stressor, supports the view that phytochemical-induced hormetic stimulation of cellular antioxidant defenses can be a useful approach toward anti-aging intervention. [1] Lima CF, Pereira-Wilson C, Rattan SIS. Molecular Nutrition and Food Research, 2010, in press. (DOI: 10.1002/mnfr.201000221)