Oxidative stress is the major driving force behind the aging process and many age-related diseases. However, direct experimental evidence of whether antioxidants, such as ascorbate (AA) and lipoic acid (LA) can slow the progression of aging process and/or reduce risks of developing degenerative disease is largely absent. This suggests a better understanding of the precise mechanism of how dietary micronutrient affect parameters of involved in cellular redox balance and aging are warranted. In this dissertation, young and old rats were used as our model to understand potential pro-oxidant events that contribute to increases in oxidative stress in various tissues and how antioxidants such as ascorbate and lipoic acid influence these events. Our major findings are that the age-related impairment of mitochondria and increased deposition of iron contribute significantly to heighten levels of oxidative stress, as evidenced by the resultant increases in the rates of oxidant appearance and in the levels of oxidative damage to DNA, lipids and proteins. We find that AA and LA strongly protected against transition metal-ion dependent increases in oxidative stress. AA effectively inhibited transition metal-mediated lipide peroxidation in human plasma. LA in its reduced form effectively binds iron and copper in a redox inactive manner and reversed chronically elevated levels of iron in the brain without removing enzyme bound transition metal ions. LA also significantly attenuated the age-related increase in oxidative stress associated with mitochondrial decay in the heart, as evidenced by the improvements in AA levels and glutathione redox status. The declines in tissue GSH levels in aged rats were strongly associated with the diminished γ-GCL activity (in parallel with decreased expression of the catalytic and modulatory subunits), and lowered Nrf2 expression and binding to ARE sequence in rat liver. Remarkably, all these events were effectively reversed by the administration of LA, modulating the parameters to return to the observed in young animals. The implications of this work open new avenues not only for further understanding of the aging process but also for possible strategies in its modulation by the micronutrients. / Graduation date: 2004

O envelhecimento cutâneo tem grande importância na pesquisa, influenciando muito no bem-estar psíquico do indivíduo e nos relacionamentos sociais, na auto-estima e na qualidade de vida. Devido a isso, é dado crescente valor à aparência e, cada vez mais as pessoas buscam a juventude da pele, visando mantê-la firme, macia, com aparência saudável e homogeneamente pigmentada. A Cosmetologia busca entender profundamente este processo, desenvolvendo diversas formulações que retardam o envelhecimento cutâneo, com ações emoliente, umectante, hidratante, tonificante, fotoprotetora e uniformizadora da textura da pele. Para atingir isto, os produtos cosméticos incorporam vitaminas, oligoelementos, extratos vegetais, antioxidantes, alfa e beta hidroxiácidos e protetores solares, dentre outros. O público está mais exigente, esclarecido e interessado nos efeitos reais das formulações cosméticas, e menos enganáveis pela falsa publicidade. Portanto, os cosmetólogos estão constantemente pesquisando substâncias novas para combater e principalmente, prevenir o envelhecimento cutâneo. Novas formulações têm sido desenvolvidas com substâncias que possam atingir a eficácia pretendida e que sejam seguras ao usuário. / The cutaneous aging has great importance in the research. It largely influences not only on the psychic well-being of the individual but also on the social relationships, self-respect and quality of life. Due to this, increasing value has been given to the appearance and, people are looking for the youth of the skin, in order to keep it firm, soft, healthy and with homogeneous pigmentation. Cosmetology tries to understand this process, developing some formulations that delay the skin aging, with emollient, humectant, moisturizing, tonic, photoprotective and conditioning skin actions. In order to reach that, vegetable extracts, vitamins, antioxidants, oligoelements, sunscreens, alpha and beta hydroxy acids, and other substances are incorporated in the cosmectic products. Nowadays, the people are more demanding, clarified and interested in the real effects of the cosmetic formulations, and they are not so easily-fooled. Therefore, the cosmetic experts are often researching new substances in order to attack and mainly to prevent the cutaneous aging, and for this new formulations have been developed with substances which are able to reach the intended effectiveness and that are safe.