MECHANISMS BY WHICH CU/ZNSOD OVEREXPRESSION IMPROVES METABOLIC HEALTH IN RATS

Despite the increasing numbers of aging individuals in our country, there is little understanding of theinteraction between the mechanisms of aging and the pathophysiology of age-related diseases. Research inthis area is essential since age is the largest risk factor for various diseases. If this relationship can be resolved,it would open new avenues for therapeutic interventions to treat/prevent age-related diseases. Oxidative stressis one of the fundamental biological processes that link aging and age-related diseases. Yet, studies usingtransgenic/knockout mice with various antioxidant enzyme levels have yielded contradictory results. Mylaboratory has pursued novel animal models and innovative approaches to examine mechanisms by whichoxidative stress plays a role in aging and age-related diseases. For this purpose, we conducted a study withgenetically-modified Sprague-Dawley (SD) rats that globally overexpress Cu/ZnSOD [Tg(hSOD1)+/0]. Notably,Tg(hSOD1)+/0 SD rats had a significant increase in lifespan and a major reduction in age-related pathologies.Moreover, while aged wild-type (WT) rats became obese and insulin resistant (a classic feature of aged WT SDrats), Tg(hSOD1)+/0 SD rats had lower plasma glucose and insulin concentrations, and increased insulinsensitivity as measured with an insulin clamp. These results were the first to show that overexpressingCu/ZnSOD had beneficial effects on aging and age-related diseases in rats, and our findings suggestthat the benefits of Cu/ZnSOD overexpression on age-related pathology may be mediated, in part,through pathways that regulate glucose metabolism. To advance these seminal findings, the goal of the current application is to assess the specificmechanisms contributing to the improved lifespan and healthspan of Tg(hSOD1)+/0 SD rats. We propose thatCu/ZnSOD overexpression increases longevity in SD rats by attenuating age-related metabolic disorders thatunderlie age-related pathophysiology. The increase in adiposity and accompanying secretory phenotypicchanges are considered to play major roles in aging and the onset/progression of various age-related diseasesthrough several mechanisms, e.g., systemic inflammation, insulin insensitivity, oxidative stress, andredox-sensitive signaling changes. Importantly, we found that Cu/ZnSOD overexpression significantly reducedthe accumulation of senescent cells in adipose tissue, and enhanced the insulin signaling pathway mainly inskeletal muscle. Here, we hypothesize that Cu/ZnSOD overexpression in SD rats improves age-relatedchanges in metabolic health by 1) attenuating secretory phenotypic changes in fat tissues and/or 2)enhancing insulin sensitivity in skeletal muscles. To further examine the possible underlying mechanismsinvolved in age-related changes in metabolic health, we recently generated two novel SD rat models: 1)overexpressing Cu/ZnSOD only in skeletal muscle [Tg(MCK-hSOD1)+/0]; and 2) overexpressing Cu/ZnSOD onlyin adipose tissue [Tg(ADN-hSOD1)+/0]. The Tg(MCK-hSOD1)+/0 (skeletal muscle) SD rats were developedbecause skeletal muscle is the predominant site for insulin-mediated glucose disposal and oxidation; while theTg(ADN-hSOD1)+/0 (adipose tissue) SD rats will allow us to examine how cellular senescence and secretoryphenotypic changes in adipose tissue contribute to insulin resistance and age-related pathology. If successful, the study will elucidate the role of oxidative stress pathways in the genesis of age-relatedmetabolic disorders. This work will be the first to directly determine whether effects of enhanced antioxidantprotection in skeletal muscle and/or adipose tissue could prevent insulin resistance, either by alteringage-related changes in the secretory phenotype of adipose tissue, and/or insulin action of skeletal muscle in ourunique rat models. This is a novel approach, which could provide critical information in identifying the cellularbasis for age-related metabolic disorders in obese individuals, many of whom have an increased risk of insulinresistance, diabetes, cancer, and cardiovascular disease. Thus, this work could have a significant impact onpublic health for many chronic diseases affecting the U.S. population, each of which is exacerbated byage-related changes in metabolic health under an obese condition.