Impact of Aging and Obesity on Insulin Parameters, T4/T3 Ratios, Metabolic Rates, Sirtuins and Longevity in Congenic LA/Ntul//-cp (Corpulent) Rats

The integrated effects of aging on thyroidal function and other hormonal and regulatory aspects of metabolism are important elements in various aspects of aging and longevity. Changes in thyroidal activity occur in aging, where they typically exhibit a U-shaped curve for plasma TSH concentrations, with variable responses in other parameters of thyroidal function and peripheral physiological actions and their pathophysiologic sequelae. The LA/Ntul//-cp rat strain, developed from a cross between a Koletsky Rat and an NIH longevity-prone LA/N strain of unknown origin exhibits one of the longest life spans of the various rodent strains that express a trait for early onset obesity in association with impairments in sympathetic and thyroidal components of non-shivering thermogenesis, insulin resistance and energy metabolism. To determine the effects of aging and obesity from adolescence through much of the projected lifespan of the obese phenotype, groups of congenic lean and obese female LA/Ntul//-cp rats were studied from 4 until 24 months of age denoting this design comprised the projected lifespan of the obese phenotype. Measures of Resting Metabolic rates (RMR), fasting plasma insulin and glucose, T3, T4, the plasma half-life of T4, and computation of T4/T3 ratios were determined as an indication of the capacity for deiodination of T4 to T3 in peripheral tissues and its cumulative effects on RMR. Body weight of obese >>> lean at all ages studied. Plasma Insulin was significantly elevated in the obese phenotype, and decreased with advancing age, while plasma glucose remained within the normal fasting range in all rats of both phenotypes. RMR of lean > obese at all ages studied and decreased with advancing age in both phenotypes. Liver T4-5’ deiodinase activity of lean > obese at all ages studied. Plasma T4/T3 ratios decreased with aging in both phenotypes, with the greatest decrease in the obese phenotype. The T1/2 of 131I-T4 was over 40 % longer in the obese phenotype littermates at 4 months of age (p=< 0.01). These results suggest that conversion of T4 to T3 in peripheral tissues in association with attenuation of hyperinsulinemia contributes to decreases in RMR with aging and is further decreased in the obese phenotype, thereby decreasing the quantifiable availability of tissue T3 mass for thyroidal actions at the genomic level, including decreases in harmful reactive oxygen species (ROS) and other entities as products of intermediary metabolism. Thus, the progressive decreases in plasma insulin and deiodination-mediated activation of T4 may represent a longevity attribute via decreases in resting metabolic rates, and in an associated attenuation of free radical generation and other metabolic factors of aging and longevity in this strain.