Prolonged lifespan by defective insulin signalling?

Increasing the individual lifespan of a living being has not only been the urgent desire of mankind throughout its history but has become an interesting focus of research in the last couple of years. Various genetic factors have been identified as being linked with the phenomenon of longevity (1 –3). From an endocrinological point of view, however, the role of insulin-like growth factor-I (IGF-I) in regulating life expectancy has recently been closely investigated. In the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster loss-of-function mutations in the IGF-I signalling pathway prolong life expectancy by 50% and more (4–8). In contrast, activating mutations in insulin and IGF-I signalling reverse the increment in lifespan (7, 8). In rodents, loss-of-function mutations in the transcription factors Pit1 and Prop1 lead to combined pituitary deficiencies and, among other hormone deficiencies, reduced insulin and IGF-I serum concentrations. Interestingly, despite the substantial dysregulation of the endocrine environment, mice with Pit1 or Prop1 mutations have a longer life expectancy than non-affected littermates (9, 10). Generalized loss-of-function mutations in the insulin receptor lead to insulin resistance associated with diabetes mellitus and obesity in rodents and humans (11, 12). As a natural consequence, the mean lifespan of affected individuals is substantially reduced. In this context, Bluher and co-workers (13, 14) generated a fat tissue-specific insulin receptor knock-out mouse. They found that, as early as 3 months of age, these mice maintained a body weight approximately 20% below the body weight of their control littermates. The reduction in body weight was caused by an approximately 60% reduction of fat tissue. Interestingly, their appetite was not reduced, resulting in a food intake equivalent to that of the control animals. As a consequence, food intake related to body weight exceeded the controls by more than 50% (14). These data imply a greater energy expenditure in the knockout animals than in the controls. The fat tissue-specific insulin receptor knock-out mice have been reported to be more resistant against developing glucose resistance and do not develop signs of lipodystrophy (13). Most interestingly, the lifespan of fat tissue-specific insulin receptor knock-out mice was significantly longer than in their nonmutated littermates (14). Whereas 50% of the control animals survived to 30 months of age, 80% of the mutated mice reached this lifespan. The mean lifetime of the mutated mice rose by about 130 days. These data suggest that, at least in the rodent, fat mass is far more important in the determination of life expectancy than calorie intake. Moreover, it is of utmost interest that local, i.e. fat specific, lack of insulin effect does not lead to insulin resistance and diabetes mellitus but to a reduced incidence of the disease by a reduction of total fat mass (13, 14). Bluher and co-worker in their most stimulating papers only fall short of explaining the mechanism of longevity in their fat tissue-specific insulin receptor knock-out mice. They speculate about a reduction in the generation of oxygen-free radicals (15, 16) or a mechanism involving IGF-I signalling but do not provide any data regarding that hypothesis. In summary, however, the above studies on the longevity (see Fig. 1) of fat tissue-specific insulin receptor knock-out mice (13) impressively demonstrate that high calorie intake does not reduce life expectancy as long as energy expenditure is maintained at a high level. For the human being, although certainly caution is warranted, this may imply that the increase of energy expenditure by constant physical activity might be more promising than a reduction of food intake to reduce morbidity and mortality.