Experimental Models Linking Diabetes Mellitus to Aging and Longevity

In some species, caloric restriction (CR) is associated with reduction of aging and increased longevity. It was observed that a reduced body size was correlated to an increased life span in mice, dogs, Caenorhabditis elegans, or Drosophila melanogaster. One very recent study could not find a clear general effect of body size on life span (Hafen, 2004; McCulloch et al., 2003). The question has been asked why smaller individuals would live longer. One explanation that has been put forward, mainly in invertebrates, is the homologous insulin/IGF signaling (IIS). In C. elegans it was suggested that the IIS can act to limit the body size. However, in some wild-type strains this correlation was much less clear. Moreover, several mutations in C. elegans led to extended longevity phenotype. Among these are the genes involved in the insulin/IGF-signaling pathway, such as daf-2 and age-1, or clk mutants related to respiratory metabolism. Similar results were obtained in Drosophila. The study in these model organisms of the IIS pathways contributed in various ways to their understanding. Genetic screens identified novel essential components in the pathways. The relation of these pathways to function helped in physiological conditions to make relation to functions such as growth, differentiation, and cell metabolism. They will continue to remain very useful models and should be extended to type 2 diabetes and aging. In mammals, these correlations do not seem to play an essential role. The data ultimately suggest that body size and longevity are linked in very special circumstances as in CR studies, and this could be related to an increased insulin sensitivity, decreased fasting glucose levels, and possibly oxidative stress.

In the context of human aging, an association between the insulin receptor and longevity can be drawn. Hyperinsulinemia is a characteristic of the diabetes melli-tus type 2 as a consequence of insulin resistance due to the resistance of IR signaling to the effect of insulin binding. Hyperinsulinemia is part of the so-called metabolic syndrome characterized by other risk factors such as abdominal obesity, hypertension, and specific dyslipide-mia, leading to increased incidence of coronary heart disease. Since atherosclerosis is a disease of later age, it is notable that in euglycemic centenarians insulinemia is low and insulin sensitivity high. This means, as seen in the decreased replicative senescence of cells originated from diabetic subjects, that diabetes type 2 is a model of partial premature aging. Thus, sensitivity, and consequently normal IR signal transduction, are a prerequisite to longevity as shown in caloric restriction studies in rodents and nonhuman primates, as well as in centenarians.

Caloric restriction has been shown to enhance longevity in Saccharomyces cerevisiae and Caenorhabditis elegans through increased expression of Sir2 (silencing information regulator 2), a NAD+-dependent histone deacetylase (Wood et al., 2004; Guarente et al., 2005). Sir2 is a member of a family of proteins called sirtuins, which also includes seven mammalian homologues, among which SIRT1 and SIRT3 have been studied in more details. Caloric restriction by increasing NAD+ levels enhances longevity in mammalian cells by activating the analog SIRT1 (Cohen et al., 2004). SIRT1 is known to target p53 and forkhead transcription factors, among others, for deacetylation (Luo et al., 2004; Motto et al., 2004). SIRT1 also reduces NFkB transcription by deacetylation of RelA/p65 (Yeung et al., 2004), and also further promotes protection against cellular stress and apoptosis by modulating the FOXO transcription factors. In addition, activation of SIRT1 may reduce adipose tissue differentiation, lipogenesis, and increase fat mobilization by suppressing PPAR-y activation (Picard et al., 2004). SIRT1 appears to link metabolic fasting signals such as increased pyruvate levels in the liver to PGC-1« activation and induction of gluconeogenesis and hepatic glucose production. SIRT1 may also reduce mitochondrial oxidation and biogenesis by acetylating and deactivating PGC-1«, whereas activation of SIRT3 in brown adipose tissue enhances UCP1 expression, thermo-genesis, and fat oxidation. Recently, the absence of a VNTR polymorphism of the SIRT3 gene that enhances its expression has been associated with reduced longevity in humans. Streptozocin-induced diabetes in mice has also been associated with the suppression of the expression of one of the sirtuin genes (Yechoor et al., 2004). More studies are needed to determine the full impact of these findings for human health and aging, but these studies offer an introduction into new molecular pathways, possibly linking excessive caloric intake, the development of obesity, and diabetes with reduced longevity.

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