Aging and age-related diseases

A number of diseases, including cancer and neurodegenerative disorders are age-dependent. Is aging itself a regulated process and if so, are there common molecular mechanisms underlying the age-dependency of several disorders? Aging has traditionally been thought to be due to ‘wear and tear’. However, this view has changed. A set of studies indicates that longevity can be affected by simple changes in the environment or mutations in simple genes. For example, reduction in food intake without malnutrition extends lifespan in a wide range of species from yeast to primates (Masoro, 2000). Longevity has also been shown to be controlled by several genetic pathways.

The Insulin/IGF-1 signaling pathway

A pivotal breakthrough in identifying genes involved in longevity came from studies in the worm C. elegans. Worms that are mutant for the gene encoding the insulin receptor can live two to three times longer than wild type worms (Kenyon et al., 1993; Kimura et al., 1997). Remarkably, flies and mice that have mutations in the insulin or the insulin like growth factor-1 (IGF-1) receptor genes are also long-lived (Tatar et al., 2001; Holzenberger et al., 2003; Bluher et al., 2003). These results indicate that insulin and IGF-1 regulate longevity in a conserved manner. Insulin and IGF-1 act by binding to their tyrosine kinase receptor and elicits the activation of phosphoinositide 3 kinase (PI3K) (Cantley, 2002). PI3K in turns phosphorylate phospholipids at the plasma membrane, which triggers the activation of the protein kinases Akt and SGK (serum glucocorticoid inducible kinase). Akt and SGK phosphorylate a variety of substrates, including FOXO transcription factors (Brazil et al., 2004).

FOXO transcription factors

The signaling pathway connecting insulin, Akt, and FOXO transcription factors provides a compelling example for a genetic pathway that regulates lifespan. We discovered that the mammalian FOXO transcription factor FOXO3 is a key target of the insulin/growth factor activated Akt pathway (Brunet et al., 2002). In the absence of growth factors, FOXO3 is localized in the nucleus, where it upregulates key target genes. In the presence of growth factors, the protein kinase Akt and SGK are activated and promote FOXO3 exclusion from the nucleus by phosphorylating FOXO3, thereby repressing FOXO3 function (Brunet et al., 2001, Brunet et al., 2002).FOXO trancription factors play important roles in a set of cellular responses, including glucose metabolism, cell death, cell cycle arrest, repair of damaged DNA , and detoxification from reactive oxygen species (Brunet et al., 1999, Brunet et al, 2001; Medema et al., 2000; Nakae et al., 2001; Kops et al., 2002; Tran et al., 2002). Using a genomic approach, we identified a series of FOXO3 target genes that are involved in various aspects of the stress response (Tran et al., 2002). These results provided evidence that FOXO factors induce stress resistance in mammalian cells, which is a key component of increased organismal longevity in a variety of species (Kirkwood and Austad, 2000).

Interaction between SIRT1 deacetylase and FOXO

The Sirtuin family of protein deacetylases is another important module that controls longevity in a wide range of organisms (Haigis and Guarente, 2006). SIRT1, a member of the Sirtuin family that is most closely related to invertebrate Sir2, deacetylates numerous substrates, including histones and specific transcription factors. We found that in response to oxidative stress stimuli, SIRT1 binds to and deacetylates FOXO3, a member of the FOXO family, and tips the balance of FOXO3 function towards cellular quiescence and oxidative stress resistance (Brunet et al., 2004). Interestingly, the enzymatic activity of SIRT1 can be targeted by small molecule inhibitors and activators (Grozinger et al, 2001; Howitz et al, 2003, Napper et al., 2005), underscoring the potential for SIRT1 as a therapeutic target to modulate longevity.

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