The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals

Abstract

The lifespan of the nematode, Caenorhabditis elegans, can be extended by mutations affecting components of the insulin-like growth factor (IGF) signaling cascade or by overexpression of SIR2, an NAD⁺-dependent protein deacetylase. The mammalian homologue of SIR2, Sirt1, has been shown to modulate the activity of FoxO, a transcription factor that is downstream of the IGF signaling system. These results suggest that Sirt1 ought to affect the IGF pathway. We report here evidence that this is the case in mice. The loss of Sirt1 protein in mice results in increased expression of the IGF binding protein IGFBP1, a secreted modulator of IGF function. A number of the anatomical characteristics of Sirt1-null mice closely resemble those of transgenic mice overexpressing IGFBP1. Our data suggest that Sirt1 is part of a regulatory loop that limits the production of IGFBP1 thereby modulating IGF signaling.

Introduction

The lifespan of animals appears to be determined by the rate at which reactive oxygen species (ROS) are generated by mitochondria (Barja, 2002). ROS cause damage to macromolecules that culminates in growth senescence (Fridovich, 2004). Both genetic and environmental factors can influence the longevity of individual organisms and these factors are thought to influence either the rate of ROS production or the ability of the organism to absorb or repair damage incurred by ROS (Barja, 2002).

In mammals, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) appear to be critical in determining lifespan (Carter et al., 2002). There is an inverse relationship between lifespan and the level of GH. Mutations that compromise the development of the anterior pituitary result in GH deficient dwarf animals who have increased longevity while transgenes that overproduce GH result in animals with shortened lifespans (reviewed in Tatar et al. (2003)).

One of the important functions of GH is to regulate the synthesis and secretion of hepatic IGF-1. Low levels of circulating IGF-1 are associated with increased longevity and have led to the idea that IGF-1 is the “pacesetter” of aging (McCarty, 2003). Studies from Caenorhabditis elegans have confirmed that IGF-1 signaling is important in lifespan determination as mutations that disrupt signaling through the IGF-1 receptor yield nematodes with extended lifespan (Carter et al., 2002, Kenyon, 2001).

Another group of genes with a role in lifespan determination are those of the sir2 class of NAD-dependent protein deacetylases (Blander and Guarente, 2004). An extra copy of the sir2 gene in C. elegans prolongs lifespan and this effect depends on an intact IGF-1 signaling system (Tissenbaum and Guarente, 2001). Similarly the extension of lifespan that accompanies caloric restriction is dependent on the presence of the sir2 gene (Lin et al., 2000).

The mammalian homologue of sir2 is called Sirt1. To investigate its role in lifespan determination, we created a mouse strain carrying a null allele of Sirt1 (McBurney et al., 2003). The Sirt1 null animals are small, suffer high rates of perinatal lethality, and are sterile. Some of these characteristics are shared with mice carrying null alleles of genes with roles in the IGF-1 signaling pathway (Liu et al., 1993, Peng et al., 2003). These similarities prompted us to investigate the status of the GH and IGF-1 pathways in our Sirt1-null mice.