Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse

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Abstract

Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell dwarf (Pit1dw/Pit1dw) mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the dwarf mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85α to IRS-2; (c) docking of p85α to p110α or p110β, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRβ-IRS-1-PI3K pathway is attenuated in the Snell dwarf mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRβ and the docking of p85α to IRS-1 are attenuated in the aged Snell dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell dwarf mouse and conforms to the nematode longevity paradigm.

Introduction

Experimental models including yeast, nematodes, fruit flies and rodents have established that aging and longevity are in part under genetic control (Guarente and Kenyon, 2000; Kenyon et al., 2001). Mutation analyses in Caenorhabditis elegans (C. elegans) have identified daf-2 and age-1 as genes whose decreased activities contribute to the mechanisms of regulation of longevity via hormone signal transduction i.e. an insulin/insulin-like growth factor-1 (IGF-1) signaling pathway (Johnson and Wood, 1982, Kenyon et al., 1993, Larsen et al., 1995, Morris et al., 1996, Kimura et al., 1997). It has been proposed that longevity in Snell (Pit1dw/Pit1dw) and Ames (Prop1df/Prop1df) dwarf mice is associated with decreased growth hormone (GH) levels caused by the Pit1 or Prop1 mutations which cause decreased circulating insulin and IGF-1 levels and result in decreased activity of the insulin/IGF-1 signaling pathway (Fig. 1; Brown-Borg et al., 1996, Sornson et al., 1996, Bartke et al., 1998, Flurkey et al., 2001, Flurkey et al., 2002). Thus a decreased activity of the insulin/IGF-1 pathway, in Snell, Ames and Laron dwarf mice and in Drosophila, suggests a similarity in the physiological processes that regulate longevity in the nematodes (Fig. 1; Dorman et al., 1995, Kenyon, 1997, Lin et al., 1997, Ogg et al., 1997, Ogg and Ruvkun, 1998, Paradis and Ruvkun, 1998, Tissenbaum and Ruvkun, 1998, Mihaylova et al., 1999). In a previous study we have shown that the levels of circulating insulin are severely decreased in Snell dwarf mice. We also observed a dramatic decrease of liver IRS-2 pool levels and its interactions with downstream signaling proteins (Hsieh et al., 2002). This includes a decrease of PI3K activity, decreased docking of the P13K regulatory subunit, p85α to IRS-2, and a decrease in docking p85α with the P13K catalytic subunits, p110α and p110β. Thus, the mutations of daf-2 and age-1 that give rise to the long-lived nematode, and the Pit1 mutation of the long-lived Snell dwarf mouse may result in similar physiological changes, i.e. decreased activity of the insulin/IGF-1 signaling pathway. In effect, the deficiency of GH in the dwarf mice may result in a decreased insulin/IGF-1 signaling pathway activity and thereby play a role in determining rodent lifespan (Brown-Borg et al., 1996, Sornson et al., 1996, Bartke et al., 1998, Flurkey et al., 2001, Flurkey et al., 2002). We have proposed that the longevity of Snell dwarf mice reflects a conservation of the C. elegans paradigm (Kenyon, 2001; Hsieh et al., 2002).

There is a striking similarity between the InR-IRS-PI3K-AKT pathway in the mouse and the DAF-2-?-Age-1-AKT pathway in C. elegans (Kenyon, 1997, Lin et al., 1997, Lin et al., 2001). IRS-1 and IRS-2 are the two major adapter proteins of the mammalian insulin/IGF-1 pathway that mediate the downstream signaling cascade via the p85α regulatory subunit of PI3K and AKT through their docking to tyrosine phosphorylated InRβ (Sun et al., 1995, Paz et al., 1997, DuPont et al., 1998, Shimomura et al., 2000, Whitehead et al., 2000). As in daf-2 mutants, lifespan may be markedly increased in dwarf mice because the GH deficiency results in decreased levels of circulating insulin/IGF-1, thereby causing metabolic changes that favor longevity. Since the DAF-2-AGE-1 pathway of C. elegans may be analogous to the InR/IGF-1R/GHR-/IRS-1-(IRS-2)-PI3K pathway in higher animals, it is important to elucidate the activity of IRS-1 and both upstream and down-stream signaling in the long-lived dwarf mutants.

These results raise an interesting possibility that decreased levels of either insulin, IGF-1 or GH in higher organisms could induce a metabolic state that favors longevity. The hormonal deficiencies in the Snell dwarf mice may impose such metabolic changes by attenuating the signaling pathways for insulin, IGF-1, and GH. In this study we measured such factors as protein pool levels, protein modification, protein–protein interaction, and kinase levels of components of the insulin signaling and show a correlation of these parameters with longevity of Snell dwarf mice.

Section snippets

Animals

All mice were born and reared in a specific pathogen-free colony (monitored quarterly) at The Jackson Laboratory. Mice were given an autoclaved diet (NIH-31 at 4% fat) ad lib and chlorinated water, acidified to prevent growth of Pseudomonas. Filtered air was delivered under positive pressure and kept at 27±1 °C and 45–55% humidity. The light: dark cycle was 14:10. Control males were housed in groups of 1–3 littermates per cage; dwarf males were also housed 1–3 per cage with at least one control

Insulin receptor-β (InRβ) and insulin receptor substrate-1 (IRS-1) characteristics and interactions

We have proposed that the low circulating insulin levels in non-fasted Snell dwarf (Pit-1dw/Pit-1dw) mice may contribute to their increased life span due to a decrease of the insulin/IGF-1 signaling pathway activity (Fig. 1). In a previous study we showed that the non-fasted levels of circulating insulin of young control males from this strain are slightly higher than typically found in young male mice (Hsieh et al., 2002). In addition we showed that the insulin levels of non-fasted young Snell

Discussion

In previous studies we have shown that circulating insulin levels in non-fasted Snell dwarf mice are severely decreased (Hsieh et al., 2002). This observation is consistent with our working hypothesis that GH deficiency in Snell dwarf mice, due to the Pit1 mutation, may result in decreased circulating insulin levels. We also proposed that this could lead to the decreased activity of this signaling pathway and mimic the physiological characteristics of the long-lived nematode. In the nematode,

Acknowledgments

This project was supported by United States Public Health Service Grant AG16622 awarded by the Longevity Assurance Genes Program of the National Institute on Aging and the UTMB Sealy Center on Aging.

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