Signaling networks in aging

Aging – long considered to be solely the result of wear and tear – is in fact regulated by specific genetic pathways. Simple changes in the environment (e.g. dietary restriction) can drastically extend lifespan, suggesting that several of these genetic pathways control longevity in response to changes in the surroundings. Here we summarize the key signaling modules identified so far that regulate aging and longevity.The first example of a specific pathway controlling longevity came from studies of Caenorhabditis elegans. Mutations that reduce the activity of the insulin receptor DAF-2 (Kenyon et al., 1993; Kimura et al., 1997) or the phosphoinositide 3-kinase (PI3K) AGE-1 (Friedman and Johnson, 1988; Morris et al., 1996) extend lifespan in adult worms by more than 100%. The insulin receptor mediates its effects via the PI3K-AKT/SGK signaling pathway, which culminates in the negative regulation of the Forkhead transcription factor FOXO/DAF-16 (Brunet et al., 1999; Kops et al., 1999; Lin et al., 1997; Ogg et al., 1997). Insulin signaling regulates aging in a conserved manner, from worms to mammals. In Drosophila melanogaster, mutations in the insulin receptor extend female lifespan by ∼85% and mutation of the insulin-receptor substrate (IRS) Chico causes an ∼48% increase in lifespan (Clancy et al., 2001; Tatar et al., 2001). Overexpression of foxo in Drosophila extends lifespan by ∼15-52% (Giannakou et al., 2004; Hwangbo et al., 2004). In mice, animals that lack one allele of the insulin-like growth factor 1 (IGF1) receptor gene show a 26% increase in mean lifespan (Holzenberger et al., 2003). The insulin signaling pathway is important in a variety of tissues to extend lifespan. Mutation of the insulin receptor in adipose tissue increases mouse lifespan by 18% (Bluher et al., 2003), whereas a brain-specific IRS2 knockout extends mouse lifespan by ∼18% (Taguchi et al., 2007).In mice, the Snell and Ames dwarf mutations, which are in the genes encoding the pituitary transcription factors PIT1 (POU1F1) and PROP1, respectively, extend lifespan by 42-67% (Brown-Borg et al., 1996; Flurkey et al., 2001). The extension in longevity in both mouse models is likely to be due to defects in the ability of the pituitary gland to secrete growth hormone (GH), because mice that have a null mutation in the GH receptor (GHR–/–) also display an ∼21-40% increase in lifespan (Coschigano et al., 2003), whereas transgenic mice that overexpress GH live significantly shorter than wild-type mice (Wolf et al., 1993). Interestingly, the Ames dwarf mice and the GHR–/– mice have reduced levels of circulating IGF1, fasting insulin and glucose (Brown-Borg et al., 1996; Coschigano et al., 2003), raising the possibility that the increased longevity of these mice is mediated by insulin/IGF1 signaling.Disruption of the expression of klotho, a cell-surface protein whose extracellular domain can act as a circulating hormone (Shiraki-Iida et al., 1998), accelerates aging in mice (Kuro-o et al., 1997). Conversely, overexpression of klotho in mice leads to an ∼19-31% lifespan extension in one strain of mice (Kurosu et al., 2005). The precise mechanisms by which klotho extends lifespan are still under investigation, but klotho has been found to repress insulin/IGF1 signaling (Kurosu et al., 2005) and to regulate phosphate and calcium homeostasis (Imura et al., 2007) by affecting fibroblast growth factor 23 (FGF23) (Urakawa et al., 2006) and the Na+/K+-ATPase (Imura et al., 2007).Mice lacking type 5 adenylyl cyclase (AC5) have an ∼32% increase in lifespan compared with wild-type littermates (Yan et al., 2007). AC5 probably transduces signals emanating from a hormonal seven-transmembrane-domain receptor, although the identity of this receptor is unknown. The increase in lifespan in AC5-deficient mice correlates with decreased levels of circulating GH, increased resistance to oxidative stress and increased Raf-MEK-ERK signaling (Yan et al., 2007). The chronological lifespan of yeast expressing a mutant form of adenylyl cyclase (CYR1) or yeast overexpressing the MAP kinase ERK2 is also increased, suggesting that the relevance of this pathway to longevity is conserved throughout evolution (Fabrizio et al., 2001; Yan et al., 2007).In adult worms, mutations in TGFβ (daf-7) or in the TGFβ receptors DAF-1 (TGFβR1) and DAF-4 (TGFβR2) extend worm lifespan by 18-120% (Shaw et al., 2007). TGFβ signaling is mediated by two SMAD transcription factors, DAF-8 and DAF-14, which inhibit the action of another SMAD transcription factor, DAF-3 (SMAD3) (Shaw et al., 2007). DAF-3, together with its co-activator DAF-5, upregulates genes involved in cell cycle arrest and apoptosis, a large number of which are also regulated by the FOXO transcription factor DAF-16 (Shaw et al., 2007). Thus, the TGFβ and the insulin pathways might regulate lifespan by acting on similar subsets of genes.In worms, the loss-of-function mutation of a cytochrome P450 (daf-9), a predicted steroidogenic hydroxylase, extends lifespan in a manner that is dependent on DAF-12 (Gerisch et al., 2001; Jia et al., 2002), a nuclear hormone receptor with closest homology to LXRα (liver X receptor alpha) in mammals. DAF-9 might regulate the synthesis of a steroid ligand that inhibits the receptor DAF-12 (Gerisch et al., 2001; Jia et al., 2002). In line with this prediction, the steroid dafachronic acid is a ligand for DAF-12 that shortens the lifespan of daf-9-mutant worms (Gerisch et al., 2007). Conversely, another steroid, pregnenolone, extends worm lifespan in a DAF-12-dependent manner (Broue et al., 2007). In flies, the steroid termed juvenile hormone has been found to reverse the lifespan extension caused by mutation of the insulin-like receptor (Tatar et al., 2001). In mammals, the effects of steroids or steroid receptors on overall lifespan have not been directly examined, but the steroid dehydro epiandorosterone sulfate (DHEA-S) has been found to be associated with increased longevity i