Tryptophan Metabolism: Entering the Field of Aging and Age
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Opinion Tryptophan metabolism: entering the field of aging and age-related pathologies Annemieke T. van der Goot and Ellen A.A. Nollen University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands Aging is an important risk factor for many debilitating organisms (reviewed in [2,3]), and several nutrient- diseases, including cancer and neurodegeneration. In sensing pathways have been reported to be involved in model organisms, interfering with metabolic signaling lifespan regulation by dietary restriction. In particular, pathways, including the insulin/insulin-like growth factor components of the mechanistic target of rapamycin (mTOR; (IGF) 1 (IIS) and TOR pathways, can protect against age- also mammalian target of rapamycin) and the insulin/ related pathologies and increase lifespan. Recent studies insulin-like growth factor (IGF) 1 (IIS) pathways appear in multiple organisms have implicated tryptophan me- to mediate the effects of dietary restriction, depending on tabolism as a powerful regulator of age-related diseases the type of intervention [4]. Genetic or pharmacological and lifespan. Its high conservation throughout evolution inhibition of the IIS and mTOR pathways, without a reduc- has enabled studies that begin to dissect the contribution tion in food intake, can extend lifespan in multiple species, of individual enzymes and metabolites. Here, we focus including Caenorhabditis elegans, Drosophila melanoga- on the emerging view of tryptophan metabolism as a ster, and Mus musculus (Table 1 and reviewed in [5]). pathway that integrates environmental and metabolic Both the IIS and mTOR pathways sense nutrient avail- signals to regulate animal biology and health. ability and subsequently adjust the metabolism, growth, and fecundity of the organism. When environmental con- Aging and age-related diseases ditions are favorable and food is abundant, growth and The past few decades have seen an increase worldwide in reproduction are stimulated. However, when environmen- both life expectancy and the relative proportion of older tal conditions are harsh and food is scarce, these nutrient- individuals in the population [1]. One consequence of an sensing pathways control the shift in energy resources aging population is an increased incidence of age-related from growth and reproduction to cellular stress defenses diseases, such as cancer and neurodegenerative disorders. and repair. This allows the animal to survive until more Thus, these demographic changes pose a major societal and favorable conditions are encountered [5]. economic burden. Several studies have shown that the mTOR pathway acts Studies, mainly from the past two decades, have shown in parallel to the IIS pathway, but there is crosstalk and that dietary alterations or genetic interference in nutrient- functional interaction between the two pathways at multi- sensing pathways can increase lifespan in several model ple levels [6]. For instance, in C. elegans it has been shown organisms [2]. These findings have changed the view of that mTOR signaling acts mostly independent of the Fork- aging from a merely stochastic process to a process that is head box (FOXO) transcription factor DAF-16, in contrast to regulated by multiple signaling pathways and downstream the IIS pathway [7,8]. Similar to IIS mutants, mTOR sig- transcription factors. Importantly, extending lifespan by naling does require the nrf-like xenobiotic response factor interfering with these pathways has been shown to protect SKN-1 [8,9]. Moreover, inhibition of mTOR in long-lived C. against a broad range of age-related pathologies (Table 1). elegans daf-2 mutants does not further increase lifespan [7]. Therefore, understanding the molecular mechanisms un- In some IIS fly mutants, rapamycin treatment could extend derlying aging and finding new components involved in the lifespan even more than changes to the IIS pathway depend- aging process could reveal new targets for treating age- ing on the degree of IIS downregulation [10]. related diseases and thereby promote a healthy life. These data indicate that lifespan extension through dietary restriction and the IIS and mTOR pathways can Nutrient-sensing pathways as central regulators of be achieved by both overlapping and distinct mechanisms. aging and age-related diseases Nevertheless, how these pathways interact is not yet Dietary restriction is one of the most reproducible and completely understood. best-studied interventions to extend lifespan in multiple Interestingly, reducing the activity of the IIS or mTOR pathways not only increases lifespan but it also delays the Corresponding author: Nollen, E.A.A. ([email protected]). onset of several age-related pathologies (Table 1). Tumor Keywords: tryptophan; TDO-2; kynurenine pathway; aging; neurodegeneration; protein homeostasis; age-related diseases. growth is suppressed upon genetic inhibition of the IIS pathway in worms [11] and mice [12], and reduced insulin/ 1471-4914/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2013.02.007 IGF-1 signaling has been shown to protect against the toxic 336 Trends in Molecular Medicine June 2013, Vol. 19, No. 6 Opinion Trends in Molecular Medicine June 2013, Vol. 19, No. 6 Table 1. Examples of metabolic pathways and their role in aging and age-related diseases Pathway Organism Aging a Cancer Neurodegeneration Longevity IIS pathway Caenorhabditis Genetic inhibition of daf-2 Genetic inhibition of daf-2 Genetic inhibition of daf-2 elegans inhibits germline tumor growth protects in an AD model [14], [72,73] and age-1 [74] extends [11] and genetic inhibition of age-1 lifespan protects in a polyQ model [13] Drosophila Not reported Not reported Genetic inhibition of the insulin melanogaster receptor substrate chico [75] or the insulin-like receptor InR [76] extends lifespan Mus musculus Liver-specific IGF-1-deficient Genetic inhibition of the insulin Loss of one allele of the insulin- mice show a reduced tumor receptor substrate 2 (Irs2) [15], like growth factor type 1 incidence and decreased or neuronal loss of IGF-1 receptor (IGF-1 receptor) [77], frequency of metastasis upon receptor [16], and loss of one or fat-specific knockout of the implantation with colon allele of the IGF-1 receptor [17] insulin receptor [78], or reduced adenocarcinoma tissue ameliorate neurodegeneration insulin receptor-2 (Irs2) fragments [12] in AD models signaling in all tissues or just in the brain [79], or insulin receptor substrate (IRS) 1 knockout [80] extends lifespan mTOR pathway C. elegans Not reported Not reported Genetic inhibition of let-363/TOR [7], TORC1 components: daf-15/ Raptor [8,81], rheb-1/Rheb [8,82], raga-1 [8], ragc-1 [8], and TORC2 component: rict-1 [8], or pharmacological inhibition with rapamycin extends lifespan [8] D. melanogaster Not reported Pharmacological inhibition of Genetic inhibition of dTOR/TOR mTOR with rapamycin [86,87], or gain of function of suppresses toxicity in a polyQ dTsc1/2/TSC1/2 [86], or [83] model. Genetic inhibition of pharmacological inhibition with Rheb, TOR, or gain of function rapamycin extends lifespan [10] of Tsc1/2 rescues from tau- [84] or htt-mediated toxicity [85] M. musculus Pharmacological inhibition of Pharmacological inhibition of Pharmacological inhibition of mTOR with rapamycin mTOR with rapamycin ester CCI- mTOR with rapamycin extends suppresses tumor growth in 779 suppresses aggregation and lifespan [89–91] cancer-prone animals [18] toxicity of polyQ [83,88] Kynurenine C. elegans Not reported Depletion of tdo-2 suppresses Depletion of tdo-2 extends pathway proteotoxicity on models for PD, lifespan [21] AD, and polyQ diseases [21] D. melanogaster Not reported Loss of function of vermillion Loss of function of vermillion and genetic or pharmacological extends lifespan [22] inhibition of cinnabar suppresses toxicity in a polyQ model [33] M. musculus Pharmacological inhibition of Pharmacological inhibition of Not reported IDO/TDO suppresses tumor KMO ameliorates growth and promotes tumor neurodegeneration in models rejection [28–31]. Knockout of for AD and HD [34] IDO prevents tumor formation [92] a Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease. effects of aggregation-prone disease proteins involved in mechanisms have been reported, including autophagy, an neurodegeneration in worms [13,14] and mice [15–17]. attenuation of translation, and cell-cycle inhibition, which Inhibition of mTOR signaling suppresses aging-related may suppress neurodegeneration because they increase pathologies. Pharmacological inhibition of the mTOR path- the removal of disease proteins, decrease their synthesis, way with rapamycin suppresses tumor growth in mice [18], and increase the expression of stress response proteins and and although the exact mechanisms by which rapamycin detoxifying enzymes. suppresses tumorigenesis remain unknown, alterations in Together, these studies show that cellular protection autophagy, cell proliferation, angiogenesis, and recruit- machineries that are thought to be compromised and ment of immune cells have been proposed to play a role. decline during aging are boosted and maintain a more Similarly, pharmacological or genetic inhibition of mTOR youthful state when insulin/IGF-1 and mTOR signaling signaling is protective in multiple fly and mouse models of are lowered. Moreover, these studies point out that there is neurodegeneration (reviewed in [19]).