The hammer of TORC1!

Abstract

Explaining aging in evolutionary terms is relatively simple: while a strong selection pressure for an individual's survival exists until the perpetuation of his progeny is secured, there cannot be selection of characters improving survival and life quality beyond this point. This evolutionary perspective lights the (long) path to increased lifespan, saying: “reproduce later!” or “remain of use to your kids as you get older!” but it leaves aging mechanisms thoroughly unexplained. Unfortunately understanding how we age proves more difficult. In 1990, ZA Medvedev listed more than 300 competing models for aging. Among them the mitochondrial free radicals theory was perceived as the most promising. It suggests a vicious circle of damages: reactive oxygen species (ROS) naturally produced by the respiratory chain cause mitochondrial DNA mutations which in turn increases ROS production by the respiratory chain. This theory stood until the mid-2000's when A Trifunovic released her study of the “mutator” mice. Mutator mice present most, if not all signs of premature aging associated with the accumulation of mitochondrial DNA damages and respiratory chain deficiencies but show no sign of ROS accumulation.1 In a recent publication Scialo et al. provide evidence in favor of a different aging paradigm.2 Drosophila melanogaster, popularly known as fruit flies, are poikilothermic animals. Instead of maintaining their own body temperature like humans, they let ambient temperature control their physiology, metabolism and lifespan. Taking advantage of this behavior Scialo et al. studied the trade-offs associated with thermic adaptation. Lifespan shows non-linear correlation with temperature, presenting optimal survival at 18°C (Fig. 1, insert), a “normal” temperature for fruit flies. The authors observed that most parameters they studied including ROS and various metabolic markers evolve with temperature but not with lifespan; whereas TORC1 and Akt signaling correlate negatively with longevity. Effectors downstream of TORC1 did show the same inverse correlation with lifespan while FOXO, a major target of Akt, did not. Figure 1: Left insert; Lifespan correlates with TORC1 signaling but not with metabolism (or ROS) in Drosophila exposed to different environmental temperature; adapted from.2 Pathways map: crosstalk between the various signaling pathways controlling TORC1. Proteins ... Analyzing Drosophila lifespan in a broad range of environmental temperatures Scialo et al. managed to dissociate FOXO signaling, ROS toxicity and membrane unsaturation from aging in wild-type flies and to underline the major role played by TORC1. This work opens important and interconnected questions: What is the status of insulin signaling? Insulin signaling is one of the most documented longevity-controlling pathways, its downregulation increases lifespan through (Akt-dependent) TORC1 inhibition and FOXO activation (Fig. 1, Pathways map). A disconnection between the 2 main targets of insulin signaling indicates either that this major longevity-controlling pathway is not involved or that thermal adaptation partly counteracts its effects. What could be the molecular intermediates of TORC1 inhibition? Akt leads to the TSC1/2-dependent formation of Rheb-GTP, a TORC1 binding partner and activator; it also phosphorylates PRAS40 inhibitory subunit, activating TORC1. AMPK antagonizes Rheb-GTP activation of TORC1 (via TSC1/2) which is also controlled by FOXO; in addition AMPK inhibits TORC1 through phosphorylation of raptor. In high amino-acids conditions binding of GTP to RagA (a small GTPases forming, with RagB/C/D, a complex bound to the lysosomal membrane) promotes TORC1 activation.3 What is the status of autophagy? TORC1 regulates this process via the phosphorylation of ULK1 and numerous studies link autophagy to increased lifespan.4 Interestingly Sirt1 controls autophagy through TORC1: de-acetylation of SIRT1 activates TSC1/2, promoting TORC1 inhibition. Following the adaptation of lifespan to temperature in Drosophila, Scialo et al. highlight the physiological responses promoting animal's adaptation to a biological pressure. As mentioned above, altruism is an expected consequence of evolutionary constraints on lifespan: “We are selected to optimize the survival of our progeny, not ourselves.” This altruism potentially establishes trade-offs for the maintenance and build-up of our organism: regulatory pathways adapted to early-life may become detrimental/maladjusted when the organism gets old. The emergence of TORC1 signaling as a lifespan-reducing system supports this view, making it one of the strongest examples of antagonistic pleiotropy,5 and corroborating the hyperfunction theory of aging. As such, TORC1's regulations have consequences beyond aging; being investigated in the context of cancer, type 2 diabetes and neurodegenerative diseases.6 Not unlike his Asgardian homonym, TORC1 appears to be a powerful and unstoppable character blind to the fact that his vibrant vitality is leading us, mortal beings, to a rapid ending.