segunda-feira, 16 de maio de 2011

Sinalização feita por um lipideo prolonga vida

N aciletanolamina é um grupo de lipideos sinalizadores celulares.
Neste trabalho os autores trabalharam inibindo esses lipideos em um verme denominado nematoide e conseguiram prolongar a vida do nematóide.

Já se conhecia que dieta prolonga a vida, mas os estudos agora começam conhecer melhor como isso ocorre em detalhes

Não espere para breve comprar esse inibidor, mas enquanto esses inibidores não chegam ao mercado, faça uma alimentação restrita em calorias e pratique exercícios.

Cell signalling: Why fasting worms age slowly

Luciano De Petrocellis & Vincenzo Di Marzo
AffiliationsCorresponding author
Nature 473, 161–163 (12 May 2011) doi:10.1038/473161a

Lipids of the N-acylethanolamine family mediate cell signalling across a wide range of organisms. In nematode worms, they translate food availability into fundamental choices about development that affect lifespan. See Letter p.226

Subject terms:Genetics and genomics Organismal biology
Whether prolonged dietary restriction can extend human life remains controversial. But this matter has been settled in the case of some invertebrates, including the widely investigated nematode Caenorhabditis elegans1. A study by Lucanic et al.2 on page 226 of this issue now suggests that decreased signalling by small lipids called N-acylethanolamines is responsible for the lifespan-extending effects of dietary restriction in C. elegans.

N-Acylethanolamines (NAEs) were first identified in the 1950s, but evidence for their signalling role emerged only when a member of this lipid family, N-arachidonoylethanolamine (anandamide), was detected in pig brains3 and recognized as an endocannabinoid — an endogenous activator of CB1 cannabinoid receptors. It is now known that these small lipids, which have fatty-acid chains of varying length and saturation level, are widespread in both the plant and animal kingdoms, and are even found in single-celled protists. In mammals, signalling through CB1 receptors by anandamide — and another endocannabinoid, 2-arachidonoylglycerol — is essential for stimulating food intake following a short period of food deprivation4. This observation provided the rationale for the development of CB1 blockers as anti-obesity agents4.

A relationship between an organism's energy status and its brain levels of endocannabinoids is not restricted to mammals, but is also found in non-mammalian vertebrates such as fish, in which these compounds also stimulate food intake (Fig. 1). In the primitive invertebrate Hydra vulgaris, which does not seem to have a protein related to cannabinoid receptors, anandamide nonetheless inhibits feeding behaviour (mouth opening). And the chordate Ciona intestinalis, which represents the phylogenetic branching point between invertebrates and vertebrates, expresses a receptor that is homologous to the human CB1 receptor. In this animal, synthetic CB1 agonists retard mouth reopening after closure4.

Figure 1: N-Acylethanolamines, feeding behaviour and lifespan.

N-Acylethanolamines (NAEs) are evolutionarily conserved lipids: they occur in a wide range of organisms, including the coelenterate Hydra vulgaris, the chordate Ciona intestinalis and the fish Carassius auratus. In all cases, these small lipids either inhibit (blunt-ended arrows) or enhance (pointed arrows) feeding behaviours. In mammals, CB1 and PPAR-α receptors mediate the effects of NAEs such as anandamide and N-oleoylethanolamine (OEA), respectively, although NAE receptors in some of the other species are unknown (black question marks). Inset: Lucanic et al.2 show that in the nematode Caenorhabditis elegans, N-eicosapentaenoylethanolamine (EPEA), the most abundant NAE in this organism, enhances feeding behaviour. This leads to exit of the animals from the dauer phase — which they originally enter when faced with food shortage — and to reduced longevity.


Full size image (79 KB)
The discovery of anandamide3 ignited interest in other NAEs, although it was immediately clear that most of these compounds do not share anandamide's high affinity for CB1 receptors. In rodents, N-oleoylethanolamine activates PPAR-α, a nuclear receptor that acts as a transcription factor, inhibiting food intake5. But apart from studies on this compound, and on the potent anti-inflammatory mediator N-palmitoylethanolamine, research in animals on NAEs that do not bind to cannabinoid receptors has been sparse, unlike work on the signalling function of these lipids in plants6, 7. Notably, NAE biosynthetic pathways, and the enzymes that inactivate these compounds, are similar in animals and plants7.

Lucanic and colleagues2 identify NAEs in C. elegans, and demonstrate that the abundance of these lipids is reduced under dietary restriction. Moreover, they show that NAE deficiency — due either to impaired biosynthesis or enhanced degradation in mutant worm strains — is sufficient to enhance longevity. Using other types of mutants, the authors further show that NAE deficiency and dietary restriction extend C. elegans lifespan through the same developmental effects (see below and Fig. 1).

Conversely, supplementing the worms' diet with N-eicosapentaenoylethanolamine (EPEA), the most abundant NAE in C. elegans, inhibited dietary-restriction-induced lifespan extension in wild-type worms; it also had the same effect in more long-lived mutants in which nutrient sensing was impaired because they lacked the signalling molecule TOR, which is necessary for food intake. Lucanic et al. propose that NAE-mediated signalling, which is presumably acting in the pharynx, coordinates nutrient sensing and energy status with the metabolic and developmental changes that ultimately determine lifespan in worms.

Rodents cope with prolonged semi-starvation by — among other things — reducing the levels of appetite-inducing endocannabinoids in their hypothalamus (the brain area that mediates homeostatic control of energy intake)4. Instead, in the face of dietary restriction, C. elegans enters a quiescent and low-energy-consuming state known as the dauer phase, in which NAE levels are at their lowest2. Lucanic and co-workers2 show that administration of exogenous EPEA can bring the nematode out of the dauer phase, and they propose that it does so by providing “a false signal of high nutrient availability” and by reversing “the metabolic adaptation to reduced food availability that confers lifespan extension”.

Perhaps the only missing information in the researchers' extensive study is the receptor through which EPEA, and possibly other NAEs, produce their effects in C. elegans — like most other invertebrates, this animal does not express the equivalent of cannabinoid receptors8. The authors did look at 'indigenous' members of the several classes of receptor that are activated by these lipids in mammals, including orphan G-protein-coupled receptors, nuclear receptors and ligand-activated ion channels9. But genetic deletion of proteins related to such potential NAE targets in C. elegans did not affect the ability of EPEA to rescue the worm from the dauer phase2, leaving the identity of the receptor mediating NAE signalling in this animal a mystery.

Nevertheless, apart from the discovery of novel molecular mechanisms underlying dietary-restriction-induced developmental changes in C. elegans, the elegant work of Lucanic and colleagues' sends another noteworthy general message: across nearly all types of living organism, NAEs are of fundamental importance as signalling molecules that act through different receptors (with sometimes more than one receptor mediating the effects of a particular NAE)9, and have diverse biological actions.

As previously suggested10 — and as supported by the identification of enzymes mediating NAE biosynthesis and degradation in even elementary forms of life — NAEs are phylogenetically ancient. So it could be that, during evolution, when cannabinoid receptors and PPAR-α were first used as signal transducers, they found endogenous NAEs and used them as activators. Regardless of the identity of their receptors, however, the lipids' key role in the control of food intake and development seems to have been conserved from simple organisms to humans (Fig. 1). Thus, finding the molecular targets of NAEs in C. elegans should be made a priority, because these proteins might also have been retained in mammals, with potential implications for medical research in ageing, obesity and associated metabolic disorders.

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