An atypical switch for metabolism and ageing

The enzyme S6K1 phosphorylates the enzyme glutamyl-prolyl tRNA synthetase to modulate metabolic activity and lifespan, revealing an atypical role for this synthetase as a target of a key metabolic signalling pathway. See Letter p.357

The observation a century ago that dietary restriction extends longevity in rodents1 led to the realization that metabolism and ageing have a close relationship. We now know that biological signalling networks that respond to nutrients and hormones modulate lifespan in a highly evolutionarily conserved manner2. The protein kinase S6K1 is a key target of one such network, the mTOR (mechanistic target of rapamycin) signalling pathway, but the mechanisms downstream of this enzyme have remained obscure. Arif et al.3 show on page 357 that another enzyme, glutamyl-prolyl tRNA synthetase (EPRS), is a direct target of S6K1, and has a previously unidentified role in fat metabolism and lifespan.

Enzymes in the same family as EPRS have a key role in decoding the genome — they catalyse the binding of amino acids to transfer RNAs for transport to the cell's translational apparatus. However, this family also fulfils many atypical roles4. The research group that performed the current study previously showed5 in vitro that EPRS can mediate the assembly of a protein complex that attenuates the translation of certain inflammation-associated RNAs. This function depends on EPRS being phosphorylated at a particular amino-acid residue, serine 999 (Ser999), but the identity of the kinase that catalyses this phosphorylation was unclear.

In the current study, Arif et al. identified this enzyme as S6K1. Mice that lack S6K1 have previously been shown6 to display reduced fat mass, resistance to nutrient excess, delayed ageing and increased healthy lifespan (healthspan) compared with control animals, and the authors set out to investigate whether EPRS is a key mediator of these effects. They generated mouse models in which EPRS phosphorylation was either blocked or mimicked by mutating Ser999 to an alternative amino acid — in the first instance, to alanine (a mutation dubbed S999A), which cannot be phosphorylated, and in the second to aspartate (S999D), which mimics permanent Ser999 phosphorylation.

Mice harbouring the S999A mutation exhibited reduced fat mass, improved metabolism and increased lifespan compared with wild-type mice, in part resembling the S6K1-deficient animals. When the S999D mutation was introduced to rescue EPRS phosphorylation in S6K1-deficient mice, a partial restoration of fat mass occurred in these animals. Together, these data suggest that EPRS phosphorylation by S6K1 plays a key part in regulating fat mass in mice, and that the absence of such phosphorylation might mediate the beneficial effects of S6K1 deletion on metabolism and ageing.

Next, Arif et al. analysed the mutants in more detail, and discovered that insulin-stimulated lipid uptake was impaired in the fat cells of S999A mice compared with control animals. The authors therefore performed a screen to identify components of the lipid-metabolism machinery that interact with EPRS. This showed that EPRS binds to the protein FATP1 — which mediates the uptake of lipid precursors called fatty acids into fat cells7 — in an insulin- and S6K1-dependent manner. These results implicate FATP1 as a key component of mTOR signalling, regulating metabolism in fat (Fig. 1).

Figure 1: A phosphorylation switch alters lipid uptake and longevity in mice.

a, As part of a large protein complex, the protein mTOR can activate the kinase enzyme S6K1. Arif et al.3 report that S6K1 phosphorylates (P) the protein glutamyl-prolyl tRNA synthetase (EPRS) on the amino-acid residue serine 999 (Ser999). This switch promotes interaction with the fatty-acid transporter protein FATP1, leading to increased lipid uptake into fat tissue. b, If Ser999 is mutated to the amino-acid residue alanine in mice (a mutation dubbed S999A), meaning that it cannot be phosphorylated, the interaction with FATP1 does not occur — these animals have lower fat mass and live longer than controls.

Although this study provides insights into metabolism and ageing, there are also some unexpected findings, unanswered questions and avenues for future investigation. Perhaps the most pressing issues relate to longevity, given the ageing human population and the recognition that ageing is a risk factor for many diseases8.

It is surprising that the increased lifespan seen in S6K1-deficient mice can be mimicked by the mutation of a single serine residue in EPRS, given the many roles and substrates of S6K1. One potential explanation is that S6K1-deficient mice have a mixture of beneficial and detrimental traits, but the overarching output confers increased lifespan. In this scenario, the EPRS-dependent pathway might simply capture the beneficial effects. To bolster such an idea, it will be crucial to determine whether S999A mice show increased healthspan, in addition to increased lifespan. It will also be important to examine mice harbouring the S999D mutation in greater detail, because, surprisingly, these seem to lack traits that are associated with enhanced mTOR–S6K1 signalling in fat, such as insulin resistance and obesity.

The precise relationship between EPRS- and S6K1-dependent longevity could be further examined in genetic experiments using the mutants generated by Arif and colleagues. For example, is the increased longevity of S6K1-deficient mice abrogated by the S999D mutation, as would be expected if that longevity is dependent on the absence of EPRS phosphorylation? Likewise, if S6K1 and EPRS act in a linear pathway, S6K1-deficient mice that have the S999A mutation should have no additional metabolic or lifespan benefits over S6K1-deficient mice that have wild-type EPRS. Such complex genetic studies would support the idea that EPRS is a key regulator of ageing in the mTOR pathway.

The authors suggest that the changes in metabolism and longevity seen in S999A mutants stem mainly from altered fat-tissue biology and are caused solely by a lack of S6K1-mediated phosphorylation. But reduced fat mass in S999A mutants begins in adulthood, whereas S6K1-deficient mice are lean at an earlier age, in part owing to defects in fat-cell development9 — pointing to the possibility that EPRS acts through other mechanisms. Furthermore, mice lacking FATP1 do not show the reduced fat mass and increased insulin sensitivity seen in S999A mice10, hinting that EPRS also acts in other tissues. This idea is supported by the fact that S6K1 has roles in metabolic regulation in the liver, muscle and central nervous system11,12. Specifically deleting S6K1 in fat and studying EPRS function in this tissue could provide further insight.

The excitement about the current study stems from the potential to target S6K1–EPRS signalling to treat metabolic disease and perhaps the pathology of ageing. Directly targeting Ser999 phosphorylation would be challenging, but it is well established that pharmacological blockade of mTOR–S6K1 signalling using the immunosuppressant drug rapamycin extends lifespan and increases healthspan in mice13. It would be useful to determine whether any of the effects of rapamycin are mediated by EPRS-dependent mechanisms, because this may help to refine strategies aimed at targeting the mTOR pathway.

Finally, it would be interesting to assess whether there are alterations in EPRS function in ageing humans, and whether genetic variation in EPRS contributes to differences in human lifespan. Only then will we know the full potential of Arif and colleagues' discovery to give insight into the causes of and potential treatments for age-related disease.Footnote 1


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Correspondence to Dominic J. Withers.

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Selman, C., Withers, D. An atypical switch for metabolism and ageing. Nature 542, 299–300 (2017).

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