Methionine restriction diets: Unravelling biological mechanisms and enhancing brain health

Summary Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component 1 , the principles that define whether nutrition may be used to influence tumour outcome are unclear 2 . Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has anti-aging and anti-obesogenic properties, influences cancer outcome through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions involving chemotherapy and radiation. MR produced therapeutic responses in chemoresistant RAS-driven colorectal cancer patient derived xenografts (PDXs) and autochthonous KRASG12D+/− ;TP53−/− -driven soft tissue sarcomas resistant to radiation. Metabolomics revealed the therapeutic mechanisms to occur through tumour cell autonomous effects on the flux through one-carbon metabolism that impacted redox and nucleotide metabolism, thus interacting with the antimetabolite or radiation intervention. Finally, in a controlled and tolerated feeding study in humans, MR resulted in similar effects on systemic metabolism as obtained in responsive mice. These findings provide evidence that a targeted dietary manipulation can affect specific tumour cell metabolism to mediate broad aspects of cancer outcome.

Summary Interventions that delay ageing mobilize mechanisms that protect and repair cellular components 1–3 , but it is unknown how these interventions might slow the functional decline of extracellular matrices 4,5 , which are also damaged during ageing 6,7 . Reduced Insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile C. elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions (Supplementary Discussion) 1,2 . It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood 2,8,9 , but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits 1,10,11 . Here we show that rIIS can promote C. elegans longevity through an program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) ortholog SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity 12–14 , but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix (ECM) genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood ECM remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that ECM remodelling is a generally essential signature of longevity assurance, and that agents promoting ECM youthfulness may have systemic benefit.