Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan

Abstract

Summary Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in C. elegans. However, the mechanism by which H3K4me3 modifiers impact longevity, and whether it involves metabolic changes, remain unclear. Here we find that H3K4me3-methyltransferase deficiency, which extends lifespan, promotes fat accumulation with a specific enrichment of mono-unsaturated fatty acids (MUFAs). This fat metabolism switch in H3K4me3-methyltransferase deficient animals is mediated at least in part by downregulation of germline targets, including S6 kinase, and by activation of an intestinal transcriptional network that upregulates delta-9 fatty acid desaturases. Interestingly, MUFA accumulation is necessary for the lifespan extension of H3K4me3-methyltransferase deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.

The impact of cellular metabolism on chromatin dynamics and epigenetics

“…Moreover, factors such as diet 49–52 , microbiome 53 , temperature 54 , malnutrition 55 , chemical exposure 56 and many others are able to induce heritable alterations in nucleic acid or histone methylation profiles that can be stably transmitted through more than 10 generations 54 . How epigenomic states are stably inherited is unknown, but perturbations to chromatin-modifying enzymes in the germline in controlled laboratory settings have yielded comparable heritable effects to what is observed in settings of human exposure 57 . This suggests that changes to the activity of chromatin-modifying enzymes that are known to be affected by metabolism, may be possible transient events that contribute to these phenotypic changes.…”

“…In both instances, the cell state transition would be irreversible since Waddington’s Landscape has changed. This may occur during germline transmission of an epigenomic phenotype due to a parental diet or a germline mutation in a chromatin-modifying enzyme 49, 57, 69 (Fig 2c). Although these proposed models are intriguing, more research is needed to reconstruct the structure of the epigenetic landscape under different metabolic conditions to investigate and distinguish between different possibilities.…”

H3K9me2 protects lifespan against the transgenerational burden of germline transcription in C. elegans

“…2017). Activation of this pathway causes the accumulation of mono-unsaturated fatty acids, and this 32 increase is sufficient to extend lifespan (Han et al 2017). 33 Greer and colleagues also show that longevity in COMPASS mutants was a heritable trait.…”

Surviving Starvation: AMPK Protects Germ Cell Integrity by Targeting Multiple Epigenetic Effectors

“…Surprisingly, recent data have demonstrated that AMPK can act cell non‐autonomously; functioning in the neurons to affect lifespan determination . More recently, changes in the status of the chromatin have also been shown to function cell non‐autonomously, and may affect the lipid metabolism in C. elegans to ultimately impinge on ageing . The challenge now is to fit these data together in a plausible scenario to account for all the phenotypes while considering canonical AMPK function; namely its role in phosphorylating pivotal protein targets involved in metabolic adjustment.…”

“…[43] More recently, changes in the status of the chromatin have also been shown to function cell nonautonomously, and may affect the lipid metabolism in C. elegans to ultimately impinge on ageing. [44] The challenge now is to fit these data together in a plausible scenario to account for all the phenotypes while considering canonical AMPK function; namely its role in phosphorylating pivotal protein targets involved in metabolic adjustment. The transgenerational effects of the stress we describe, in addition to all the stresses that are met with an epigenetic response, suggest that the soma and the germ line must communicate and AMPK may be one of these links required to mediate changes in the germ line downstream of sensing stress in the somatic tissues.…”