S-adenosyl methionine synthetase SAMS-5 mediates dietary restriction-induced longevity in Caenorhabditis elegans

Abstract

S-adenosyl methionine synthetase (SAMS) catalyzes the biosynthesis of S-adenosyl methionine (SAM), which serves as a universal methyl group donor for numerous biochemical reactions. Previous studies have clearly demonstrated that SAMS-1, a C. elegans homolog of mammalian SAMS, is critical for dietary restriction (DR)-induced longevity in Caenorhabditis elegans. In addition to SAMS-1, three other SAMS paralogs have been identified in C. elegans. However, their roles in longevity regulation have never been explored. Here, we show that depletion of sams-5, but not sams-3 or sams-4, can extend lifespan in worms. However, the phenotypes and expression pattern of sams-5 are distinct from sams-1, suggesting that these two SAMSs might regulate DR-induced longevity via different mechanisms. Through the genetic epistasis analysis, we have identified that sams-5 is required for DR-induced longevity in a pha-4/FOXA dependent manner.

Fig 1. Loss of sams-5 induces longevity in C. elegans.

A) Lifespan analysis of wild-type (N2) worms grown on control (blue), sams-1(red), sams-3 (yellow), sams-4 (green) or sams-5 (orange) RNAi bacteria. B) Lifespan analysis of wild-type N2 animals (blue) and sams-5(gk145) mutants (red). Additional lifespan replicates are included in S1 Table.

Fig 2. Comparison of phenotypes between sams-1 and sams-5 mutants.

A) Images of Day 1 adults of wild type animals, sams-1 mutants, and sams-5 mutants. Scale bar, 100 μm. B) Oil red O staining was applied to L4 N2 wild type animals treated with control vector, sams-1 RNAi, and sams-5 RNAi. Scale bar, 50 μm. C) Reproduction timing and D) Brood sizes of wild type worms and sams-5(gk147) mutants (n = 10).

Fig 3. The expression patterns of SAMS-5.

A) Images of transgenic larvae carrying sams-5p::sams-5::gfp. Scale bar: Upper panel, 20 μm; lower panel, 50 μm. B) The expression of SAMS-5 in the larval stages and Day 1 adults. Various cells and organs are indicated by white arrows. Scale bar, 100 μm.

Fig 4. Lifespan extension in sams-5 mutants is independent of daf-16, but dependent on pha-4.

Lifespan analysis of A) wild-type N2 animals (blue and red) and daf-16(mu86) worms (green and orange) grown on control or sams-5 RNAi bacteria. B) wild-type N2 animals (blue and green) and sams-5(gk147) mutants (red and orange) grown on control or pha-4 RNAi bacteria from L4 stage. C) wild type N2 animals (blue), sams-5 overexpressing mutants (green), eat-2 mutants (red), and eat-2;sams-5 overexpressing mutants (orange). Additional lifespan replicates are included in S1 Table. D) Images of L1/L2 wild type N2 animals or eat-2 mutants expressing sams-5p::sams-5::gfp (left). Scale bar, 20 μm. Quantification of sams-5-::gfp expression (right).