Reduced expression of alpha-1,2-mannosidase I extends lifespan in Drosophila melanogaster and Caenorhabditis elegans

Creators: Liu, Ya-Lin; Lu, Wan-Chih; Brummel, Theodore J.; Yuh, Chiou-Hwa; Lin, Pei-Ting; Kao, Tzu-Yu; Li, Fang-Yi; Liao, Pin-Chao; Benzer, Seymour; Wang, Horng-Dar

Abstract

Exposure to sub-lethal levels of stress, or hormesis, was a means to induce longevity. By screening for mutations that enhance resistance to multiple stresses, we identified multiple alleles of alpha-1,2-mannosidase I (mas1) which, in addition to promoting stress resistance, also extended longevity. Longevity enhancement is also observed when mas1 expression is reduced via RNA interference in both Drosophila melanogaster and Caenorhabditis elegans. The screen also identified Edem1 (Edm1), a gene downstream of mas1, as a modulator of lifespan. As double mutants for both mas1 and Edm1 showed no additional longevity enhancement, it appeared that both mutations function within a common pathway to extend lifespan. Molecular analysis of these mutants revealed that the expression of BiP, a putative biomarker of dietary restriction (DR), is down-regulated in response to reductions in mas1 expression. These findings suggested that mutations in mas1 may extend longevity by modulating DR.

Additional Information

© 2009 Wiley. We thank Drs Micheline Laurent and William Ja for the critical reading and editing of the manuscript. We thank Dr Yi-Chun Wu for providing the materials for the worm work, and Dr Ting-Fen Tsai for the liver tissues from the different aged mice. We are grateful for the suggestions from Drs Jui-Chou Hsu and Tzu-Kang Sang on the manuscript. We thank Miss Yi-Yun Wang for the graphic assistance. The work is supported by the grants from National Science Counsel (NSC 94- 2311-B-007-008, 94-2311-B-007-015, 95-2311-B-007-006, 96-2311-B-007-003) and in part by the APEX funding 97N2504E1 from BRC at National Tsing Hua University to H.-D. Wang and a grant from the National Institute of Aging (R15 AG027749) to T.J. Brummel. Supporting Information Additional Supporting Information may be found in the online version of this article: Fig. S1 The isolation of the 1.6-kb DNA sequence, p1130, up-regulated in EP1130. Fig. S2 EP1307 mutant in alpha-1,2-mannosidase I (mas1) exhibits a longer lifespan. Fig. S3 Nonparallel gene-by-DR interaction plots between the mutants and the control. Fig. S4 Dietary restriction does not further extend the enhanced lifespan of the mas1-RNAi-knockdowned flies. Fig. S5 A similar pattern of reduced fecundity of the mutant and control flies in the restricted (5%SY) food compared to the abundant (15%SY) food. Table S1 A summary of the lifespan of the male mutants at 25 C. Table S2 A summary of the lifespan of the female mutants at 25 C. Table S3 Oxidative stress and starvation tests in the mutants. Table S4 A summary of the lifespan of the RNA interference knockdown of mas1 in Drosophila melanogaster and Caenorhabditis elegans. Table S5 A summary of the lifespan of the virgin female heterozygous and transheterozygous mutants at 25 C. Table S6 A summary of the lifespan of the mutants on restricted 5% SY and abundant 15%SY diet.

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