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Separation of reproductive decline from lifespan extension during methionine restriction

Nature Aging volume 4, pages 1089–1101 (2024)Cite this article

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Abstract

Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that we developed for Drosophila melanogaster, we surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline.

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Fig. 1: Methionine restriction extends lifespan but limits reproduction in Drosophila.
Fig. 2: MR restores redox balance and enhances TCA flux that declines during aging.
Fig. 3: Folic acid supplementation rescues fertility limitations while maintaining longevity during MR.
Fig. 4: FA supplementation rescues MR-induced sperm viability and transfer decline.
Fig. 5: MR-FA maintains sperm redox balance and enhances sperm energy metabolism.

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Data availability

The raw mass spectrometry data supporting the findings of the present study are available at GitHub (https://github.com/LocasaleLab/MR-FA_Nature-Aging-2024). Analysis of metabolites was carried out with MetaboAnalyst v.6.0 (http://www.metaboanalyst.ca/MetaboAnalyst/) and GENE-E (https://software.broadinstitute.org/GENE-E/) using the Kyoto Encyclopedia of Genes and Genomes pathway database (http://www.genome.jp/kegg/). Source data are provided with this paper.

Code availability

The code used to perform bioinformatics analysis in this study is available at GitHub (https://github.com/LocasaleLab/MFA-Collaboration-2024).

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Acknowledgements

Support from the National Institutes of Health (grant R01CA193256 to J.W.L.) is gratefully acknowledged. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We gratefully acknowledge members of the Locasale laboratory for helpful discussions and apologize to those whose work we did not cite due to space constraints.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA

    Fangchao Wei, Shiyu Liu, Juan Liu, Annamarie E. Allen, Michael A. Reid & Jason W. Locasale

  2. Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA

    Yudong Sun

  3. Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA

    Jason W. Locasale

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Contributions

J.W.L. and F.C.W. designed the study and wrote and edited the paper. F.C.W. performed the experiments and the data analysis. S.Y.L. designed and optimized the calculation method of metabolic flux. J.L. assisted in metabolomics data analysis. Y.D.S., A.E.A. and M.A.R. optimized the CDD.

Corresponding author

Correspondence to Jason W. Locasale.

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Competing interests

J.W.L. advises Restoration Foodworks, Cornerstone Pharmaceuticals and Nanocare Technologies and receives funding from the National Institutes of Health and American Cancer Society. These interests had no role in this study. J.W.L. and F.C.W. have filed an invention disclosure related to this manuscript. The other authors declare no competing interests.

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Nature Aging thanks Christian Frezza, Naama Kanarek, Andromachi Pouikli, and the other, anonymous, reviewer(s) for their contributions to the peer review of this work.

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Extended data

Extended Data Fig. 1 Effects of different diets on physiological changes of Drosophila.

(a) Experimental design. (b) Lifespan. n = 150 (male n = 100, female n = 50). (c) Reproduction (male n = 25, female n = 25). (d) Egg development time (n = 15). (e) Climbing activity. n = 125 (male n = 75, female n = 50). (f) Body weight. n = 50 flies per group unless otherwise specified. n = 3 biological replicates. Mean ± s.e.m. P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 2 Effects of dietary methionine restriction (MR) on physiological changes.

(a) Dietary methionine concentration. (b) Egg count. (c) Male fertility assessment. ****P < 0.0001.(d-f) Climbing activity (n = 25) (d), body weight (e), and egg development time (laid by mated female) (n = 15) (f) of males. (g) Female fertility assessment. ****P < 0.0001.(h-j) Climbing activity (n = 25) (h), body weight (i), and egg development time (n = 15) (j) of female. Egg development was on control diet. n = 50 flies per group unless otherwise specified. Scale bar, 1 cm. Mean ± s.e.m. P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 3 Characterization of MR time windows and effect on lifespan.

(a-j) Schematic of dietary MR at different life stages of Drosophila. Blue boxes on graphs indicate duration of MR during lifespan, 2 weeks. male n = 50, female n = 50. n = 3 biological replicates. a, *P = 0.039, **P = 0.0068, *P = 0.013, **P = 0.0032, **P = 0.0031, **P = 0.0026, **P = 0.0061, **P = 0.0053, **P = 0.0065; b, **P = 0.005, **P = 0.0086; c, *P = 0.034, *P = 0.015; d, *P = 0.039, **P = 0.0053, **P = 0.0029, *P = 0.033; f, *P = 0.039, **P = 0.0038, *P = 0.021, **P = 0.005, **P = 0.0011, **P = 0.0085, **P = 0.0022, **P = 0.0081, *P = 0.033; g, **P = 0.0032, **P = 0.001, **P = 0.0018, *P = 0.019; h, *P = 0.011, *P = 0.013, *P = 0.034; i, **P = 0.0061, **P = 0.0061, *P = 0.021. Mean ± s.e.m. P values were obtained by multiple t-test.

Source data

Extended Data Fig. 4 Count the numbers of offspring from the hatched eggs.

10% methionine diet reduces reproduction of young (a, b) and old (c, d). Egg development was on control diet. n = 50 flies. n = 3 biological replicates. a, ****P < 0.0001; b, ****P < 0.0001; c, ***P = 0.0004; d, ***P = 0.0005. Mean ± s.e.m. P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 5 Effects of dietary MR on metabolism.

(a) Heat map of metabolites. (b) Partial least-squares discriminant analysis (PLS-DA). (c-e) Volcano plots of metabolites. FC, fold change. n = 10 flies. n = 3 biological replicates. Mean ± s.e.m. P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 6 TCA cycling metabolic flux analysis in cells.

(a) 293 T, human embryonic kidney cell. ****P < 0.0001. (b) GC-1, mouse spermatogonia cell. ****P < 0.0001. (c) GC-2, mouse spermatocyte cell. ****P < 0.0001. n = 1×105 cells. n = 3 biological replicates. Regarding the determination of the flux, we employed a comprehensive approach, optimizing 10,000 simulated replicates and selecting the 50 simulated replicates (show the average) with the smallest discrepancy in the final target metabolite as the final solution set. Mean ± s.e.m. P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 7 Effects of antibiotic-containing diets on physiological changes.

(a) Dietary FA concentration. (b) Concentration of FA in the diet. (c) Body FA concentration (n = 100). (d) Lifespan on antibiotic-contain diets. (e) Reproduction on antibiotic-containing diets. MR/Ctrl *P = 0.031, MR-FA/MR *P = 0.039. n = 50 flies. n = 3 biological replicates. Mean ± s.e.m. NS = P > 0.05, P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 8 Relative labeling enrichment for methionine and Central carbon metabolic flux analysis.

Relative labeling enrichment for methionine in whole male young (a) and old (b) flies fed with labeled U-13C5-methionine tracer for 3 d. M + 0-M + 5 mark the number of labeled carbons. a, ***P = 0.0001 and ****P < 0.0001. b, ***P = 0.0001 and ****P < 0.0001. (c) Central carbon metabolic flux analysis. NS = P > 0.05, ****P < 0.0001.n = 10 flies. n = 3 biological replicates. Mean ± s.e.m, NS = P > 0.05, P values were obtained by unpaired, two-tailed t-test.

Source data

Extended Data Fig. 9 Effects of dietary MR-FA on sperm development.

(a) Testes staining. Phase 1 to phase 3 involve spermatogenesis and mature sperm are enriched in phase 4. Scale bar, 100 μm. young n = 10. (b) Different phases of spermatogenesis. Scale bar, 50 μm. young n = 10, old n = 10. Each experiment was repeated independently three times with similar results.

Source data

Extended Data Fig. 10 Effects of dietary MR/MR-FA on sperm metabolism.

(a) Heat map of metabolites. (b) Central carbon flux analysis. Regarding the determination of the flux, we employed a comprehensive approach, optimizing 10,000 simulated replicates and selecting the 50 simulated replicates (show the average) with the smallest discrepancy in the final target metabolite as the final solution set. *P = 0.024 and ****P < 0.0001. (c) Volcano plots of metabolites. Young flies n = 30, old flies n = 90. n = 3 biological replicates. FC, fold change. Mean ± s.e.m. NS = P > 0.05, P values were obtained by unpaired, two-tailed t-test.

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Wei, F., Liu, S., Liu, J. et al. Separation of reproductive decline from lifespan extension during methionine restriction. Nat Aging 4, 1089–1101 (2024). https://doi.org/10.1038/s43587-024-00674-4

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