Abstract
During aging, the loss of metabolic homeostasis drives a myriad of pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex in mice have, so far, produced detrimental phenotypes. Here, as an alternative approach, we alter energy homeostasis by manipulating the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and extend the lifespan of heterozygous males. Next, we apply an integrated omics approach to show that metabolic functions are rejuvenated in old mutants, which also display a fasting-like metabolic profile and resistance to high-fat diet. At the cellular level, heterozygous cells exhibit enhanced nutrient sensitivity, reduced ATP levels, and AMPK activation. Finally, lifelong intermittent fasting abolishes the longevity benefits. Our findings suggest that perturbing AMP biosynthesis may modulate vertebrate lifespan and propose APRT as a promising target for promoting metabolic health.
| Original language | English |
|---|---|
| Pages (from-to) | 1350-1364.e10 |
| Journal | Developmental Cell |
| Volume | 58 |
| Issue number | 15 |
| DOIs | |
| State | Published - 7 Aug 2023 |
Bibliographical note
Publisher Copyright:© 2023 Elsevier Inc.
Funding
We thank the Harel lab, Sagiv Shifman, Tamar Avin-Wittenberg, Eran Meshorer, Anne Brunet, and Berenice Benayoun for stimulating discussion and feedback on the manuscript. We thank Ella Yanay and Ashayma Abu-tair for help with killifish maintenance, Yaakov Nahmias and Konstantinos Ioannidis for help with the Seahorse assay, Naomi Melamed-Book and Rachel Rosen from the core facilities (HUJI), Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Sergey Malitsky, and Maxim Itkin for help with mass spectrometry, and Param Priya Singh and Anne Brunet for advice with the GSEA code. Supported by the Zuckerman Program (I.H.), Abisch-Frenkel Foundation 19/HU04 (I.H.), Switzerland, ISF 2178/19 (I.H.), Israel Ministry of Science 3-17631 (I.H.), 3-16872 (I.H.), the Moore Foundation GBMF9341 (I.H.), United States, BSF-NSF 2020611 (I.H.), the Israel Ministry of Agriculture 12-16-0010 (I.H), ERC StG # 101078188 (I.H), and the Lady Davis Postdoctoral Fellowship (G.A.). We thank the Harel lab, Sagiv Shifman, Tamar Avin-Wittenberg, Eran Meshorer, Anne Brunet, and Berenice Benayoun for stimulating discussion and feedback on the manuscript. We thank Ella Yanay and Ashayma Abu-tair for help with killifish maintenance, Yaakov Nahmias and Konstantinos Ioannidis for help with the Seahorse assay, Naomi Melamed-Book and Rachel Rosen from the core facilities (HUJI), Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Sergey Malitsky, and Maxim Itkin for help with mass spectrometry, and Param Priya Singh and Anne Brunet for advice with the GSEA code. Supported by the Zuckerman Program (I.H.), Abisch-Frenkel Foundation 19/HU04 (I.H.), Switzerland, ISF 2178/19 (I.H.), Israel Ministry of Science 3-17631 (I.H.), 3-16872 (I.H.), the Moore Foundation GBMF9341 (I.H.), United States, BSF-NSF 2020611 (I.H.), the Israel Ministry of Agriculture 12-16-0010 (I.H), ERC StG #101078188 (I.H), and the Lady Davis Postdoctoral Fellowship (G.A.). Conceptualization, G.A. T.A. and I.H.; methodology, G.A. T.A. and A.V.; software, T.A. and K.S.; validation, G.A. T.A. and I.H.; formal analysis, T.A. G.A. J.D. K.S. E.Y.L. and I.H.; investigation, G.A. U.G. A.O.-G. T.A. T.L. and M.S.; resources, data curation, writing—original draft, G.A. T.A. and I.H.; writing—review and editing, T.A. and I.H.; visualization, T.A. and G.A.; supervision, I.H. and E.Y.L.; project administration, G.A. and T.A.; funding acquisition, I.H. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
| Funders | Funder number |
|---|---|
| Harel lab, Sagiv Shifman | |
| Israel Ministry of Science 3-17631 | 3-16872 |
| Blanche Moore Foundation | GBMF9341, BSF-NSF 2020611 |
| European Commission | 101078188 |
| Ministry of Agriculture and Rural Development | 12-16-0010 |
| Abisch-Frenkel-Stiftung | 19/HU04, ISF 2178/19 |
Keywords
- AMP biosynthesis
- AMPK
- APRT
- CRISPR
- aging
- killifish
- longevity
- metabolism
- nutrient sensing
- sex differences