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Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity

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Abstract

Species longevity varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of longevity could converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study focuses on the comparative approach in heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot, and mass spectrometry, respectively. Our results demonstrate (1) the existence of differences in species-specific gene expression and protein content of mTORC1, (2) that the achievement of a high longevity phenotype correlates with decreased and inhibited mTORC1, (3) a decreased content of mTORC1 activators in long-lived animals, and (4) that these differences are independent of phylogeny. Our findings, taken together, support an important role for mTORC1 downregulation in the evolution of long-lived mammals.

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Acknowledgments

MJ is a ‘Serra Hunter’ Fellow. NMM received a predoctoral fellowship from the Generalitat of Catalonia (AGAUR, ref 2018FI_B2_00104). RB received a predoctoral fellowship from the ‘Impuls Program’ funded by the University of Lleida and Banco Santander (UdL, ref 0864/2016). We thank Salvador Batolome, from the Laboratory of Luminescence and Biomolecular Spectroscopy (Autonomous University of Barcelona, Barcelona, Catalonia, Spain), for ddPCR technical support.

Funding

This work was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (grant number PI14/00328), the Spanish Ministry of Science, Innovation and Universities (RTI2018–099200-B-I00), and the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250) to RP. This study has been co-financed by FEDER funds from the European Union (‘A way to build Europe’).

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Authors

Contributions

GB and RP designed the study. NMM., MJ, IP, RB, IS, AN, and EG performed experimental work. NMM and RP analysed the data. RP supervised the design and data interpretation. The manuscript was written by NMM, GB, and RP and edited by RP. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Gustavo Barja or Reinald Pamplona.

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The authors declare that they have no conflict of interest.

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ESM 1

mTORC1 core components are correlated in heart tissue from mammalian species. Pearson correlation was performed. Pearson r values are reported in Figure 3. Linear regression (LR) model was performed when significant relationships were found. Minimum signification level was set at p<0.05. Gene expression, protein content and phosphorylation were log-transformed to accomplish the assumptions of normality. (PNG 537 kb)

High Resolution Image (TIF 787 kb)

ESM 2

mTORC1 subunits and regulators that are not correlated with animal longevity after correcting for phylogenetic relationships. A) Effect of Pagel’s λ value on phylogeny branch length, when assuming absent (λ=0) or strong (λ=1) phylogenetic signal in the data. (PNG 1359 kb)

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ESM 3

Individual mTORC1 protein content and phosphorylation from animal’s heart. A) mTOR total protein content, mTORSer2448 and its respective Coomassie. B) PRAS40 total protein content, PRAS40Thr246 and its respective Coomassie. C) Raptor protein content and its respective Coomassie. D) FKBP12 protein content and its respective Coomassie. M = Mouse; R = Rat; G = Gerbil; GP = Guinea pig; Rb = Rabbit; P = Pig; C = Cow; H = Horse. (PNG 2047 kb)

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ESM 4

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Mota-Martorell, N., Jove, M., Pradas, I. et al. Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity. GeroScience 42, 1157–1173 (2020). https://doi.org/10.1007/s11357-020-00210-3

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  • DOI: https://doi.org/10.1007/s11357-020-00210-3

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