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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Antikainen H, Driscoll M, Haspel G, Dobrowolski R. TOR-mediated regulation of metabolism in aging. Aging Cell. 2017;16:1219–33. https://doi.org/10.1111/acel.12689.
Bárcena C, López-Otín C, Kroemer G. Methionine restriction for improving progeria: another autophagy-inducing anti-aging strategy? Autophagy. 2019;15:558–9. https://doi.org/10.1080/15548627.2018.1533059.
Barja G. Mitochondrial free radical production and aging in mammals and birds. Ann N Y Acad Sci. 1998;854:224–38. https://doi.org/10.1111/j.1749-6632.1998.tb09905.x.
Barja G. The gene cluster hypothesis of aging and longevity. Biogerontology. 2008;9:57–66. https://doi.org/10.1007/s10522-007-9115-5.
Barja G. Longevity and evolution. New York: Nova Science Publishers, Inc.; 2010.
Barja G. Towards a unified mechanistic theory of aging. Exp Gerontol. 2019;124:110627. https://doi.org/10.1016/j.exger.2019.05.016.
Barja G, Cadenas S, Rojas C, Pérez-Campo R, López-Torres M. Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds. Free Radic Res. 1994;21:317–27. https://doi.org/10.3109/10715769409056584.
Bowles JT. The evolution of aging: a new approach to an old problem of biology. Med Hypotheses. 1998;51:179–221. https://doi.org/10.1016/S0306-9877(98)90079-2.
Bozek K, Khrameeva EE, Reznick J, Omerbašić D, Bennett NC, Lewin GR, et al. Lipidome determinants of maximal lifespan in mammals. Sci Rep. 2017;7:1–5. https://doi.org/10.1038/s41598-017-00037-7.
Cabré R, Jové M, Naudí A, Ayala V, Piñol-Ripoll G, Gil-Villar MP, et al. Specific metabolomics adaptations define a differential regional vulnerability in the adult human cerebral cortex. Front Mol Neurosci. 2016;9. https://doi.org/10.3389/fnmol.2016.00138.
Caraveo G, Soste M, Cappelleti V, Fanning S, van Rossum DB, Whitesell L, et al. FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome. Proc Natl Acad Sci. 2017;114:311–22. https://doi.org/10.1073/pnas.1711926115.
Caron A, Richard D, Laplante M. The roles of mTOR complexes in lipid metabolism. Annu Rev Nutr. 2015;35:321–48. https://doi.org/10.1146/annurev-nutr-071714-034355.
Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem. 2005;280:25485–90. https://doi.org/10.1074/jbc.M501707200.
Chong J, Wishart DS, Xia J. Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr Protoc Bioinforma. 2019;68. https://doi.org/10.1002/cpbi.86.
Cooper N, Thomas GH, FitzJohn RG. Shedding light on the ‘dark side’ of phylogenetic comparative methods. Methods Ecol Evol. 2016;7:693–9. https://doi.org/10.1111/2041-210X.12533.
Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex. Nature. 2007;450:736–40. https://doi.org/10.1038/nature06322.
Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39:171–83. https://doi.org/10.1016/j.molcel.2010.06.022.
Figueiredo VC, Markworth JF, Cameron-Smith D. Considerations on mTOR regulation at serine 2448: implications for muscle metabolism studies. Cell Mol Life Sci. 2017;74:2537–45. https://doi.org/10.1007/s00018-017-2481-5.
Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science. 2010;328(80):321–6. https://doi.org/10.1126/science.1172539.
Fredslund J, Schauser L, Madsen LH, Sandal N, Stougaard J. PriFi: using a multiple alignment of related sequences to find primers for amplification of homologs. Nucleic Acids Res. 2005;33:516–20. https://doi.org/10.1093/nar/gki425.
Fushan AA, Turanov AA, Lee S-G, Kim EB, Lobanov AV, Yim SH, et al. Gene expression defines natural changes in mammalian lifespan. Aging Cell. 2015;14:352–65. https://doi.org/10.1111/acel.12283.
Gomez A, Gomez J, Torres ML, Naudi A, Mota-Martorell N, Pamplona R, et al. Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restriction. J Bioenerg Biomembr. 2015;47. https://doi.org/10.1007/s10863-015-9608-x.
Gu X, Orozco JM, Saxton RA, et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science. 2017;358(80):813–8. https://doi.org/10.1126/science.aao3265.
Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255–62. https://doi.org/10.1038/35041700.
Hoeffer CA, Tang W, Wong H, Santillan A, Patterson RJ, Martinez LA, et al. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron. 2008;60:832–45. https://doi.org/10.1016/j.neuron.2008.09.037.
Jeon JS, Oh J-J, Kwak HC, Yun HY, Kim HC, Kim YM, et al. Age-related changes in sulfur amino acid metabolism in male C57BL/6 mice. Biomol Ther (Seoul). 2018;26:167–74. https://doi.org/10.4062/biomolther.2017.054.
Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–45. https://doi.org/10.1038/nature11861.
Jones OR, Scheuerlein A, Salguero-Gómez R, Camarda CG, Schaible R, Casper BB, et al. Diversity of ageing across the tree of life. Nature. 2014;505:169–73. https://doi.org/10.1038/nature12789.
Jové M, Naudí A, Aledo JC, Cabré R, Ayala V, Portero-Otin M, et al. Plasma long-chain free fatty acids predict mammalian longevity. Sci Rep. 2013;3:3346. https://doi.org/10.1038/srep03346.
Kapahi P, Chen D, Rogers AN, Katewa SD, Li PWL, Thomas EL, et al. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab. 2010;11:453–65. https://doi.org/10.1016/j.cmet.2010.05.001.
Kenyon CJ. The genetics of ageing. Nature. 2010;464:504–12. https://doi.org/10.1038/nature08980.
Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature. 2011;479:223–7. https://doi.org/10.1038/nature10533.
Kumar S, Stecher G, Suleski M, Hedges SB. TimeTree: a resource for timelines, timetrees, and divergence times. Mol Biol Evol. 2017;34:1812–9. https://doi.org/10.1093/molbev/msx116.
Lewis KN, Rubinstein ND, Buffenstein R. A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence. GeroScience. 2018;40:105–21. https://doi.org/10.1007/s11357-018-0014-2.
Libertini G. An adaptive theory of the increasing mortality with increasing chronological age in populations in the wild. J Theor Biol. 1988;132:145–62. https://doi.org/10.1016/S0022-5193(88)80153-X.
Liu Y, Song D, Xu B, Li H, Dai X, Chen B. Development of a matrix-based candidate reference material of total homocysteine in human serum. Anal Bioanal Chem. 2017;409:3329–35. https://doi.org/10.1007/s00216-017-0272-3.
Longo VD, Mitteldorf J, Skulachev VP. Programmed and altruistic ageing. Nat Rev Genet. 2005;6:866–72. https://doi.org/10.1038/nrg1706.
Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, et al. Interventions to slow aging in humans: are we ready? Aging Cell. 2015;14:497–510. https://doi.org/10.1111/acel.12338.
Lushchak O, Strilbytska O, Piskovatska V, Storey KB, Koliada A, Vaiserman A. The role of the TOR pathway in mediating the link between nutrition and longevity. Mech Ageing Dev. 2017;164:127–38. https://doi.org/10.1016/j.mad.2017.03.005.
Ma S, Gladyshev VN. Molecular signatures of longevity: insights from cross-species comparative studies. Semin Cell Dev Biol. 2017;70:190–203. https://doi.org/10.1016/j.semcdb.2017.08.007.
Ma S, Yim SH, Lee S-G, Kim EB, Lee SR, Chang KT, et al. Organization of the mammalian metabolome according to organ function, lineage specialization and longevity. Cell Metab. 2015;22:332–43. https://doi.org/10.1016/j.cmet.2015.07.005.
Ma S, Upneja A, Galecki A, Tsai YM, Burant CF, Raskind S, et al. Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity. Elife. 2016;5:1–25. https://doi.org/10.7554/eLife.19130.
Mitteldorf J. Aging is a group-selected adaptation: theory, evidence, and medical implications. Boca Ratón: CRC Press; 2016.
Mitteldorf J. Can aging be programmed? Biochem. 2018;83:1524–33. https://doi.org/10.1134/S0006297918120106.
Miwa S, Jow H, Baty K, Johnson A, Czapiewski R, Saretzki G, et al. Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nat Commun. 2014;5:1–12. https://doi.org/10.1038/ncomms4837.
Mota-Martorell N, Pradas I, Jové M, Naudí A, Pamplona R. Biosíntesis de novo de glicerofosfolípidos y longevidad. Rev Esp Geriatr Gerontol. 2019;54:88–93. https://doi.org/10.1016/j.regg.2018.05.006.
Muntané G, Farré X, Rodríguez JA, Pegueroles C, Hughes DA, de Magalhães JP, et al. Biological processes modulating longevity across primates: a phylogenetic genome-phenome analysis. Mol Biol Evol. 2018;35:1990–2004. https://doi.org/10.1093/molbev/msy105.
Nascimento EBM, Snel M, Guigas B, van der Zon GCM, Kriek J, Maassen JA, et al. Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1. Cell Signal. 2010;22:961–7. https://doi.org/10.1016/j.cellsig.2010.02.002.
Naudí A, Jové M, Ayala V, Portero-Otín M, Barja G, Pamplona R. Membrane lipid unsaturation as physiological adaptation to animal longevity. Front Physiol. 2013;4:372. https://doi.org/10.3389/fphys.2013.00372.
Pamplona R, Barja G. Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection. Biochim Biophys Acta Bioenerg. 2006;1757:496–508. https://doi.org/10.1016/j.bbabio.2006.01.009.
Pamplona R, Barja G. Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. Ageing Res Rev. 2007;6:189–210. https://doi.org/10.1016/j.arr.2007.06.002.
Pamplona R, Barja G. An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms. Biogerontology. 2011;12:409–35. https://doi.org/10.1007/s10522-011-9348-1.
Pamplona R, Barja G, Portero-Otín M. Membrane fatty acid unsaturation, protection against oxidative stress and maximum life span. Ann N Y Acad Sci. 2002;959:475–90. https://doi.org/10.1111/j.1749-6632.2002.tb02118.x.
Papadopoli D, Boulay K, Kazak L, et al. mTOR as a central regulator of lifespan and aging. F1000Research. 2019;8:998. https://doi.org/10.12688/f1000research.17196.1.
Passtoors WM, Beekman M, Deelen J, van der Breggen R, Maier AB, Guigas B, et al. Gene expression analysis of mTOR pathway: association with human longevity. Aging Cell. 2013;12:24–31. https://doi.org/10.1111/acel.12015.
Perez-Campo R, López-Torres M, Cadenas S, Rojas C, Barja G. The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol B Biochem Syst Environ Physiol. 1998;168:149–58. https://doi.org/10.1007/s003600050131.
Ruckenstuhl C, Netzberger C, Entfellner I, Carmona-Gutierrez D, Kickenweiz T, Stekovic S, et al. Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. PLoS Genet. 2014;10:e1004347. https://doi.org/10.1371/journal.pgen.1004347.
Sahm A, Bens M, Henning Y, et al. Higher gene expression stability during aging in long-lived giant mole-rats than in short-lived rats. Aging (Albany NY). 2018;10:3938–56. https://doi.org/10.18632/aging.101683.
Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25:903–15. https://doi.org/10.1016/j.molcel.2007.03.003.
Schieke SM, Phillips D, McCoy JP, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006;281:27643–52. https://doi.org/10.1074/jbc.M603536200.
Selman C, Tullet JMA, Wieser D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326(80):140–4. https://doi.org/10.1126/science.1177221.
Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy. 2008;4:176–84. https://doi.org/10.4161/auto.5269.
Singh PP, Demmitt BA, Nath RD, Brunet A. The henetics of aging: a vertebrate perspective. Cell. 2019;177:200–20. https://doi.org/10.1016/j.cell.2019.02.038.
Skulachev VP. Aging is a specific biological function rather than the result of a disorder in complex living systems: biochemical evidence in support of Weismann’s hypothesis. Biochemistry (Mosc). 1997;62:1191–5.
Tyshkovskiy A, Bozaykut P, Borodinova AA, et al. Identification and application of gene expression signatures associated with lifespan extension. Cell Metab. 2019;30:573–593.e8. https://doi.org/10.1016/j.cmet.2019.06.018.
Valvezan AJ, Manning BD. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat Metab. 2019;1:321–33. https://doi.org/10.1038/s42255-019-0038-7.
Weichhart T. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology. 2018;64:127–34. https://doi.org/10.1159/000484629.
Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4:913–20. https://doi.org/10.1016/j.celrep.2013.07.030.
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.
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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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 (2020). https://doi.org/10.1007/s11357-020-00210-3
- Methionine cycle metabolites