CoChat
Sign Up
PreprintCited by 65Genetics, Aging, and Longevity in Model OrganismsMitochondrial Function and PathologyTelomeres, Telomerase, and Senescence

Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging

Open access
Heinze, Ivonne, Bens, Martin, Calzia, Enrico, Holtze, Susanne, Dakhovnik, Oleksandr, Sahm, Arne, Kirkpatrick, Joanna M., Szafranski, Karol, Romanov, Natalie, Holzer, Kerstin, Singer, Stephan, Ermolaeva, Maria, Platzer, Matthias, Hildebrandt, Thomas, Ori, Alessandro·2017·BMC Biology
DOI 10.1101/220343PMC PMC6090990

Preprint — published as 10.1186/s12915-018-0547-y · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

Mammals display wide range of variation in their lifespan. Investigating the molecular networks that distinguish long-from short-lived species has proven useful to identify determinants of longevity. Here, we compared the liver of long-lived naked mole-rats (NMRs) and the phylogenetically closely related, shorter-lived, guinea pigs using an integrated omic approach. We found that NMRs livers display a unique expression pattern of mitochondrial proteins that result in distinct metabolic features of their mitochondria. For instance, we observed a generally reduced respiration rate associated with lower protein levels of respiratory chain components, particularly complex I, and increased capacity to utilize fatty acids. Interestingly, we show that the same molecular networks are affected during aging in both NMR and humans, supporting a direct link to the extraordinary longevity of both species. Finally, we identified a novel longevity pathway and validated it experimentally in the nematode C. elegans .

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/220343

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 74

  1. Fushan AA , Turanov AA , Lee S-G , Kim EB , Lobanov A V , Yim SH , et al. Gene expression defines natural changes in mammalian lifespan. Aging Cell. 2015;352–65. · DOI
  2. Sahm A , Bens M , Szafranski K , Holtze S , Groth M , Goerlach M , et al. Long-lived rodents reveal signatures of positive selection in genes associated with lifespan and eusociality. doi.org. 2017;191999. · DOI
  3. Lewis KN , Mele J , Hornsby PJ , Buffenstein R . Stress resistance in the naked mole-rat: the bare essentials - a mini-review. Gerontology. 2012;453–62. · DOI
  4. Skulachev VP , Holtze S , Vyssokikh MY , Bakeeva LE , Skulachev M V. , Markov A V. , et al. Neoteny, Prolongation of Youth: From Naked Mole Rats to “Naked Apes” (Humans). Physiol. Rev. 2017;699–720. · DOI
  5. Kim EB , Fang X , Fushan AA , Huang Z , Lobanov A V. , Han L , et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature. 2011;223– 7. · DOI · Paper page
  6. Fang X , Seim I , Huang Z , Gerashchenko M V. , Xiong Z , Turanov AA , et al. Adaptations to a Subterranean Environment and Longevity Revealed by the Analysis of Mole Rat Genomes. Cell Rep. 2014;1354–64. · DOI
  7. Yu C , Li Y , Holmes A , Szafranski K , Faulkes CG , Coen CW , et al. RNA sequencing reveals differential expression of mitochondrial and oxidation reduction genes in the long-lived naked mole-rat when compared to mice. PLoS One. 2011;e26729. · DOI
  8. Pérez VI , Buffenstein R , Masamsetti V , Leonard S , Salmon AB , Mele J , et al. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc. Natl. Acad. Sci. U. S. A. 2009;3059–64. · DOI · Paper page
  9. Rodriguez KA , Edrey YH , Osmulski P , Gaczynska M , Buffenstein R . Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat. PLoS One. 2012;e35890. · DOI
  10. Buffenstein R . Negligible senescence in the longest living rodent, the naked mole-rat: Insights from a successfully aging species [Internet]. J. Comp. Physiol. B Biochem. Syst. Environ. Physiol. 2008. p. 439–45. · DOI · Paper page
  11. Lewis KN , Wason E , Edrey YH , Kristan DM , Nevo E , Buffenstein R . Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proc. Natl. Acad. Sci. U. S. A. 2015;3722–7. · DOI
  12. Tian X , Azpurua J , Hine C , Vaidya A , Myakishev-Rempel M , Ablaeva J , et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;346–9. · DOI
  13. Andziak B , O’Connor TP , Qi W , DeWaal EM , Pierce A , Chaudhuri AR , et al. High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell. 2006;463–71. · DOI
  14. Holtze S , Eldarov CM , Vays VB , Vangeli IM , Vysokikh MY , Bakeeva LE , et al. Study of age-dependent structural and functional changes of mitochondria in skeletal muscles and heart of naked mole rats (Heterocephalus glaber). Biochem. 2016;1429–37. · DOI
  15. Lewis KN , Andziak B , Yang T , Buffenstein R . The naked mole-rat response to oxidative stress: just deal with it. Antioxid. Redox Signal. 2013;1388–99. · DOI
  16. Finkel T . The metabolic regulation of aging. Nat. Med. 2015;1416–23. · DOI · Paper page
  17. Fontana L , Partridge L . Promoting Health and Longevity through Diet: From Model Organisms to Humans. Cell. 2015;106–18. · DOI · Paper page
  18. Davinelli S , Willcox DC , Scapagnini G . Extending healthy ageing: nutrient sensitive pathway and centenarian population. Immun. Ageing. 2012;9. · DOI
  19. Sahm A , Bens M , Platzer M , Cellerino A . Parallel evolution of genes controlling mitonuclear balance in short-lived annual fishes. Aging Cell. 2017 Feb 11; · DOI
  20. Houtkooper RH , Mouchiroud L , Ryu D , Moullan N , Katsyuba E , Knott G , et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013;451–7. · DOI · Paper page
  21. Brandt T , Mourier A , Tain LS , Partridge L , Larsson N-G , Kühlbrandt W . Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila. Elife. 2017; · DOI
  22. Park TJ , Reznick J , Peterson BL , Blass G , Omerbašić D , Bennett NC , et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science (80-.). 2017;307–11. · DOI · Paper page
  23. Ori A , Toyama BH , Harris MS , Bock T , Iskar M , Bork P , et al. Integrated Transcriptome and Proteome Analyses Reveal Organ-Specific Proteome Deterioration in Old Rats. Cell Syst. 2015;224–37. · DOI · Paper page
  24. Vogel C , Marcotte EM . Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 2012;227–32. · DOI · Paper page
  25. Nyström T , Yang J , Molin M . Peroxiredoxins, gerontogenes linking aging to genome instability and cancer. Genes Dev. 2012;2001–8. · DOI
  26. Hanzén S , Vielfort K , Yang J , Roger F , Andersson V , Zamarbide-Forés S , et al. Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins. Cell. 2016;140–51. · DOI
  27. Biteau B , Karpac J , Supoyo S , DeGennaro M , Lehmann R , Jasper H . Lifespan extension by preserving proliferative homeostasis in Drosophila. Kim SK, editor. PLoS Genet. 2010;1–15. · DOI
  28. Erol A . The Functions of PPARs in Aging and Longevity. PPAR Res. 2007;39654. · DOI · Paper page
  29. Bustos V , Partridge L . Good Ol’ Fat: Links between Lipid Signaling and Longevity. Trends Biochem. Sci. 2017; · DOI
  30. Cellerino A , Ori A . What have we learned on aging from omics studies? Semin. Cell Dev. Biol. 2017; · DOI
  31. Delire B , Lebrun V , Selvais C , Henriet P , Bertrand A , Horsmans Y , et al. Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling. Aging (Albany. NY). 2016;98–113. · DOI · Paper page
  32. Buczak K , Ori A , Kirkpatrick JM , Holzer K , Dauch D , Roessler S , et al. Spatial tissue proteomics quantifies inter- and intra-tumor heterogeneity in hepatocellular carcinoma. Mol. Cell. Proteomics. 2018; · DOI
  33. Hattori K , Inoue M , Inoue T , Arai H , Tamura H . A novel sulfotransferase abundantly expressed in the dauer larvae of Caenorhabditis elegans. J. Biochem. 2006;355–62. · DOI
  34. Fielenbach N , Antebi A . C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 2008;2149–65. · DOI
  35. Murphy CT , McCarroll SA , Bargmann CI , Fraser A , Kamath RS , Ahringer J , et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003;277–83. · DOI · Paper page
  36. White RR , Milholland B , MacRae SL , Lin M , Zheng D , Vijg J . Comprehensive transcriptional landscape of aging mouse liver. BMC Genomics. 2015;899. · DOI
  37. Beltrán-Sánchez H , Finch C . Age is just a number. Elife. 2018; · DOI
  38. Durieux J , Wolff S , Dillin A . The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011;79–91. · DOI · Paper page
  39. Baumgart M , Priebe S , Groth M , Hartmann N , Menzel U , Pandolfini L , et al. Longitudinal RNA-seq analysis of vertebrate aging identifies mitochondrial complex i as a small-molecule-sensitive modifier of lifespan. Cell Syst. 2016;122–32. · DOI
  40. 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;3837. · DOI
  41. Sgarbi G , Matarrese P , Pinti M , Lanzarini C , Ascione B , Gibellini L , et al. Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. Aging (Albany. NY). 2014;296–310. · DOI · Paper page
  42. Sengupta S , Peterson TR , Laplante M , Oh S , Sabatini DM . mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 2010;1100–4. · DOI · Paper page
  43. Luis NM , Wang L , Ortega M , Deng H , Katewa SD , Li PW-L , et al. Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction. Cell Rep. 2016;1207–16. · DOI
  44. Mitchell SJ , Madrigal-Matute J , Scheibye-Knudsen M , Fang E , Aon M , González-Reyes JA , et al. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab. 2016;1093–112. · DOI · Paper page
  45. Hahn O , Grönke S , Stubbs TM , Ficz G , Hendrich O , Krueger F , et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 2017;1194. · DOI · Paper page
  46. Kim HE , Grant AR , Simic MS , Kohnz RA , Nomura DK , Durieux J , et al. Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response. Cell. 2016;1539–1552.e16. · DOI
  47. Weir HJ , Yao P , Huynh FK , Escoubas CC , Goncalves RL , Burkewitz K , et al. Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab. 2017; · DOI · Paper page
  48. Toth M , Tchernof A . Lipid metabolism in the elderly. Eur. J. Clin. Nutr. 2000;S121–5. · DOI
  49. Solomon TPJ , Marchetti CM , Krishnan RK , Gonzalez F , Kirwan JP . Effects of aging on basal fat oxidation in obese humans. Metabolism. 2008;1141–7. · DOI
  50. St-Onge M-P , Gallagher D . Body composition changes with aging: the cause or the result of alterations in metabolic rate and macronutrient oxidation? Nutrition. 2010;152–5. · DOI · Paper page
  51. Franceschi C , Campisi J , LR M, J C, JL K, HY C. Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases. Journals Gerontol. Ser. A Biol. Sci. Med. Sci. 2014;S4–9. · DOI · Paper page
  52. Done AJ , Gage MJ , Nieto NC , Traustadóttir T . Exercise-induced Nrf2-signaling is impaired in aging. Free Radic. Biol. Med. 2016;130–8. · DOI
  53. Safdar A , deBeer J , Tarnopolsky MA . Dysfunctional Nrf2–Keap1 redox signaling in skeletal muscle of the sedentary old. Free Radic. Biol. Med. 2010;1487–93. · DOI
  54. Bens M , Szafranski K , Holtze S , Sahm A , Groth M , Kestler HA , et al. Naked mole-rat transcriptome signatures of socially-suppressed sexual maturation and links of reproduction to aging. bioRxiv. 2017;221333. · DOI
  55. Buffenstein R , Jarvis JUM . The Naked Mole Rat--A New Record for the Oldest Living Rodent. Sci. Aging Knowl. Environ. 2002;7pe–7. · DOI
  56. Dammann P , Šumbera R , Maßmann C , Scherag A , Burda H . Extended Longevity of Reproductives Appears to be Common in Fukomys Mole-Rats (Rodentia, Bathyergidae). de Polavieja GG, editor. PLoS One. 2011;e18757. · DOI
  57. Dammann P , Burda H . Sexual activity and reproduction delay ageing in a mammal. Curr. Biol. 2006;R117–8. · DOI
  58. Bens M , Sahm A , Groth M , Jahn N , Morhart M , Holtze S , et al. FRAMA: from RNA-seq data to annotated mRNA assemblies. BMC Genomics. 2016;54. · DOI
  59. Sahm A , Bens M , Platzer M , Szafranski K . PosiGene: automated and easy-to-use pipeline for genome-wide detection of positively selected genes. Nucleic Acids Res. 2017;e100–e100. · DOI
  60. Hughes CS , Foehr S , Garfield DA , Furlong EE , Steinmetz LM , Krijgsveld J . Ultrasensitive proteome analysis using paramagnetic bead technology. Mol. Syst. Biol. 2014;757. · DOI
  61. Cox J , Neuhauser N , Michalski A , Scheltema RA , Olsen J V. , Mann M . Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment. J. Proteome Res. 2011;1794–805. · DOI
  62. Cox J , Mann M . MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 2008;1367–72. · DOI · Paper page
  63. Elias JE , Gygi SP . Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat. Methods. 2007;207–14. · DOI · Paper page
  64. Ritchie ME , Phipson B , Wu D , Hu Y , Law CW , Shi W , et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;e47–e47. · DOI · Paper page
  65. Benjamini Y , Hochberg Y . Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing [Internet]. J. R. Stat. Soc. Ser. B. 1995. p. 289–300. · DOI · Paper page
  66. Brosch M , Yu L , Hubbard T , Choudhary J . Accurate and sensitive peptide identification with Mascot Percolator. J. Proteome Res. 2009;3176–81. · DOI
  67. Gatto L , Lilley KS . MSnbase-an R/Bioconductor package for isobaric tagged mass spectrometry data visualization, processing and quantitation. Bioinformatics. 2012;288–9. · DOI
  68. Huber W , von Heydebreck A , Sültmann H , Poustka A , Vingron M . Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics. 2002;S96–104. · DOI · Paper page
  69. Bruderer R , Bernhardt OM , Gandhi T , Miladinović SM , Cheng L-Y , Messner S , et al. Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol. Cell. Proteomics. 2015;1400–10. · DOI · Paper page
  70. Storey JD . A direct approach to false discovery rates. J. R. Stat. Soc. Ser. B (Statistical Methodol. 2002;479–98. · DOI · Paper page
  71. Luo W , Friedman MS , Shedden K , Hankenson KD , Woolf PJ . GAGE: generally applicable gene set enrichment for pathway analysis. BMC Bioinformatics. 2009;161. · DOI · Paper page
  72. Subramanian A , Tamayo P , Mootha VK , Mukherjee S , Ebert BL , Gillette MA , et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U. S. A. 2005;15545–50. · DOI · Paper page
  73. Supek F , Bošnjak M , Škunca N , Šmuc T . REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One. 2011;e21800. · DOI · Paper page
  74. Vizcaíno JA , Csordas A , Del-Toro N , Dianes JA , Griss J , Lavidas I , et al. 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 2016;D447–56. · DOI

Authors
Heinze, I., Bens, M., Calzia, E., Holtze, S., Dakhovnik, O., Sahm, A., Kirkpatrick, J. M., Szafranski, K., Romanov, N., Holzer, K., Singer, S., Ermolaeva, M., Platzer, M., Hildebrandt, T., & Ori, A.
Affiliations
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
  • Universität Ulm (DE)
  • Leibniz Institute for Zoo and Wildlife Research (DE)
  • European Molecular Biology Laboratory (DE)
  • Universitätsmedizin Greifswald (DE)
Corresponding author
  • Platzer, Matthias
  • Hildebrandt, Thomas
ORCID
Venue
BMC Biology
Publisher
openRxiv
Published
2017-11-17
Volume
16
Issue
1
Pages
82-82
ISSN
1741-7007 (ISSN-L)
DOI
10.1101/220343
PMC
PMC6090990
OpenAlex
W2884076930
Cited by
65
References
1
Citations by year
2026: 1 · 2025: 9 · 2024: 2 · 2023: 9 · 2022: 10 · 2021: 14 · 2020: 11 · 2019: 7 · 2018: 1
FWCI
3.24
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Australian Government
  • Deutsche Forschungsgemeinschaft (SFB/TR209 (Project B04), SAW-2012-FLI-2, PL 173/8-1, SFB/TR-209, GRK1715, Project B04)
  • Leibniz-Gemeinschaft (SAW‐2012‐FLI‐2, SAW-2012-FLI)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords
naked mole-rat, longevity, aging, liver proteome, mitochondrial proteins, mitochondrial respiration, respiratory chain complex I, fatty acid utilization, detoxification pathways, cross-species comparison, guinea pig, Caenorhabditis elegans, senescence
MeSH terms
Adult, Aged, Aged, 80 and over, Aging, Animals, Guinea Pigs, Humans, Liver, Longevity, Male, Middle Aged, Species Specificity, Caenorhabditis elegans, Mole Rats, Proteome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review