The naked mole rat – An alternative model species for biomedical ageing research

Naked mole rats (Heterocephalus glaber) are hardly mentioned in the list of the most beautiful animals. Nevertheless, they have an extraordinary reproductive system, are resistant to cancer and oxygen deprivation and (healthyly) grow astonishingly old, considering their small body size. What mechanisms underly these enviable skills?

Project details
Duration: since 09/2012
Third-party funded: yes
Involved Department(s): Dept Reproduction Management
Leibniz-IZW Project Leader(s): Thomas Hildebrandt (Dept Reproduction Management) 
Leibniz-IZW Project Team:

Susanne Holtze, Guido Fritsch (all: Dept Reproduction Management)
Consortium Partner(s):

Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Lomonossov Moscow State University (Russia), Washington University in St. Louis (USA)
Current Funding Organisation: Leibniz Research Alliance "Resilient Ageing"
Research Foci:
Understanding traits and evolutionary adaptations
Understanding the environmental context
Developing theories, methods, and tools

 

Naked mole rats (Heterocephalus glaber) represent true outliers among mammals – their eccentric outer appearance has earned them certain fame as “the world’s ugliest mammal”, but their truly unique values lie beneath the wrinkled skin. These almost hairless rodents of cylindrical body shape and approximately 30 g, carry their incisors on the outside of their mouth and apparently successfully ignore various natural laws: Besides their cancer and hypoxia resistance they can reach almost biblical ages in relation to their small body size. Surprisingly, their mortality risk does not increase over the lifespan. In our ageing human society, ‘healthy ageing’ (see https://www.leibniz-gesundes-altern.de/en) is of growing importance to research and medicine. The naked mole rat is a fascinating example of the huge variety of natural evolutionary adaptations from which we can learn and which we need to protect.

Our research is focused on the peculiarities of reproduction [publication no. 6, 14, 22, 26] and physiology [1-5, 7-10,12-13, 15-21, 25] of these small superheroes, with particular emphasis on the traits permitting them to age healthily [1, 4, 8-16, 18-21, 23, 25]. Together with various collaborators and funded by several research grants (i.a. SAW-2012-FLI-2; SAS-2016-2020-IZW-LFV; SAW-2018-DRFZ), we investigate the genetic and molecular processes underlying their unique physiological adaptations [1-5, 8, 10, 12, 14-16, 25].

Since 2008, we keep and successfully breed naked mole rats at the Leibniz-IZW for research. At the moment, almost 400 individuals in 12 colonies are ranging through artificial, transparent tunnel systems, mimicking their subterranean habitat in the Horn of Africa. As in their original habitat the animals feed on tubers and roots. The total collection of microbial organisms (bacteria and microbes) within the gastrointestinal tract is referred to as ‘intestinal microbiome’; its composition has been related to health and life expectancy. We found similarities in the intestinal microbiome of both, captive and free-ranging naked mole rats to supercentenarians as well as to Hazda hunter gatherers, who have gained fame for possessing the healthiest intestinal microbiome among humans [18, 21].

We further assessed the atmospheric composition of naked mole rat burrows in the wild for the first time, which – considering the extreme hypoxia tolerance of naked mole rats – is surprisingly similar to the normal atmosphere [25]. Why then are they so hypoxia-resistant? Most likely, this adaptation becomes relevant when all colony members are resting in the communal nest. Comparable to the social system of eusocial insects, naked mole rats live in colonies of up to 300 individuals. Likewise, reproduction is monopolized by a single female, the queen, and one or few males, the pasha(s) [7, 12, 34]. Interestingly, the life expectancy of queens and pashas is higher than that of workers, although all animals have the potential to become breeders.

To explore the transcriptomic differences underlying this phenomenon (SAW-2012-FLI2), besides differences in the expression patterns of genes related to sexual hormones, we found alterations related to energy and fat metabolism, mitochondria (the power plants of the cells) and further ageing-associated metabolic pathways [22, 32]. These might be relevant as targets for future therapeutic interventions. Also, morphology and function of naked mole rat mitochondria are maintained for a larger proportion of the life span compared to rat and mouse [15-16, 21, 23, 27-28]. In human and mouse the telomeres, which are protecting the chromosomal ends, shorten with increasing age, whereas in naked mole rat blood they retain or even increase in length [20]. We further investigate age-associated changes in bone structure with the help of modern imaging modalities, particularly regarding naked mole rat queens, whose spines disproportionally elongate. We found the epiphyseal clefts that enable longitudinal bone growth to close surprisingly late in naked mole rat life, at an age between 5 and 10 years [17]. Such retention of juvenile characteristics (neoteny) is found in many traits and developmental aspects of naked mole rats [17, 20-21, 27-28]. Besides a first characterization of the immune system of the healthily ageing naked mole rats [2, 18] (SAW-2018-DRFZ), we currently investigate the complex social system of this fascinating species.

Publications

  1. Martinez Q, Okrouhlík J, Šumbera R Wright M, Araújo R, Braude S, Hildebrandt TB, Holtze S, Ruf I & Fabre P-H. (2023). Mammalian maxilloturbinal evolution does not reflect thermal biology. Nat Commun 14, 4425.
  2. Gorshkova EA, Gubernatorova EO, Dvorianinova EM, Yurakova TR, Marey MV, Averina OA., Holtze S, Hildebrandt TB, ... & Nedospasov, S. A. (2023). Macrophages from naked mole-rat possess distinct immunometabolic signatures upon polarization. Frontiers in Immunology, 14, 1172467.
  3. Gerhardt P, Begall S, Frädrich C., Renko K, Hildebrandt TB, Holtze S, Heinrich A, Sahm A, Xheni M, Köhrle J, Rijntjes E, Henning Y. (2023). Comparative analysis of thyroid hormone systems in rodents with subterranean lifestyle. Scientific Reports, 13, 3122.
  4. Wetzel M, Courtiol A, Hofer H, Holtze S, Hildebrandt TB. (2023). Pup Recruitment in a Eusocial Mammal—Which Factors Influence Early Pup Survival in Naked Mole-Rats?. Animals, 13, 630.
  5. Braude S, Holtze S, Bennett NC, Begall S. (2022). Editorial: Recent advances in the ecology and evolution of the Bathyergidae. Front. Ecol. Evol. 10:1017185. doi: 10.3389/fevo.2022.1017185.
  6. Vays V, Vangely I, Eldarov C, Popkov V, Holtze S, Hildebrandt T, Averina OA, Bakeeva L, Zorov D. (2022). Unique features of the tissue structure in the naked mole rat (Heterocephalus glaber): hypertrophy of the endoplasmic reticulum and spatial mitochondrial rearrangements in hepatocytes. Int. J. Mol. Sci. 23, 9067, 1-15.
  7. Szafranski K, Wetzel M, Holtze S, Büntjen I, Lieckfeldt D, Ludwig A, Huse K, Platzer M, Hildebrandt TB. (2022). The mating pattern of captive naked mole-rats is best described by a monogamy model. Frontiers Ecology and Evolution 10, 1-9.
  8. Vays V, Vangely I, Eldarov C, Holtze S, Hildebrandt T, Bakeeva L, Skulachev V. (2021). Progressive reorganization of mitochondrial apparatus in aging skeletal muscle of naked mole rats (Heterocephalus glaber) as revealed by electron microscopy: potential role in continual maintenance of muscle activity. Aging (Albany NY). 13:24524-24541. doi: 10.18632/aging.203720.
  9. Holtze S, Gorshkova E, Braude S, Cellerino A, Dammann P, Hildebrandt TB,  Hoeflich A, Hoffmann S, Koch P, Terzibasi Tozzini E, Skulachev M, Skulachev VP, Sahm A. (2021). Alternative animal models of aging research. Frontiers in Molecular Biosciences, 8, 311.
  10. Del Marmol D, Holtze S, Kichler N, Sahm A, Bihin B, Bourguignon V, Dogné S, Szafranski K, Hildebrandt TB, Flamion B. (2021). Abundance and size of hyaluronan in naked mole-rat tissues and plasma. Scientific Reports 11,7951. doi: 10.1038/s41598-021-86967-9. PMID: 33846452.
  11. Walz M, Höflich C, Walz C, Ohde D, Brenmoehl J, Sawitzky M, Vernunft A, Zettl UK, Holtze S, Hildebrandt TB, Wolf E, Hoeflich A. (2021). Development of a Sensitive Bioassay for the Analysis of IGF-Related Activation of AKT/mTOR Signaling in Biological Matrices. Cells 10, 482. doi: 10.3390/cells10030482. PMID: 33668197; PMCID: PMC7995968.
  12. Braude S*, Holtze S*, Begall S, Brenmoehl J, Burda H, Dammann P, del Marmol D, Gorshkova  E, Henning Y, Hoeflich A, Höhn A, Jung T, Hamo D, Sahm A, Shebzukhov Y, Šumbera R, Miwa S, von Zglinicki T, Hildebrandt TB. (2021). Surprisingly long survival of pre-mature conclusions about naked mole-rat biology. Biological Reviews 96, 376-393. doi:10.1111/brv.12660
  13. Holtze S, Koch R, Hildebrandt TB, Lemma A, Szafranski K, Platzer M, Alemayehu F, Goeritz F, Braude S. (2020). Hematologic adaptation to the subterranean environment by the naked mole-rat, Heterocephalus glaber (Ctenohystryca: Heterocephalidae). Journal of Mammalogy, 100, 1000-1009. doi.org/10.1093/jmammal/gyaa053
  14. Braude S, Holtze S, Hildebrandt T, Koch R. (2020). Naked mole‐rats do not disperse or deliver pups in correlation with moon phase. African Journal of Ecology Afr J Ecol., 00:1–4. doi: 10.1111/aje.12721.
  15. Eldarov CM, Vangely IM, Vays VB, Sheval EV, Holtze S, Hildebrandt TB, Kolosova NG, Popkov VA, Plotnikov EY, Zorov DB, Bakeeva LE, Skulachev VP. (2020). Mitochondria in the Nuclei of Rat Myocardial Cells. Cells 9, 712. doi: 10.3390/cells9030712. PMID: 32183238.
  16. Vyssokikh MY, Holtze S, Averina OA, Lyamzaev KG, Panteleeva AA, Marey MV, Zinovkin RA, Severin FF, Skulachev MV, Fasel N, Hildebrandt TB, Skulachev VP. (2020). Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program. Proceedings of the National Academy of Sciences, 117(12), 6491-6501. doi: 10.1073/pnas.1916414117. Epub 2020 Mar 9. PMID: 32152094.
  17. Carmeli-Ligati S, Shipov A, Dumont M, Holtze S, Hildebrandt T, Shahar R (2019). The structure, composition and mechanical properties of the skeleton of the naked mole-rat (Heterocephalus glaber). Bone. 128:115035. doi:10.1016/j.bone.2019.115035.
  18. Shebzukhov Y, Holtze S, Hirseland H, Schäfer H, Radbruch A, Hildebrandt T, Grützkau A. (2019). Identification of cross-reactive antibodies for the detection of lymphocytes, myeloid cells and haematopoietic precursors in the naked mole rat. Eur J Immunol 49, 2103-2110. doi: 10.1002/eji.201948124.
  19. Dammann P, Scherag A, Zak N, Szafranski K, Holtze S, Begall S, Burda H, Kestler HA, Hildebrandt T, Platzer M (2019). Comment on 'Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age'. eLife. 2019;8. doi:10.7554/eLife.45415.
  20. Shekhidem AH, Sharvit L, Leman E, Manov I, Roichman A, Holtze S, M Huffman D, Y Cohen H, Hildebrandt T, Shams I, Atzmon G (2019). Telomeres and Longevity: A Cause or an Effect? International journal of molecular sciences 20, 3233. doi:10.3390/ijms20133233.
  21. Bakeeva L, Vays V, Vangeli I, Eldarov C, Holtze S, Hildebrandt T, Skulachev V (2019). Delayed Onset of Age-Dependent Changes in Ultrastructure of Myocardial Mitochondria as One of the Neotenic Features in Naked Mole Rats (Heterocephalus glaber). Int J Mol Sci 20, 566. doi:10.3390/ijms20030566. PMID: 30699925.
  22. Bens M, Szafranski K, Holtze S, Sahm A, Groth M, Kestler HA, Hildebrandt TB, Platzer M (2018). Naked mole-rat transcriptome signatures of socially-suppressed sexual maturation and links of reproduction to aging. BMC Biol. 16:77. doi:10.1186/s12915-018-0546-z.
  23. Heinze I, Bens M, Calzia E, Holtze S, Dakhovnik O, Vyssokikh M, Sahm A, Kirkpatrick JM, Szafranski K, Romanov N, Singer S, Ermolaeva M, Platzer M, Hildebrandt TB, Ori A (2018). Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging. BMC Biol 16,82. doi:10.1186/s12915-018-0547-y.
  24. Sahm A, Bens M, Szafranski K, Holtze S, Groth M, Görlach M, Calkhoven C, Müller C, Schwab M, Kestler HA, Cellerino A, Burda H, Hildebrandt TB, Dammann P, Platzer M (2018). Long-lived rodents reveal signatures of positive selection in genes associated with lifespan. PLoS genetics 14.3: e1007272. doi:10.1371/journal.pgen.1007272.
  25. Holtze S, Braude S, Lemma A, Koch R, Morhart M, Szafranski K, Platzer M, Alemayehu F, Goeritz F, Hildebrandt TB (2017). The microenvironment of naked mole-rat burrows in East Africa. Afr J Ecol. 56, 279-289. doi:10.1111/aje.12448.
  26. Debebe T, Biagi E, Soverini M, Holtze S, Hildebrandt TB, Birkemeyer C, Wyohannis D, Lemma A, Brigidi P, Savkovic V, König B, Candela M, Birkenmeier G (2017): Unraveling the gut microbiome of the long-lived naked mole-rat. Sci Rep 7:9590. doi:10.1038/s41598-017-10287-0.
  27. Skulachev VP*, Holtze S*, Vyssokikh MY, Bakeeva LE, Skulachev MV, Markov AV, Hildebrandt TB*, Sadovnichii VA* (2017): Neoteny, Prolongation of Youth: From Naked Mole Rats to "Naked Apes" (Humans). Physiol Rev 97, 699-720. doi:10.1152/physrev.00040.2015.
  28. Holtze S, Eldarov CM, Vays VB, Vangeli IM, Vysokikh MY, Bakeeva LE, Skulachev VP, Hildebrandt TB (2016): Study of Age-Dependent Structural and Functional Changes of Mitochondria in Skeletal Muscles and Heart of Naked Mole Rats (Heterocephalus glaber). Biochemistry (Mosc) 81, 429-1437. doi:10.1134/S000629791612004X.
  29. Debebe T, Holtze S, Morhart M, Hildebrandt TB, Rodewald S, Huse K, Platzer M, Wyohannes D, Yirga S, Lemma A, Thieme R, König B, Birkenmeier G (2016): Analysis of cultivable microbiota and diet intake pattern of the long-lived naked mole-rat. Gut Pathog 28, 8-25. doi:10.1186/s13099-016-0107-3.
  30. Montero AG, Vole C, Burda H, Malkemper EP, Holtze S, Morhart M, Saragusty S, Hildebrandt TB, Begall S (2016): Non-Breeding Eusocial Mole-Rats Produce Viable Sperm—Spermiogram and Functional Testicular Morphology of Fukomys anselli. PloS one 11, e0150112. doi:10.1371/journal.pone.0150112.
  31. Dziegelewska M, Holtze S, Vole C, Wachter U, Menzel U, Morhart M, Groth M, Szafranski K, Sahm A, Sponholz C, Dammann P, Huse K, Hildebrandt T, Platzer M (2016): Low sulfide levels and a high degree of cystathionine β-synthase (CBS) activation by S-adenosylmethionine (SAM) in the long-lived naked mole-rat. Redox Biol 8, 192-198. doi:10.1016/j.redox.2016.01.008. PMID: 26803480.
  32. Bens M, Sahm A, Groth M, Jahn N, Morhart M, Holtze S, Hildebrandt TB, Platzer M, Szafranski K (2016): FRAMA: from RNA-seq data to annotated mRNA assemblies. BMC Genomics 17, 54. doi:10.1186/s12864-015-2349-8.
  33. Thieme R, Kurz S, Kolb M, Debebe T, Holtze S, Morhart M, Huse K, Szafranski K, Platzer M, Hildebrandt TB, Birkenmeier G (2015): Analysis of Alpha-2 Macroglobulin from the Long-Lived and Cancer-Resistant Naked Mole-Rat and Human Plasma. PLoS One 10, e0130470. doi:10.1371/journal.pone.0130470. eCollection 2015.
  34. Roellig K, Drews B, Goeritz F, Hildebrandt TB (2011): The long gestation of the small naked mole-rat (Heterocephalus glaber Rüppell, 1842) studied with ultrasound biomicroscopy and 3D-ultrasonography. PloS one 6, e17744. doi:10.1371/journal.pone.0017744.