PROGEROID SYNDROME WITH SIGNS OF AUTOPHAGY DYSFUNCTION IN THE NAKED MOLE RAT (Heterocephalus glaber)

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

The naked mole rat is considered a unique non-aging animal species and is widely used in laboratories to study lifespan biology. Previously, our group was the first to describe a new fatal disease of the naked mole rat, called "idiopathic cachexia". A detailed study of pathological changes in the organs of diseased animals together with data on changes in gene expression allows us to interpret this disease as a very specific variant of accelerated aging (progeroid syndrome or progeria) in these animals. Signs of the disease include cachexia, cataracts, lipofuscinosis and the appearance of amyloid bodies (corpora amylacea) in the brain, severe degeneration of myocardial cells, fatty degeneration and generalized lipofuscinosis of the liver and kidneys with signatures of dysfunction of autophagy processes in these organs. Further study is needed to elucidate the mechanism of development of this disease in animals with negligible aging, such as naked mole rats, and may have implications for understanding the mechanisms of aging and lifespan extension.

About the authors

V. N. Mansikkh

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University; FSBI "National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov", Ministry of Health of the Russian Federation

Email: mansikkh@mail.ru
Moscow, Russia; Moscow, Russia

E. V. Sheval

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Moscow, Russia

M. V. Marey

FSBI "National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov", Ministry of Health of the Russian Federation

Moscow, Russia

O. A. Averina

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Moscow, Russia

M. Yu. Vyssokhik

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University; FSBI "National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov", Ministry of Health of the Russian Federation

Moscow, Russia; Moscow, Russia

References

  1. Buffenstein, R. (2005) The naked mole-rat: a new long-living model for human aging research, J. Gerontol. A Biol. Sci. Med. Sci., 60, 1369-1377, https://doi.org/10.1093/gerona/60.11.1369.
  2. Buffenstein, R. (2008) Negligible senescence in the longest living rodent. the naked mole rat: insights from a successfully aging species, J. Comp. Physiol., 178, 439-445, https://doi.org/10.1007/s00360-007-0237-5.
  3. Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., Markov, A. V., Hildebrandt, T. B., and Sadovnichii, V. A. (2017) Neoteny, prolongation of youth: from naked mole rats to “naked apes” (humans), Physiol. Rev., 97, 699-720, https://doi.org/10.1152/physrev.00040.2015.
  4. Liang, S., Mele, J., Wu, Y., Buffenstein, R., and Hornsby, P. J. (2010) Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber), Aging Cell, 9, 626-635, https://doi.org/10.1111/j.1474-9726.2010.00588.x.
  5. Miyawaki, S., Kawamura, Y., Oiwa, Y., Shimizu, A., Hachiya, T., Bono, H., Koya, I., Okada, Y., Kimura, T., Tsuchiya, Y., Suzuki, S., Onishi, N., Kuzumaki, N., Matsuzaki, Y., Narita, M., Ikeda, E., Okanoya, K., Seino, K., Saya, H., Okano, H., and Miura, K. (2016) Tumour resistance in induced pluripotent stem cells derived from naked mole-rats, Nat. Commun., 7, 11471, https://doi.org/10.1038/ncomms11471.
  6. Delaney, M. A., Ward, J. M., Walsh, T. F., Chinnadurai, S. K., Kerns, K., Kinsel, M. J., and Treuting, P. M. (2016) Initial case reports of cancer in naked mole-rats (Heterocephalus glaber), Vet. Pathol., 53, 691-696, https://doi.org/10.1177/0300985816630796.
  7. Gorbunova, V., Seluanov, A., Zhang, Z., Gladyshev, V. N., and Vijg, J. (2014) Comparative genetics of longevity and cancer: insights from long-lived rodents, Nat. Rev. Genet., 15, 531-540, https://doi.org/10.1038/nrg3728.
  8. Oka, K., Fujioka, S., Kawamura, Y., Komohara, Y., Chujo, T., Sekiguchi, K., Yamamura, Y., Oiwa, Y., Omamiuda-­Ishikawa, N., Komaki, S., Sutoh, Y., Sakurai, S., Tomizawa, K., Bono, H., Shimizu, A., Araki, K., Yamamoto, T., Yamada, Y., Oshiumi, H., and Miura, K. (2022) Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats, Commun. Biol., 5, 287, https://doi.org/10.1038/s42003-022-03241-y.
  9. Edrey, Y. H., Hanes, M., Pinto, M., Mele, J., and Buffenstein, R. (2011) Successful aging and sustained good health in the naked mole rat: a long-lived mammalian model for biogerontology and biomedical research, ILAR J., 52, 41-53, https://doi.org/10.1093/ilar.52.1.41.
  10. Buffenstein, R., Park, T., Hanes, M., and Artwohl, J. E. (2012) Naked mole rat, In The Laboratory Rabbit Guinea Pig, Hamster, Other Rodents, Elsevier, Amsterdam, pp. 1055-1074, https://doi.org/10.1016/B978-0-12-380920-9.00045-6.
  11. Манских В. Н. (2010) Устойчивость морских свинок к опухолевому росту: реальность феномена и его возможные причины, Вопр. Онкол., 56, 514-520.
  12. Delaney, M. A., Nagy, L., Kinsel, M. J., and Treuting, P. M. (2013) Spontaneous histologic lesions of the adult naked mole rat (Heterocephalus glaber): a retrospective survey of lesions in a zoo population, Vet. Pathol., 50, 607-621, https://doi.org/10.1177/0300985812471543.
  13. Delaney, M. A., Kinsel, M. J., and Treuting, P. M. (2016) Renal pathology in a nontraditional aging model: the naked mole-rat (Heterocephalus glaber), Vet. Pathol., 53, 493-503, https://doi.org/10.1177/0300985815612557.
  14. Manskikh, V. N., Averina, O. A., and Nikiforova, A. I. (2017) Spontaneous and experimentally induced pathologies in the naked mole rat (Heterocephalus glaber), Biochemistry (Moscow), 82, 1504-1512, https://doi.org/10.1134/S0006297917120094.
  15. Delaney, M. A., Imai, D. M., and Buffenstein, R. (2021) Spontaneous disease and pathology of naked mole-rats, Adv. Exp. Med. Biol., 1319, 353-380, https://doi.org/10.1007/978-3-030-65943-1_15.
  16. Manskikh, V. N. (2015) Chronic progressive nephropathy in rodents as a disease caused by an expanding somatic mutant clone, Biochemistry (Moscow), 80, 582-585, https://doi.org/10.1134/S0006297915050090.
  17. Adrianov, M. A., Bobrov, M., Mamedov, I., Manskikh, V., Sheval, E. V., Rachkova, A. A., Shelechova, A. M., Eldarov, C. M., Averina, O. A., and Vyssokikh, M. Y. (2025) A set of microRNAs are differentially expressed in cachexic naked mole rat colony members after chronic heavy burden under normoxia, Biochimie, 232, 83-90, https://doi.org/10.1016/j.biochi.2025.01.010.
  18. Suvarna, K., Layton, C. and Bancroft, J. D. (2019) Bancrofts Theory and Practice of Histological Techniques, 9th Edition, Elsevier.
  19. Tucker, M. J. (1997) Diseases of the Wistar Rat, Taylor and Francis, London, https://doi.org/10.4324/9780203211250.
  20. Maronpot, R. R. (1999) Pathology of the Mouse, Cache River Press, Vienna, IL.
  21. Percy, D. H., Griffey, S. M., and Barthold, S. W. (2016) Pathology of Laboratory Rodents and Rabbits, Wiley-Blackwell.
  22. Mohr, U. (1996) Pathobiology of Aging Mouse, Vols. 1/2, ILSI Press.
  23. Vyssokikh, M. Yu., Vigovskiy, M. A., Philippov, V. V., Boroday, Ya. R., Marey, M. V., Grigorieva, O. A., Vepkhvadze, T. F., Kurochkina, N. S., Manukhova, L. A., Efimenko, A. Yu., Popov, D. V., and Skulachev, V. P. (2024) Age-dependent changes in the production of mitochondrial reactive oxygen species in human skeletal muscle, Biochemistry (Moscow), 89, 299-312, https://doi.org/10.1134/S0006297924020093.
  24. Du, J., Liu, W., Li, M., Li, Z., Li, X., Dai, Y., Liu, G., Wang, X., Zhu, P., Gladyshev, V. N., and Zhou, X. (2024) Comparative time-series multi-omics analyses suggest H1.2 involvement in anoxic adaptation and cancer resistance, PLoS Biol., 22, e3002778, https://doi.org/10.1371/journal.pbio.3002778.
  25. Kim, J., Chee, W.-Y., Yabuta, N., Kajiwara, K., Nada, S., and Okada, M. (2020) Atg5-mediated autophagy controls apoptosis/anoikis via p53/Rb pathway in naked mole-rat fibroblasts, Biochem. Biophys. Res. Commun., 528, 146-153, https://doi.org/10.1016/j.bbrc.2020.05.083.
  26. Zhao, S., Li, L., Wang, S., Yu, C., Xiao, B., Lin, L., Cong, W., Cheng, J., Yang, W., Sun, W., and Cui, S. (2016) H2O2 treatment or serum deprivation induces autophagy and apoptosis in naked mole-rat skin fibroblasts by inhibiting the PI3K/Akt signaling pathway. Oncotarget, 7, 84839-84850, https://doi.org/10.18632/oncotarget.13321.
  27. Maranni, E., Usunoff, K. G., and Feirabend, N. K. P. (2009) Lipofuscin and lipofuscinosis, Encyclopedia Neurosci., 481-486, https://doi.org/10.1016/B978-008045046-9.00126-1.
  28. Ward, J.M., Cartoceti, A.N., and Delaney, M.A. (2021) Brain lesions in aging zoo-housed naked mole-rats (Heterocephalus glaber), Vet Pathol., 58, 142-146, https://doi.org/10.1177/0300985820969982.
  29. Suzuki, K., Kubota, Y., Sekito, T., and Ohsumi, Y. (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization, Genes Cells, 12, 209-218, https://doi.org/10.1111/j.1365-2443.2007.01050.x.
  30. Orsi, A., Razi, M., Dooley, H. C., Robinson, D., Weston, A. E., Collinson, L. M., and Tooze, S. A. (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy, Mol. Biol. Cell., 23, 1860-1873, https://doi.org/10.1091/mbc.E11-09-0746.
  31. Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., Choi, M. E., Chu, C. T., Codogno, P., Colombo, M. I., Cuervo, A. M., Deretic, V., Dikic, I., Elazar, Z., Eskelinen, E.-L., Fimia, G. M., Gewirtz, D. A., Green, D. R., Hansen, M., Jäättelä, M., Johansen, T., Juhász, G., Karantza, V., Kraft, C., Kroemer, G., Ktistakis, N. T., Kumar, S., Lopez-Otin, C., Macleod, K. F., Madeo, F., Martinez, J., Meléndez, A., Mizushima, N., Münz, C., Penninger, J. M., Perera, R. M., et al. (2021) Autophagy in major human diseases, EMBO J., 40, e108863, https://doi.org/10.15252/embj.2021108863.
  32. Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., et al. (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, 17, 1-382, https://doi.org/10.1080/15548627.2020.1797280.
  33. Viiri, J., Amadio, M., Marchesi, N., Hyttinen, J. M. T., Kivinen, N., Sironenm R., Rillam, K., Akhtar, S., Provenzani, A., D’Agostino, A. G., Govoni, S., Pascale, A., Agostini, H., Petrovski, G., Salminen, A., and Kaarniranta, K. (2013) Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells, PLoS One, 8, e69563, https://doi.org/10.1371/journal.pone.0069563.
  34. Sakuma, K., Kinoshita, M., Ito, Y., Aizawa, M., Aoi, W., and Yamaguchi, A. (2015) 3p62/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice, J. Cachexia Sarcopenia Muscle, 7, 204-212, https://doi.org/10.1002/jcsm.12045.
  35. Peng, Y., Shapiro, S. L., Banduseela, V. C., Dieterich, I. A., Hewitt, K. J., Bresnick, E. H., Kong, G., Zhang, J., Schueler, K. L., Keller, M. P., Attie, A. D., Hacker, T. A., Sullivan, R., Kielar-Grevstad, E., Arriola Apelo, S. I., Lamming, D. W., Anderson, R. M., and Puglielli, L. (2018) Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype, Aging Cell, 17, e12820, https://doi.org/10.1111/acel.12820.
  36. Sulzer, D., Mosharov, E., Talloczy, Z., Zucca, F. A., Simon, J. D., and Zecca, L. (2008) Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease, J. Neurochem., 106, 24-36, https://doi.org/10.1111/j.1471-4159.2008.05385.x.
  37. Song, S. B., Shim, W., and Hwang, E. S. (2023) Lipofuscin granule accumulation requires autophagy activation, Mol. Cells, 46, 486-495, https://doi.org/10.14348/molcells.2023.0019.
  38. Reichel, W., and Garcia-Bunuel, R. (1970) Pathologic findings in progeria: myocardial fibrosis and lipofuscin pigment, Am. J. Clin. Pathol., 53, 243-253, https://doi.org/10.1093/ajcp/53.2.243.
  39. Burtner, C. R., and Kennedy, B. K. (2010) Progeria syndromes and ageing: what is the connection? Nat. Rev. Mol. Cell Biol., 11, 567-578, https://doi.org/10.1038/nrm2944.
  40. Harkema, L., Youssef, S. A., and de Bruin, A. (2016) Pathology of mouse models of accelerated aging, Vet. Pathol., 53, 366-389, https://doi.org/10.1177/0300985815625169.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Russian Academy of Sciences

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).