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  • Perspective
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Synthetic torpor: advancing metabolic regulation for medical innovations

Nature Metabolism volume 7, pages 1511–1523 (2025)Cite this article

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Abstract

Torpor is a naturally occurring state of metabolic suppression that enables animals to adapt and survive extreme environmental conditions. Inspired by this adaptation, researchers have pursued synthetic torpor—an artificially induced, reversible hypometabolic state with transformative medical potential. Achieving synthetic torpor has been pursued for over a hundred years, with earlier work focused on identifying drugs for systemically suppressing metabolism. Breakthroughs in 2020 identified key torpor-regulating neurons in mice, opening new opportunities for neuromodulation-based metabolic control. Synthetic torpor has been applied in animal models for various medical applications, including ischaemic protection, organ preservation, radiation protection and lifespan extension. This Perspective examines the fundamental concepts of natural torpor, advances in approaches to induce synthetic torpor and medical applications of synthetic torpor. The capability of synthetic torpor to suppress whole-body metabolism has the potential to transform medicine by offering novel strategies for medical interventions.

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Fig. 1: Synthetic torpor induction approaches.
Fig. 2: Milestones in the development of synthetic torpor.
Fig. 3: Medical applications of synthetic torpor.

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References

  1. Simpson, S. Temperature range in the monkey in ether anaesthesia. (Preliminary note.). Proc. Physiol. Soc. July 19, (1902).

  2. Aronson, H. B., Duffield, J. R., Francis, B. G. & Ginsberg, H. Hibernation in anaesthesia–review of 100 non-European cases. South Afr. Med. J. 28, 823–827 (1954).

    CAS  Google Scholar 

  3. Swan, H., Jenkins, D. & Knox, K. Anti-metabolic extract from the brain of Protopterus aethiopicus. Nature 217, 671–671 (1968).

    Article  CAS  PubMed  Google Scholar 

  4. Dawe, A. R. & Spurrier, W. A. Hibernation induced in ground squirrels by blood transfusion. Science 163, 298–299 (1969).

    Article  CAS  PubMed  Google Scholar 

  5. Blackstone, E., Morrison, M. & Roth, M. B. H2S induces a suspended animation-like state in mice. Science 308, 518 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Ren, C. et al. Hypoxia, hibernation and neuroprotection: an experimental study in mice. Aging Dis. 9, 761–768 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Matsuo, T. et al. Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation. Nat. Commun. 12, 2074 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang, J., Kaasik, K., Blackburn, M. R., Cheng & Lee, C. Constant darkness is a circadian metabolic signal in mammals. Nature 439, 340–343 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Dark, J., Miller, D. R. & Zucker, I. Reduced glucose availability induces torpor in Siberian hamsters. Am. J. Physiol. 267, R496–R501 (1994).

    CAS  PubMed  Google Scholar 

  10. Zakharova, N. M. et al. A pharmacological composition for induction of a reversible torpor-like state and hypothermia in rats. Life Sci. 219, 190–198 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Ju, H. et al. Sustained torpidity following multi-dose administration of 3-iodothyronamine in mice. J. Cell. Physiol. 226, 853–858 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Oeltgen, P. R. et al. Hibernation ‘trigger’: opioid-like inhibitory action on brain function of the monkey. Pharmacol. Biochem. Behav. 17, 1271–1274 (1982).

    Article  CAS  PubMed  Google Scholar 

  13. Hrvatin, S. et al. Neurons that regulate mouse torpor. Nature 583, 115–121 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, Z. et al. Estrogen-sensitive medial preoptic area neurons coordinate torpor in mice. Nat. Commun. 11, 6378 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Takahashi, T. M. et al. A discrete neuronal circuit induces a hibernation-like state in rodents. Nature 583, 109–114 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. Zhang, S. et al. Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia. Nat. Commun. 13, 6890 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang, Y. et al. Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound. Nat. Metab. 5, 789–803 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Scott, K. A. et al. Mechanosensation of the heart and gut elicits hypometabolism and vigilance in mice. Nat. Metab. 7, 263–275 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ma, W. X. et al. Adenosine and P1 receptors: key targets in the regulation of sleep, torpor, and hibernation. Front. Pharm. 14, 1098976 (2023).

    Article  CAS  Google Scholar 

  20. Tøien, Ø. et al. Hibernation in black bears: independence of metabolic suppression from body temperature. Science 331, 906–909 (2011).

    Article  PubMed  Google Scholar 

  21. Cerri, M. et al. The inhibition of neurons in the central nervous pathways for thermoregulatory cold defense induces a suspended animation state in the rat. J. Neurosci. 33, 2984–2993 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Simpson, S. & Herring, P. T. The effect of cold narcosis on reflex action in warm-blooded animals. J. Physiol. 32, 305–311 (1905).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cassidy, G. J., Dworkin, S. & Finney, W. H. Insulin and the mechanism of hibernation. Am. J. Physiol. 73, 417–428 (1925).

    Article  CAS  Google Scholar 

  24. Dworkin, S. & Finney, W. H. Artificial hibernation in the woodchuck (Arctomys monax). Am. J. Physiol. 80, 75–81 (1927).

    Article  CAS  Google Scholar 

  25. Burns, J. T. Regulation of Mammalian Hibernation. PhD thesis, Louisiana State University Historical Dissertations and Theses https://doi.org/10.31390/gradschool_disstheses.3097 (1977).

  26. Suomalainen, P. & Herlevi, A. M. The alarm reaction and the hibernating gland. Science 114, 300 (1951).

    Article  CAS  PubMed  Google Scholar 

  27. Laborit, H. & Huguenard, P. Present technic of artificial hibernation. Presse Med. 60, 455–1456 (1952).

    Google Scholar 

  28. Shackman, R., Wood-Smith, F. G., Graber, I. G., Melrose, D. G. & Lynn, R. B. The lytic cocktail observations on surgical patients. Lancet 267, 617–620 (1954).

    Article  CAS  PubMed  Google Scholar 

  29. Agüero, O. Artificial hibernation (“lytic cocktail”) in the treatment of eclampsia. Am. J. Obstet. Gynecol. 73, 777–783 (1957).

    Article  PubMed  Google Scholar 

  30. Delaney, R. G., Lahiri, S. & Fishman, A. P. Aestivation of the African lungfish Protopterus aethiopicus: cardiovascular and respiratory functions. J. Exp. Biol. 61, 111–128 (1974).

    Article  CAS  PubMed  Google Scholar 

  31. Swan, H. & Schätte, C. Antimetabolic extract from the brain of the hibernating ground squirrel Citellus tridecemlineatus. Science 195, 84–85 (1977).

    Article  CAS  PubMed  Google Scholar 

  32. Bruce, D. S., Tuggy, M. L. & Pearson, P. J. Summer hibernation induced in ground squirrels (Citellus tridecemlineatus) by urine or plasma from hibernating bats (Myotis lucifugus or Eptesicus fuscus). Cryobiology 21, 371–374 (1984).

    Article  Google Scholar 

  33. Bruce, D. S. et al. Opioids and hibernation. I. Effects of naloxone on bear HIT’S depression of guinea pig ileum contractility and on induction of summer hibernation in the ground squirrel. Life Sci. 41, 2107–2113 (1987).

    Article  CAS  PubMed  Google Scholar 

  34. Bruce, D. S. et al. Is the polar bear (Ursus maritimus) a hibernator? Continued studies on opioids and hibernation. Pharmacol. Biochem. Behav. 35, 705–711 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Diedrich, V., Kumstel, S. & Steinlechner, S. Spontaneous daily torpor and fasting-induced torpor in Djungarian hamsters are characterized by distinct patterns of metabolic rate. J. Comp. Physiol. B 185, 355–366 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Abbotts, B., Wang, L. C. H. & Glass, J. D. Absence of evidence for a hibernation “trigger” in blood dialyzate of Richardson’s ground squirrel. Cryobiology 16, 179–183 (1979).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, L. C. H. et al. The “hibernation induction trigger”: specificity and validity of bioassay using the 13-lined ground squirrel. Cryobiology 25, 355–362 (1988).

    Article  CAS  PubMed  Google Scholar 

  38. Oeltgen, P. R., Nilekani, S. P., Nuchols, P. A., Spurrier, W. A. & Su, T. P. Further studies on opioids and hibernation: delta opioid receptor ligand selectively induced hibernation in summer-active ground squirrels. Life Sci. 43, 1565–1574 (1988).

    Article  CAS  PubMed  Google Scholar 

  39. Stein, A., Kraus, D. W., Doeller, J. E. & Bailey, S. M. Inhalation exposure model of hydrogen sulfide (H2S)-induced hypometabolism in the male Sprague-Dawley rat. Methods Enzymol. 555, 19–35 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Aslami, H., Schultz, M. J. & Juffermans, N. P. Potential applications of hydrogen sulfide-induced suspended animation. Curr. Med. Chem. 16, 1295–1303 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Satterly, S. A. et al. Hydrogen sulfide improves resuscitation via non-hibernatory mechanisms in a porcine shock model. J. Surg. Res. 199, 197–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Haouzi, P. et al. H2S induced hypometabolism in mice is missing in sedated sheep. Respir. Physiol. Neurobiol. 160, 109–115 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Zhao, Z., Van Oort, A., Tao, Z., O’Brien, W. G. & Lee, C. C. Metabolite profiling of 5′-AMP-induced hypometabolism. Metabolomics 10, 63–76 (2014).

    Article  PubMed  Google Scholar 

  44. Swoap, S. J., Rathvon, M. & Gutilla, M. AMP does not induce torpor. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, 468–473 (2007).

    Article  Google Scholar 

  45. Strijkstra, A. M. et al. in Living in a Seasonal World: Thermoregulatory and Metabolic Adaptations (eds Arnold, W., Bieber, C., Millesi, E. & Ruf, T.) 351–362 (Springer, 2012).

  46. Zhang, F. et al. When hypothermia meets hypotension and hyperglycemia: the diverse effects of adenosine 5′-monophosphate on cerebral ischemia in rats. J. Cereb. Blood Flow. Metab. 29, 1022–1034 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Zakharova, N. M., Tarahovsky, Y. S., Komelina, N. P., Fadeeva, I. S. & Kovtun, A. L. Long-term pharmacological torpor of rats with feedback-controlled drug administration. Life Sci. Space Res. 28, 18–21 (2021).

    Google Scholar 

  48. Sperry, M. M. et al. Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation. eLife 13, RP93796 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Egawa, M., Yoshimatsu, H. & Bray, G. A. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. Am. J. Physiol. 260, R328–R334 (1991).

    CAS  PubMed  Google Scholar 

  50. Paul, M. J., Freeman, D. A., Jin, H. P. & Dark, J. Neuropeptide Y induces torpor-like hypothermia in Siberian hamsters. Brain Res. 1055, 83–92 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Tupone, D., Madden, C. J. & Morrison, S. F. Central activation of the A1 adenosine receptor (A1AR) induces a hypothermic, torpor-like state in the rat. J. Neurosci. 33, 14512–14525 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shimaoka, H. et al. Induction of hibernation-like hypothermia by central activation of the A1 adenosine receptor in a non-hibernator, the rat. J. Physiol. Sci. 68, 425–430 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Hitrec, T. et al. Neural control of fasting-induced torpor in mice. Sci. Rep. 9, 15462 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Morrison, S. F., Cano, G., Hernan, S. L., Chiavetta, P. & Tupone, D. Inhibition of the hypothalamic ventromedial periventricular area activates a dynorphin pathway-dependent thermoregulatory inversion in rats. Curr. Biol. 35, 59–76 (2025).

    Article  CAS  PubMed  Google Scholar 

  55. Engström Ruud, L. et al. Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor. Cell Rep. 43, 113960 (2024).

    Article  PubMed  Google Scholar 

  56. Ambler, M., Hitrec, T., Wilson, A., Cerri, M. & Pickering, A. Neurons in the dorsomedial hypothalamus promote, prolong, and deepen torpor in the mouse. J. Neurosci. 42, 4267–4277 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hare, M. T., Carter, M. E. & Swoap, S. J. Activation of oxytocinergic neurons enhances torpor in mice. J. Comp. Physiol. B 194, 95–104 (2024).

    Article  CAS  PubMed  Google Scholar 

  58. Jayne, L. et al. A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan. Nat. Aging 5, 437–449 (2025).

  59. Zhang, Z. et al. Primate preoptic neurons drive hypothermia and cold defense. Innovation 4, 100358 (2022).

    PubMed  PubMed Central  Google Scholar 

  60. Yamaguchi, H. et al. Dorsomedial and preoptic hypothalamic circuits control torpor. Curr. Biol. 33, 5381–5389 (2023).

    Article  CAS  PubMed  Google Scholar 

  61. Kim, T. et al. Effect of low intensity transcranial ultrasound stimulation on neuromodulation in animals and humans: an updated systematic review. Front. Neurosci. 15, 620863 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Beisteiner, R., Hallett, M. & Lozano, A. M. Ultrasound neuromodulation as a new brain therapy. Adv. Sci. 10, 2205634 (2023).

    Article  Google Scholar 

  63. Borlongan, C. V., Hayashi, T., Oeltgen, P. R., Su, T. P. & Wang, Y. Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol. 7, 31 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Iwata, M. et al. Delta opioid receptors stimulation with [d-Ala2, d-Leu5] enkephalin does not provide neuroprotection in the hippocampus in rats subjected to forebrain ischemia. Neurosci. Lett. 414, 242–246 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Elrod, J. W. et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc. Natl Acad. Sci. USA 104, 15560–15565 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Miao, Y. F. et al. 5′-adenosine monophosphate-induced hypothermia attenuates brain ischemia/reperfusion injury in a rat model by inhibiting the inflammatory response. Mediators Inflamm. 2015, 520745 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bos, E. M. et al. Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 20, 1901–1905 (2009).

    Article  PubMed Central  Google Scholar 

  68. Kyo, S. et al. Quiescence-inducing neurons-induced hypometabolism ameliorates acute kidney injury in a mouse model mimicking cardiovascular surgery requiring circulatory arrest. JTCVS Open 12, 201–210 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Chien, S. et al. Two-day preservation of major organs with autoperfusion multiorgan preparation and hibernation induction trigger: a preliminary report. J. Thorac. Cardiovasc. Surg. 102, 224–234 (1991).

    Article  CAS  PubMed  Google Scholar 

  70. Cerri, M. et al. Hibernation for space travel: impact on radioprotection. Life Sci. Space Res. 11, 1–9 (2016).

    Google Scholar 

  71. Ghosh, S., Indracanti, N., Joshi, J., Ray, J. & Indraganti, P. K. Pharmacologically induced reversible hypometabolic state mitigates radiation induced lethality in mice. Sci. Rep. 7, 14900 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Puspitasari, A. et al. Synthetic torpor protects rats from exposure to accelerated heavy ions. Sci. Rep. 12, 16405 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tinganelli, W. et al. Hibernation and radioprotection: gene expression in the liver and testicle of rats irradiated under synthetic torpor. Int. J. Mol. Sci. 20, 352 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Luppi, M. et al. Phosphorylation and dephosphorylation of tau protein during synthetic torpor. Front. Neuroanat. 13, 459026 (2019).

    Article  Google Scholar 

  75. Squarcio, F. et al. Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation. Front. Physiol. 14, 1129278 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Golpich, M., Amini, E., Kefayat, A., Fesharaki, M. & Moshtaghian, J. In vitro and in vivo anti-cancer effects of hibernating common carp (Cyprinus carpio) plasma on metastatic triple-negative breast cancer. Sci. Rep. 12, 2855 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Daniels, I. S., OBrien, W. G., Nath, V., Zhao, Z. & Lee, C. C. AMP deaminase 3 deficiency enhanced 5′-AMP induction of hypometabolism. PLoS ONE 8, e75418 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Takahashi, T. M. et al. Optogenetic induction of hibernation-like state with modified human Opsin4 in mice. Cell Rep. Methods 2, 100336 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health DP1DK143574 (to H.C.), R01NS128461 (to H.C.), JSPS Grant-in-Aid for Scientific Research (A) 24H00604 (to G.A.S.) and JSPS Grant-in-Aid for Transformative Research Areas (A) 23H04941 (to G.A.S.).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA

    Wenbo Wu & Hong Chen

  2. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA

    Wenbo Wu & Hong Chen

  3. RIKEN Center for Biosystems Dynamics Research, Kobe, Japan

    Genshiro A. Sunagawa

  4. Suntory SunRiSE Fellow, Suntory Foundation of Life Sciences, Kyoto, Japan

    Genshiro A. Sunagawa

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  1. Wenbo Wu
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  2. Genshiro A. Sunagawa
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H.C. and W.U. wrote the initial draft of the manuscript. G.A.S. revised the manuscript. All authors contributed to the content and organization of this Perspective; contributed to writing, editing and revising the manuscript; and approved the final version.

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Correspondence to Hong Chen.

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Nature Metabolism thanks Sinisa Hrvatin, Matteo Cerri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism team.

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Wu, W., Sunagawa, G.A. & Chen, H. Synthetic torpor: advancing metabolic regulation for medical innovations. Nat Metab 7, 1511–1523 (2025). https://doi.org/10.1038/s42255-025-01345-3

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