Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

Key Points

  • Biomimetic studies of non-laboratory wild animals are useful for identifying mechanisms that protect or increase susceptibility to disease

  • Domestic and captive felids are vulnerable to chronic kidney disease (CKD), supporting the hypothesis that high protein intake — particularly from red meats and in combination with dehydration — is nephrotoxic

  • Extreme models of ageing, such as Hutchinson–Gilford progeria syndrome and the naked mole rat, can be used to investigate the mechanisms of vascular progeric processes in CKD

  • Current evidence suggests that elevated serum phosphate levels promote ageing and cellular senescence

  • The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) may offer protection against diseases in extreme environmental conditions and may promote longevity in the animal kingdom; NRF2 agonists (such as resveratrol and sulforaphane) might improve the uraemic complications of CKD

  • Lipid composition of membranes has a role in seasonal acclimatization of metabolic activities in the animal kingdom

  • Hibernating wild bears with anuria are protected against many of the complications observed in humans with CKD, such as muscle wasting, osteoporosis and azotaemia; future studies should investigate the mechanisms behind these protective effects


Many of the >2 million animal species that inhabit Earth have developed survival mechanisms that aid in the prevention of obesity, kidney disease, starvation, dehydration and vascular ageing; however, some animals remain susceptible to these complications. Domestic and captive wild felids, for example, show susceptibility to chronic kidney disease (CKD), potentially linked to the high protein intake of these animals. By contrast, naked mole rats are a model of longevity and are protected from extreme environmental conditions through mechanisms that provide resistance to oxidative stress. Biomimetic studies suggest that the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) offers protection in extreme environmental conditions and promotes longevity in the animal kingdom. Similarly, during months of fasting, immobilization and anuria, hibernating bears are protected from muscle wasting, azotaemia, thrombotic complications, organ damage and osteoporosis — features that are often associated with CKD. Improved understanding of the susceptibility and protective mechanisms of these animals and others could provide insights into novel strategies to prevent and treat several human diseases, such as CKD and ageing-associated complications. An integrated collaboration between nephrologists and experts from other fields, such as veterinarians, zoologists, biologists, anthropologists and ecologists, could introduce a novel approach for improving human health and help nephrologists to find novel treatment strategies for CKD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Novel insight into treatment strategies of CKD from studies of wild animals.
Figure 2: Effect of red meat intake on kidney functions.
Figure 3: Extreme models of ageing with a marked discrepancy between chronological and biological age can be used to learn more about progeric processes in CKD.
Figure 4: The role of phosphate in ageing.
Figure 5: Strategies to increase lifespan, protect organs and avoid renal ischaemia–reperfusion injury.
Figure 6: Nitrogen metabolism in hibernating bears.


  1. 1

    Stenvinkel, P. & Johnson, R. J. Kidney biomimicry — a rediscovered scientific field that could provide hope to patients with kidney disease. Arch. Med. Res. 44, 584–590 (2013).

    Article  Google Scholar 

  2. 2

    Krogh, A. The progress of physiology. Am. J. Physiol. 90, 243–251 (1929).

    Article  Google Scholar 

  3. 3

    Smith, H. W. Comparative physiology of the kidney. JAMA 153, 1512–1514 (1953).

    CAS  Article  Google Scholar 

  4. 4

    Sperber, I. Studies on the mammalian kidney. Zool. Bidrag Uppsala 22, 249–432 (1944).

    Google Scholar 

  5. 5

    O'Connor, T. P., Lee, A., Jarvis, J. U. & Buffenstein, R. Prolonged longevity in naked mole-rats: age-related changes in metabolism, body composition and gastrointestinal function. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 133, 835–842 (2002).

    Article  Google Scholar 

  6. 6

    Davis, R. W., Castellini, M. A., Kooyman, G. L. & Maue, R. Renal glomerular filtration rate and hepatic blood flow during voluntary diving in Weddell seals. Am. J. Physiol. 245, R743–R748 (1983).

    CAS  PubMed  Google Scholar 

  7. 7

    Stenvinkel, P., Jani, A. H. & Johnson, R. J. Hibernating bears (Ursidae): metabolic magicians of definite interest for the nephrologist. Kidney Int. 83, 207–212 (2013).

    CAS  Article  Google Scholar 

  8. 8

    Stenvinkel, P. et al. Metabolic changes in summer active and anuric hibernating free-ranging brown bears (Ursus arctos). PLOS One 8, e72934 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Levin, A. et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 390, 1888–1917 (2017).

    Article  Google Scholar 

  10. 10

    Stenvinkel, P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J. Intern. Med. 268, 456–467 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Kooman, J. P., Kotanko, P., Schols, A. M., Shiels, P. G. & Stenvinkel, P. Chronic kidney disease and premature ageing. Nat. Rev. Nephrol. 10, 732–742 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Lew, Q. J. et al. Red meat intake and risk of ESRD. J. Am. Soc. Nephrol. 28, 304–312 (2017).

    Article  Google Scholar 

  13. 13

    Goraya, N. & Wesson, D. E. Is dietary red meat kidney toxic? J. Am. Soc. Nephrol. 28, 5–7 (2017).

    Article  Google Scholar 

  14. 14

    Reynolds, B. S. & Lefebvre, H. P. Feline CKD: pathophysiology and risk factors — what do we know? J. Feline Med. Surg. 15 (Suppl. 1), 3–14 (2013).

    Article  Google Scholar 

  15. 15

    Jiménez, A. et al. Membranous glomerulonephritis in the Iberian lynx (Lynx pardinus). Vet. Immunol. Immunopathol. 121, 34–43 (2008).

    Article  Google Scholar 

  16. 16

    Chetboul, V. et al. Spontaneous feline hypertension: clinical and echocardiographic abnormalities, and survival rate. J. Vet. Intern. Med. 17, 89–95 (2003).

    Article  Google Scholar 

  17. 17

    Cannon, A. B., Westropp, J. L., Ruby, A. L. & Kass, P. H. Evaluation of trends in urolith composition in cats: 5,230 cases J. Am. Vet. Assoc. 231, 570–576 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Brown, C. A., Elliott, J., Schmiedt, C. W. & Brown, S. A. Chronic kidney disease in aged cats: clinical features, morphology, and proposed pathogeneses. Vet. Pathol. 53, 309–326 (2016).

    CAS  Article  Google Scholar 

  19. 19

    Munson, L. et al. Extrinsic factors significantly affect patterns of disease in free-ranging and captive cheetah (Acinonyx jubatus) populations. J. Wildl. Dis. 41, 542–548 (2005).

    Article  Google Scholar 

  20. 20

    Waki, M. F., Martorelli, C. R., Mosko, P. E., Erdmann, P. & Kogika, M. M. Classification into stages of chronic kidney disease in dogs and cats — clinical, laboratorial and therapeutic approach (Portuguese). Cienia Rural 40, 2226–2234 (2010).

    Article  Google Scholar 

  21. 21

    Junginger, J. et al. Pathology in captive wild felids at German zoological gardens. PLOS One 10, e0130573 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Elliott, J. & Barber, P. J. Feline chronic renal failure: clinical findings in 80 cases diagnosed between 1992 and 1995. J. Small Anim. Pract. 39, 78–85 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Zini, E. et al. Renal morphology in cats with diabetes mellitus. Vet. Pathol. 51, 1143–1150 (2014).

    CAS  Article  Google Scholar 

  24. 24

    Bolton, L. A. & Munson, L. Glomerulosclerosis in captive cheetahs (Acinonyx jubatus). Vet. Pathol. 36, 14–22 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Oaks, J. L. et al. Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 427, 630–633 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Eisert, R. Hypercarnivory and the brain: protein requirements of cats reconsidered. J. Comp. Physiol. B 181, 1–17 (2011).

    CAS  Article  Google Scholar 

  27. 27

    Meyer, T. W., Lawrence, W. E. & Brenner, B. M. Dietary protein and the progression of renal disease. Kidney Int. Suppl. 16, S243–S247 (1983).

    CAS  PubMed  Google Scholar 

  28. 28

    Kramer, H. Kidney disease and the westernization and industrialization of food. Am. J. Kidney Dis. 70, 111–121 (2017).

    Article  Google Scholar 

  29. 29

    DiBartola, S. P., Buffington, C. A., Chew, D. J., McLoughlin, M. A. & Sparks, R. A. Development of chronic renal disease in cats fed a commercial diet. J. Am. Vet. Med. Assoc. 202, 744–751 (1993).

    CAS  PubMed  Google Scholar 

  30. 30

    Juraschek, S. P., Appel, L. J., Anderson, C. A. & Miller, E. R. Effect of a high-protein diet on kidney function in healthy adults: results from the OmniHeart trial. Am. J. Kidney Dis. 61, 547–554 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Brenner, B. M., Meyer, T. W. & Hostetter, T. H. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N. Engl. J. Med. 307, 652–659 (1982).

    CAS  Article  Google Scholar 

  32. 32

    Mafra, D. et al. Red meat intake in chronic kidney disease patients: two sides of the coin. Nutrition 46, 26–32 (2018).

    CAS  Article  Google Scholar 

  33. 33

    Haring, B. et al. Dietary protein sources and risk for incident chronic kidney disease: results from the atherosclerosis risk in communities (ARIC) study. J. Ren Nutr. 4, 233–242 (2017).

    Article  CAS  Google Scholar 

  34. 34

    Rebholz, C. M. et al. DASH (Dietary Approaches to Stop Hypertension) diet and risk of subsequent kidney disease. Am. J. Kidney Dis. 68, 853–861 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Lin, C. K. et al. Comparison of renal function and other health outcomes in vegetarians versus omnivores in Taiwan. J. Health Popul. Nutr. 28, 470–475 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Kontessis, P. et al. Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins. Kidney Int. 38, 136–144 (1990).

    CAS  Article  Google Scholar 

  37. 37

    Azadbakht, L., Atabak, S. & Esmaillzadeh, A. Soy protein intake, cardiorenal indices, and C-reactive protein in type 2 diabetes with nephropathy: a longitudinal randomized clinical trial. Diabetes Care 31, 648–654 (2008).

    CAS  Article  Google Scholar 

  38. 38

    Nongouch, A. & Davenport, A. The effect of vegetarian diet on skin autofluorescence measurements in haemodialysis patients. Br. J. Nutr. 113, 1040–1043 (2015).

    Article  CAS  Google Scholar 

  39. 39

    Gluba-Brzózka, A., Franczyk, B. & Rysz, J. Vegetarian diet in chronic kidney disease — a friend or foe. Nutrients 9, 374 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Larsson, S. C. & Orsini, N. Red meat and processed meat consumption and all-cause mortality: a meta-analysis. Am. J. Epidemiol. 179, 282–289 (2014).

    Article  Google Scholar 

  41. 41

    Crippa, A., Larsson, S. C., Discacciati, A., Wolk, A. & Orsini, N. Red and processed meat consumption and risk of bladder cancer: a dose-response meta-analysis of epidemiological studies. Eur. J. Nutr. (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Kaluza, J., Wolk, A. & Larsson, S. C. Red meat consumption and risk of stroke: a meta-analysis of prospective studies. Stroke 43, 2556–2560 (2012).

    CAS  Article  Google Scholar 

  43. 43

    Micha, R., Wallace, S. K. & Mozaffarian, D. Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis. Circulation 121, 2271–2283 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Micha, R., Michas, G. & Mozaffarian, D. Unprocessed red and processed meats and risk of coronary artery disease and type 2 diabetes — an updated review of the evidence. Curr. Atheroscler Rep. 14, 515–524 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    de Mello, V. D., Zelmanovitz, T., Perassolo, M. S., Azevedo, M. J. & Gross, J. L. Withdrawal of red meat from the usual diet reduces albuminuria and improves serum fatty acid profile in type 2 diabetes patients with macroalbuminuria. Am. J. Clin. Nutr. 83, 1032–1038 (2006).

    CAS  Article  Google Scholar 

  46. 46

    de Mello, V. D., Zelmanovitz, T., Azevedo, M. J., de Paula, T. P. & Gross, J. L. Long-term effect of a chicken-based diet versus enalapril on albuminuria in type 2 diabetic patients with microalbuminuria. J. Renal Nutr. 18, 440–447 (2008).

    Article  Google Scholar 

  47. 47

    Elliott, J., Rawlings, J. M., Markwell, P. J. & Barber, P. J. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J. Small Anim. Pract. 41, 235–242 (2000).

    CAS  Article  Google Scholar 

  48. 48

    Alisson-Silva, F., Kawanishi, K. & Varki, A. Human risk of diseases associated with red meat intake: analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid. Mol. Aspects Med. 51, 16–30 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Tang, W. H. et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116, 448–455 (2015).

    CAS  Article  Google Scholar 

  50. 50

    Sun, X. et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem. Biophys. Res. Commun. 481, 63–70 (2016).

    CAS  Article  Google Scholar 

  51. 51

    Missailidis, C. et al. Serum trimethylamine-N-oxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLOS One 11, e0141738 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Koeth, R. A. et al. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20, 799–812 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Martin, O. C. et al. Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats. Nutr. Cancer 67, 119–125 (2015).

    CAS  Article  Google Scholar 

  55. 55

    McClelland, R. et al. Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake. Aging 8, 1135–1149 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Martínez-Moreno, J. M. et al. High phosphate induces a pro-inflammatory response by vascular smooth muscle cells and modulation by vitamin D derivatives. Clin. Sci. 131, 1449–1463 (2017).

    Article  CAS  Google Scholar 

  57. 57

    Choi, H. K., Atkinson, K., Karlson, E. W., Willett, W., & Curhan, G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N. Engl. J. Med. 350, 1093–1103 (2004).

    CAS  Article  Google Scholar 

  58. 58

    Hammett, F. S. The nitrogen excretion of the cat during a purine-free and a purine-rich diet. J. Biol. Chem. 22, 551–558 (1915).

    CAS  Google Scholar 

  59. 59

    Villegas, R. et al. Purine-rich foods, protein intake, and the prevalence of hyperuricemia: the Shanghai Men's Health Study. Nutr. Metab. Cardiovasc. Dis. 22, 409–416 (2012).

    CAS  Article  Google Scholar 

  60. 60

    Clifford, A. J., Riumallo, J. A., Youn, V. R. & Scrimshaw, N. S. Effect of oral purines on serum and urinary uric acid of normal, hyperuricemic and gouty humans. J. Nutr. 106, 428–450 (1976).

    CAS  Article  Google Scholar 

  61. 61

    Nakanishi, N. et al. Low urine pH Is a predictor of chronic kidney disease. Kidney Blood Press Res. 35, 77–81 (2012).

    CAS  Article  Google Scholar 

  62. 62

    Appel, S. L., Houston, D. M., Moore, A. E. & Weese, J. S. Feline urate urolithiasis. Can. Vet. J. 51, 493–496 (2010).

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Osborne, C. A., Lulich, J. P., Ulrich, L. K., & Bird, K. A. Feline crystalluria. Detection and interpretation. Vet. Clin. North Am. Small Anim. Pract. 26, 369–391 (1996).

    CAS  Article  Google Scholar 

  64. 64

    Ryu, E. S. et al. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am. J. Physiol. Renal Physiol. 304, F471–F480 (2013).

    CAS  Article  Google Scholar 

  65. 65

    Greene, J. P. et al. Risk factors associated with the development of chronic kidney disease in cats evaluated at primary care veterinary hospitals. J. Am. Vet. Med. Assoc. 244, 320–327 (2014).

    Article  Google Scholar 

  66. 66

    Campese, V. M. Con: Mesoamerican nephropathy: is the problem dehydration or rehydration? Nephrol. Dial Transplant 32, 603–606 (2017).

    Article  Google Scholar 

  67. 67

    Johnson, R. J. Heat stress as a potential etiology of Mesoamerican and Sri Lankan nephropathy: a late night consult with Sherlock Holmes. Nephrol. Dial Transplant 32, 598–602 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    McFarland, W. N., Wimsatt, W., A. Urine flow and composition in the vampire bat. Am. Zool. 5, 662–667 (1965).

    Google Scholar 

  69. 69

    Singer, M. A. Vampire, bat, shrew, and bear: comparative physiology and chronic renal failure. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 282, R1583–R1592 (2002).

    CAS  Article  Google Scholar 

  70. 70

    Hoff, C. C. & Reidesel, M. L. (eds) Physiological Systems in Semiarid Environments. (University of New Mexico Press, 1969).

    Book  Google Scholar 

  71. 71

    Holloway, B. W. & Ripley, S. H. Nucleic acid content of reticulocytes and its relation to uptake of radioactive leucine in vitro. J. Biol. Chem. 196, 695–701 (1952).

    CAS  PubMed  Google Scholar 

  72. 72

    Fulop, T. et al. Aging, frailty and age-related diseases. Biogerontology 11, 547–563 (2010).

    CAS  Article  Google Scholar 

  73. 73

    Shiels, P. G., McGuiness, D., Eriksson, M., Kooman, J. P. & Stenvinkel, P. The role of epigenetics in renal ageing. Nat. Rev. Nephrol. 13, 471–482 (2017).

    CAS  Article  Google Scholar 

  74. 74

    López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell Metab. 153, 1194–1217 (2013).

    Article  CAS  Google Scholar 

  75. 75

    Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J. & van Deursen, J. M. Cellular senescence in renal ageing and disease. Nat. Rev. Nephrol. 13, 77–89 (2017).

    CAS  Article  Google Scholar 

  76. 76

    Stenvinkel, P. & Larsson, T. Chronic kidney disease: a clinical model of premature aging. Am. J. Kidney Dis. 62, 339–351 (2013).

    Article  Google Scholar 

  77. 77

    Karam, Z. & Tuazon, J. Anatomic and physiologic changes of the aging kidney. Clin. Geriatr. Med. 29, 555–564 (2013).

    Article  Google Scholar 

  78. 78

    Kaplan, C., Pasternack, B., Shah, H. & Gallo, G. Age-related incidence of sclerotic glomeruli in human kidneys. Am. J. Pathol. 80, 227–234 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Kooman, J. et al. Inflammation and premature aging in advanced chronic kidney disease. Am. J. Physiol. Renal Physiol. 313, F938–F950 (2017).

    Article  Google Scholar 

  80. 80

    Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    CAS  Article  Google Scholar 

  81. 81

    Bhargava, P. & Schnellmann, R. G. Mitochondrial energetics in the kidney. Nat. Rev. Nephrol. 13, 629–646 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Glassock, R. J. & Rule, A. D. The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli. Kidney Int. 82, 270–277 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Roncal-Jimenez, C. A. et al. Aging-associated renal disease in mice is fructokinase dependent. Am. J. Physiol. Renal Physiol. 311, F722–F730 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Sosnowska, D. et al. A heart that beats for 500 years: age-related changes in cardiac proteasome activity, oxidative protein damage and expression of heat shock proteins, inflammatory factors, and mitochondrial complexes in Arctica islandica, the longest-living noncolonial animal. J. Gerontol. A Biol. Sci. Med. Sci. 69, 1448–1461 (2014).

    CAS  Article  Google Scholar 

  86. 86

    Nielsen, J. et al. Eye lens radiocarbon reveals centuries of longevity in the Greenland shark (Somniosus microcephalus). Science 353, 702–704 (2016).

    CAS  Article  Google Scholar 

  87. 87

    Finch, C. E. Update on slow aging and negligible senescence — a mini-review. Gerontology 55, 307–313 (2009).

    Article  Google Scholar 

  88. 88

    Valenzano, D. R. et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr. Biol. 16, 296–300 (2006).

    CAS  Article  Google Scholar 

  89. 89

    Buffenstein, R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J. Comp. Physiol. B 4, 439–445 (2008).

    Article  Google Scholar 

  90. 90

    Jarvis, J. U. M. & Bennet, N. C. in The Biology of the Naked Mole-Rat. (eds Sherman, P. W., Jarvis, J. U. M. & Alexander, R. D.) 66–96 (Princeton University Press, 1991).

    Google Scholar 

  91. 91

    Yahav, S., Buffenstein, R. & Pettifor, J. M. Calcium and inorganic phosphorus metabolism in naked mole rats Hetercephalus glaber is only indirectly affected by cholecalciferol. Gen. Comp. Endocrinol. 89, 161–166 (1993).

    CAS  Article  Google Scholar 

  92. 92

    De Waal, E. M. et al. Elevated protein carbonylation and oxidative stress do not affect protein structure and function in the long-living naked-mole rat: a proteomic approach. Biochem. Biophys. Res. Commun. 434, 815–819 (2013).

    CAS  Article  Google Scholar 

  93. 93

    Triplett, J. C. et al. Age-related changes in the proteostasis network in the brain of the naked mole-rat: implications promoting healthy longevity. Biochim. Biophys. Acta 1852, 2213–2224 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Dai, D. F., Wessells, R. J., Bodmer, R. & Rabinovitch, P. S. in The Comparative Biology of Aging. (ed Wolf N. S.) 259–286 (Springer, 2010).

    Book  Google Scholar 

  95. 95

    Grimes, K. M., Lindsey, M. L., Gelfond, J. A. & Buffenstein, R. Getting to the heart of the matter: age-related changes in diastolic heart function in the longest-lived rodent, the naked mole rat. J. Gerontol. A Biol. Sci. Med. Sci. 67, 384–394 (2012).

    Article  Google Scholar 

  96. 96

    Grimes, K. M., Reddy, A. K., Lindsey, M. L. & Buffenstein, R. And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat. Am. J. Physiol. Heart Circ. Physiol. 307, H284–291 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Lagunas-Rangel, F. A. & Chávez-Valencia, V. Learning of nature: the curious case of the naked mole rat. Mech. Ageing Dev. 164, 76–81 (2017).

    Article  Google Scholar 

  98. 98

    Skulachev, V. P. et al. Neoteny, prolongation of youth: from naked mole rats to “naked apes” (humans). Physiol. Rev. 97, 699–720 (2017).

    Article  Google Scholar 

  99. 99

    Comfort, A. The biology of senescence. 3rd edn (Elsevier, 1979).

    Google Scholar 

  100. 100

    Tian, X. et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346–349 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Itoh, K., Ye, P., Matsumiya, T., Tanji, K., & Ozaki, T. Emerging functional cross-talk between the Keap1–Nrf2 system and mitochondria. J. Clin. Biochem. Nutr. 56, 91–97 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Lewis, K. N., Mele, J., Hayes, J. D., & Buffenstein, R. Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integr. Comp. Biol. 50, 829–843 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Lewis, K. N. et al. Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proc. Natl Acad. Sci. USA 112, 3722–3727 (2015).

    CAS  PubMed  Google Scholar 

  104. 104

    Pomatto, L. C. D., Tower, J. & Davies, K. J. A. Sexual dimorphism and aging differentially regulate adaptive homeostasis. J. Gerontol. A Biol. Sci. Med. Sci. (2017).

    Article  CAS  Google Scholar 

  105. 105

    Kubben, N. et al. Repression of the antioxidant Nrf2 pathway in premature aging. Cell 165, 1361–1374 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Kubben, N. & Misteli, T. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat. Rev. Mol. Cell Biol. 18, 595–609 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Chopra, A. & Lineweaver, C. H. in Proceedings of the 8th Australian Space Science Conference. 1st edn (eds Short, W. & Cairns, I.) 49–55 (National Space Society of Australia Ltd, 2008).

    Google Scholar 

  108. 108

    Ohno, S. The reason for as well as the consequence of the cambrian explosion in animal evolution. J. Mol. Evol. 44, S23–S27 (1997).

    CAS  Article  Google Scholar 

  109. 109

    Bowen, H. J. M. Environmental Chemistry of the Elements. (Academic Press, 1979).

    Google Scholar 

  110. 110

    Benner, S. A., Ellington, A. D. & Tauer, A. Modern metabolism as a palimpsest of the RNA world. Proc. Natl Acad. Sci. USA 86, 7054–7058 (1989).

    CAS  Article  Google Scholar 

  111. 111

    Blair-West, J. R. et al. Behavioral and tissue responses to severe phosphorus depletion in cattle. Am. J. Physiol. 263, R656–R663 (1992).

    CAS  PubMed  Google Scholar 

  112. 112

    Hu, M. C., Shiizaki, K., Kuro-o M. & Moe, O. W. Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu. Rev. Physiol. 75, 503–533 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Swapna, M. Applied Mineralogy: Applications in Industry and Environment. (Springer, 2011).

    Google Scholar 

  114. 114

    Lenton, S., Nylander, T., Teixeira, S. C. & Holt, C. A review of the biology of calcium phosphate sequestration with special reference to milk. Dairy Sci. Technol. 95, 3–14 (2015).

    CAS  Article  Google Scholar 

  115. 115

    Kuro-o, M., Matsumura, Y. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    CAS  Article  Google Scholar 

  116. 116

    Kuro-o, M. The FGF23 and Klotho system beyond mineral metabolism. Clin. Exp. Nephrol. 21, 64–69 (2017).

    CAS  Article  Google Scholar 

  117. 117

    Maltese, G. et al. The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. J. Cell. Mol. Med. 21, 621–627 (2017).

    CAS  Article  Google Scholar 

  118. 118

    Beck, G. R., Moran, E. & Knecht, N. Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2. Exp. Cell Res. 288, 288–300 (2003).

    CAS  Article  Google Scholar 

  119. 119

    Shanahan, C. M. Mechanisms of vascular calcification in CKD — evidence for premature ageing? Nat. Rev. Nephrol. 9, 661–670 (2013).

    CAS  Article  Google Scholar 

  120. 120

    Stenvinkel, P. et al. CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease. Aging 9, 494–507 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Troyano, N. et al. Hyperphosphatemia induces cellular senescence in human aorta smooth muscle cells through integrin linked kinase (ILK) up-regulation. Mech. Ageing Dev. 152, 43–55 (2015).

    CAS  Article  Google Scholar 

  122. 122

    Di Marco, G. S. et al. Increased inorganic phosphate induces human endothelial cell apoptosis in vitro. Am. J. Physiol. Renal Physiol. 294, F1381–F1387 (2008).

    CAS  Article  Google Scholar 

  123. 123

    Jono, S. et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ. Res. 87, E10–E17 (2000).

    CAS  Article  Google Scholar 

  124. 124

    Sage, A. P., Lu, J., Tintut, Y. & Demer, L. L. Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int. 79, 414–422 (2011).

    CAS  Article  Google Scholar 

  125. 125

    Villa-Bellosta, R. & Sorribas, V. Phosphonoformic acid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition. Arterioscler. Thromb. Vasc. Biol. 29, 761–766 (2009).

    CAS  Article  Google Scholar 

  126. 126

    Yamada, S. et al. Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model. Calcif. Tissue Int. 96, 347–358 (2015).

    CAS  Article  Google Scholar 

  127. 127

    Jeyapalan, J. C. & Sedivy, J. M. Cellular senescence and organismal aging. Mech. Ageing Dev. 129, 467–474 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Kuro-o, M. A potential link between phosphate and aging — lessons from Klotho-deficient mice. Mech. Ageing Dev. 131, 270–275 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Merideth, M. A. et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N. Engl. J. Med. 358, 592–604 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Villa-Bellosta, R. et al. Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment. Circulation 127, 2442–2451 (2013).

    CAS  Article  Google Scholar 

  131. 131

    Chang, A. R., Lazo, M., Appel, L. J., Gutierrez, O. M. & Grams, M. E. High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am. J. Clin. Nutr. 99, 320–327 (2014).

    CAS  Article  Google Scholar 

  132. 132

    Hamano, T. et al. Fetuin-mineral complex reflects extraosseous calcification stress in CKD. J. Am. Soc. Nephrol. 21, 1998–2007 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Smith, E. R., Ford, M. L., Tomlinson, L. A., Rajkumar, C., McMahon, L. P., & Holt, S. G. Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD. Nephrol. Dial. Transplant. 27, 1957–1966 (2012).

    CAS  Article  Google Scholar 

  134. 134

    Smith, E. R., Hanssen, E., McMahon, L. P. & Holt, S. G. Fetuin-A-containing calciprotein particles reduce mineral stress in the macrophage. PLOS One 8, e60904 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Smith, E. R. et al. Serum calcification propensity predicts all-cause mortality in predialysis CKD. J. Am. Soc. Nephrol. 25, 339–348 (2014).

    CAS  Article  Google Scholar 

  136. 136

    Teare, J. A. ISIS Reference Ranges for Physiological Values in Captive Wildlife (Electronic Resource). (International Species Information System, 2002).

    Google Scholar 

  137. 137

    Moe, S. M. et al. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney Int. Suppl. 113, S1–S130 (2009).

    Google Scholar 

  138. 138

    Fouque, D., Horne, R., Cozzolino, M. & Kalantar-Zadeh, K. Balancing nutrition and serum phosphorus in maintenance dialysis. Am. J. Kidney Dis. 64, 143–150 (2014).

    CAS  Article  Google Scholar 

  139. 139

    Peter, W. L. S., Wazny, L. D., Weinhandl, E., Cardone, K. E. & Hudson, J. Q. A. Review of phosphate binders in chronic kidney fisease: incremental progress or just higher costs? Drugs 14, 329–345 (2016).

    Google Scholar 

  140. 140

    Kawai, M., Kinoshita, S., Ozono, K. & Michigami, T. Inorganic phosphate activates the AKT/mTORC1 pathway and shortens the life span of an α-Klotho-deficient model. J. Am. Soc. Nephrol. 27, 2810–2824 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    ter Braake, A. D., Shanahan, C. M. & de Baaij, J. H. F. Magnesium counteracts vascular calcification: passive interference or active modulation? Arterioscler. Thromb. Vasc. Biol. 37, 1431–1445 (2017).

    CAS  Article  Google Scholar 

  142. 142

    Miller, M. et al. Changes in serum calcium, phosphorus, and magnesium levels in captive ruminants affected by diet manipulation. J. Zoo Wildl. Med. 41, 404–408 (2010).

    Article  Google Scholar 

  143. 143

    Koh, G. Y. & Rowling, M. J. Resistant starch as a novel dietary strategy to maintain kidney health in diabetes mellitus. Nutr. Rev. 75, 350–360 (2017).

    Article  Google Scholar 

  144. 144

    Bilinski, T., Paszkiewicz, T. & Zadrag-Ecza, R. Energy excess is the main cause of accelerated aging of mammals. Oncotarget 6, 12090–12919 (2016).

    Google Scholar 

  145. 145

    Stenvinkel, P., Kooman, J. P. & Shiels, P. G. Nutrients and ageing: what can we learn about ageing interactions from animal biology? Curr. Opin. Clin. Nutr. Metab. Care 19, 19–25 (2016).

    CAS  Article  Google Scholar 

  146. 146

    Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14603 (2017).

    Article  CAS  Google Scholar 

  147. 147

    Lanaspa, M. A. et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J. Biol. Chem. 287, 40732–40744 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Sanchez-Lozada, L. G. et al. Uric Acid-Induced Endothelial Dysfunction Is Associated with Mitochondrial Alterations and Decreased Intracellular ATP Concentrations. Nephron. Exp. Nephrol. 121, e71–e78 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Johnson, R. J. The Fat Switch. (, 2012).

    Book  Google Scholar 

  150. 150

    Dolinsky, V. W. et al. Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats. J. Physiol. 590, 2783–2799 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Hall, J. A., Dominy, J. E., Lee, Y. & Puigserver, P. The sirtuin family's role in aging and age-associated pathologies. J. Clin. Invest. 123, 973–979 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Cantó, C. & Auwerx, J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol. Metab. 20, 325–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Kulkarni, S. R., Armstrong, L. E. & Slitt, A. Caloric restriction-mediated induction of lipid metabolism gene expression in liver is enhanced by Keap1-knockdown. Pharm. Res. 30, 2221–2231 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Sanchez-Roman, I. & Barja, G. Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction. Exp. Gerontol. 48, 1030–1042 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Yang, G. et al. Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid. Redox Signal 18, 1906–1919 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Pietri, R., Román-Morales, E. & López-Garriga, J. Hydrogen sulfide and hemeproteins: knowledge and mysteries. Antioxid. Redox Signal 15, 393–404 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    Wallace, J. L. & Wang, R. Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter. Nat. Rev. Drug Discov. 14, 329–345 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    McIsaac, R. S., Lewis, K. N., Gibney, P. A. & Buffenstein, R. From yeast to human: exploring the comparative biology of methionine restriction in extending eukaryotic life span. Ann. NY Acad. Sci. 1363, 155–170 (2016).

    CAS  Article  Google Scholar 

  161. 161

    Dziegelewska, M. et al. 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 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  162. 162

    Pamplona, R. & Barja, G. Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine conenction. Biochim. et Biophys. Acta 1757, 496–508 (2006).

    CAS  Article  Google Scholar 

  163. 163

    Valli, A. et al. Elevated serum levels of S-adenosylhomocysteine, but not homocysteine, are associated with cardiovascular disease in stage 5 chronic kidney disease patients. Clin. Chim. Acta 395, 106–110 (2008).

    CAS  Article  Google Scholar 

  164. 164

    Suliman, M. E., Filho, J. C., Bárány, P., Lindholm, B. & Bergström, J. Effects of methionine loading on plasma and erythrocyte sulphur amino acids and sulph-hydryls before and after co-factor supplementation in haemodialysis patients. Nephrol. Dial Transplant 16, 102–110 (2001).

    CAS  Article  Google Scholar 

  165. 165

    Brown-Borg, H. M. & Buffenstein, R. Cutting back on the essentials: can manipulating intake of specific amino acids modulate health and lifespan? Aging Res. Rev. 39, 87–95 (2017).

    CAS  Article  Google Scholar 

  166. 166

    Weber, G. J., Pushpakumar, S. B. & Sen, U. Hydrogen sulfide alleviates hypertensive kidney dysfunction through an epigenetic mechanism. Am. J. Physiol. Heart Circ. Physiol. 312, H874–H885 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Cooney, C. A. Are somatic cells inherently deficient in methylation metabolism? A proposed mechanism for DNA methylation loss, senescence and aging. Growth Dev. Aging 57, 261–273 (1993).

    CAS  PubMed  Google Scholar 

  168. 168

    Park, T. J. et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356, 307–311 (2017).

    CAS  Article  Google Scholar 

  169. 169

    Pfeiffer, C. J. Renal cellular and tissue specializations in the bottlenose dolphin (Tursiops truncatus) and the beluga whale (Delphinapteras leucas). Aquatic Mammals 23, 75–84 (1997).

    Google Scholar 

  170. 170

    Andrews, M. T., Russeth, K. P., Drewes, L. R. & Henry, P. G. Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R383–393 (2009).

    CAS  Article  Google Scholar 

  171. 171

    Jani, A. et al. Renal protection from prolonged cold ischemia and warm reperfusion in hibernating squirrels. Transplantation 92, 1215–1221 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Vázquez-Medina, J. P. et al. Prolonged fasting activates Nrf2 in post-weaned elephant seals. J. Exp. Biol. 216, 2870–2878 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Vázquez-Medina, J. P., Zenteno-Savín, T., Elsner, R. & Ortiz, R. M. Coping with physiological oxidative stress: a review of antioxidant strategies in seals. J. Comp. Physiol. B 182, 741–750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Vázquez-Medina, J. P., Zenteno-Savín, T., Forman, H. J., Crocker, D. E. & Ortiz, R. M. Prolonged fasting increases glutathione biosynthesis in postweaned northern elephant seals. J. Exp. Biol. 214, 1294–1299 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Nezu, M. et al. Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression. Kidney Int. 91, 387–401 (2017).

    CAS  Article  Google Scholar 

  176. 176

    Cirillo, P. et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J. Am. Soc. Nephrol. 20, 545–553 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Nigro, D. et al. Chronic administration of saturated fats and fructose differently affect SREBP activity resulting in different modulation of Nrf2 and Nlrp3 inflammasome pathways in mice liver. J. Nutr. Biochem. 42, 160–171 (2017).

    CAS  Article  Google Scholar 

  178. 178

    Perez-Pinzon, M. A. Mechanisms of neuroprotection during ischemic preconditioning: lessons from anoxic tolerance. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 147, 291–299 (2007).

    Article  CAS  Google Scholar 

  179. 179

    Geiser, F. & Ruf, T. Hibernation versus daily torpor in mammals and birds: physiological variables and classification of torpor patterns. Physiol. Zool. 68, 935–966 (1995).

    Article  Google Scholar 

  180. 180

    Turbill, C., Ruf, T., Mang, T. & Arnold, W. Regulation of heart rate and rumen temperature in red deer: effects of season and food intake. J. Exp. Biol. 214, 963–970 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  181. 181

    Signer, C., Ruf, T. & Arnold, W. Hypometabolism and basking: the strategies of alpine ibex to endure harsh over-wintering conditions. Funct. Ecol. 25, 537–547 (2011).

    Article  Google Scholar 

  182. 182

    Arnold, W. et al. Nocturnal hypometabolism as an overwintering strategy of red deer (Cervus elaphus). Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R174–R181 (2004).

    CAS  Article  Google Scholar 

  183. 183

    Arnold, W. in Life in the Cold: Ecological, Physiological, and Molecular Mechanisms. (eds Carey, C., Florant, G. L., Wunder, B. A. & Horwitz, B.) 65–80. (Westview Press, 1993).

    Google Scholar 

  184. 184

    Parker, K. L., Barboza, P. S. & Gillingham, M. P. Nutrition integrates environmental responses of ungulates. Funct. Ecol. 23, 57–69 (2009).

    Article  Google Scholar 

  185. 185

    Arnold, W. et al. Contrary seasonal changes of rates of nutrient uptake, organ mass, and voluntary food intake in red deer (Cervus elaphus). Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R277–R285 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  186. 186

    Loudon, A. S. I. Photoperiod and the regulation of annual and circannual cycles of food intake. Proc. Nutr. Soc. 53, 495–507 (1994).

    CAS  Article  Google Scholar 

  187. 187

    Hume, D. et al. Seasonal changes in morphology and function of the gastrointestinal tract of free-living alpine marmots (Marmota marmota). J. Comp. Physiol. B 172, 197–207 (2002).

    CAS  Article  Google Scholar 

  188. 188

    Rigano, K. S. et al. Life in the fat lane: seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears. J. Comp. Physiol. B 187, 649–676 (2017).

    CAS  Article  Google Scholar 

  189. 189

    Sommer, F. et al. The gut microbiota modulates energy metabolism in the hibernating brown bear Ursus arctos. Cell Rep. 14, 1655–1661 (2016).

    CAS  Article  Google Scholar 

  190. 190

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

    CAS  Article  Google Scholar 

  191. 191

    Arnold, W., Ruf, T., Frey-Roos, F. & Bruns, U. Diet-independent remodeling of cellular membranes precedes seasonally changing body temperature in a hibernator. PLOS One 6, e18641 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  192. 192

    Arnold, W., Giroud, S., Valencak, T. G. & Ruf, T. Ecophysiology of omega fatty acids: a lid for every jar. Physiology 30, 232–240 (2015).

    CAS  Article  Google Scholar 

  193. 193

    Helge, J. W. et al. Training affects muscle phospholipid fatty acid composition in humans. J. Appl. Physiol. 90, 670–677 (2001).

    CAS  Article  Google Scholar 

  194. 194

    Mitchell, T. W., Buffenstein, R. & Hulbert, A. J. Membrane phospholipid composition may contribute to exceptional longevity of the naked mole-rat (Heterocephalus glaber): a comparative study using shotgun lipidomics. Exp. Gerontol. 42, 1053–1062 (2007).

    CAS  Article  Google Scholar 

  195. 195

    Giroud, S. et al. Membrane phospholipid fatty acid composition regulates cardiac SERCA activity in a hibernator, the Syrian hamster (Mesocricetus auratus). PLOS One 8, e63111 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  196. 196

    Arnold, W., Ruf, T. & Kuntz, R. Seasonal adjustment of energy budget in a large wild mammal, the Przewalski horse (Equus ferus przewalskii) II. Energy expenditure. J. Exp. Biol. 209, 4566–4573 (2006).

    Article  Google Scholar 

  197. 197

    Maillet, D. & Weber, J. M. Relationship between n-3 PUFA content and energy metabolism in the flight muscles of a migrating shorebird: evidence for natural doping. J. Exp. Biol. 210, 413–420 (2007).

    CAS  Article  Google Scholar 

  198. 198

    Hulbert, A. J., Kelly, M. A. & Abbott, S. K. Polyunsaturated fats, membrane lipids and animal longevity. J. Comp. Physiol. B 184, 149–166 (2014).

    CAS  Article  Google Scholar 

  199. 199

    Chen, D. Q. et al. The link between phenotype and fatty acid metabolism in advanced chronic kidney disease. Nephrol. Dial Transplant. 32, 1154–1166 (2017).

    CAS  Article  Google Scholar 

  200. 200

    Gao, L. et al. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J. Biol. Chem. 282, 2529–2537 (2007).

    CAS  Article  Google Scholar 

  201. 201

    Andersen, J. B., Rourke, B. C., Caiozzo, V. J., Bennett, A. F. & Hicks, J. W. Postprandial cardiac hypertrophy in pythons. Nature 434, 37 (2005).

    CAS  Article  Google Scholar 

  202. 202

    Riquelme, C. A. et al. Fatty acids identified in the Burmese python promote beneficial cardiac growth. Science 334, 528–531 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  203. 203

    Hall, J. C. & Rosbash, M. Oscillating molecules and how they move corcadian clocks across evolutionary boundaries. Proc. Natl Acad. Sci. USA 90, 5382–5383 (1993).

    CAS  Article  Google Scholar 

  204. 204

    Turek, F. W. et al. Obesity and metabolic syndrome in circadian clock mutant mice. Science 308, 1043–1045 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  205. 205

    Pekovic-Vaughan, V. et al. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. Genes Dev. 28, 548–560 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  206. 206

    Gumz, M. L. Molecular basis of circadian rhythmicity in renal physiology and pathophysiology. Exp. Physiol. 101, 1025–1029 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  207. 207

    Smolensky, M. H., Hermida, R. C., Reinberg, A., Sackett-Lundeen, L. & Portaluppi, F. Circadian disruption: new clinical perspective of disease pathology and basis for chronotherapeutic intervention. Chronobiol. Int. 33, 1101–1119 (2016).

    Article  Google Scholar 

  208. 208

    Obi, Y. et al. Seasonal variations in transition, mortality and kidney transplantation among patients with end-stage renal disease in the USA. Nephrol. Dial. Transplant. 32, 907 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  209. 209

    Evans, A. L. et al. Drivers of hibernation in the brown bear. Front. Zool. 13, 7 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  210. 210

    Arinell, K. et al. Brown bears (Ursus arctos) seem resistant to atherosclerosis despite highly elevated plasma lipids during hibernation and active state. Clin. Transl Sci. 5, 269–272 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. 211

    Iles, T. L., Laske, T. G., Garschelis, D. L. & Iaizzo, P. A. Blood clotting behavior is innately modulated in Ursus americanus during early and late denning relative to summer months. J. Exp. Biol. 220, 455–459 (2017).

    Article  Google Scholar 

  212. 212

    Brown, D. C., Mulhausen, R. O., Andrew, D. J. & Seal, U. S. Renal function in anesthetized dormant and active bears. Am. J. Physiol. 220, 293–298 (1971).

    CAS  Article  Google Scholar 

  213. 213

    Prunescu, C., Serban-Parau, N., Brock, J. H., Vaughan, D. M. & Prunescu, P. Liver and kidney structure and iron content in romanian brown bears (Ursus arctos) before and after hibernation. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 134, 21–26 (2003).

    Article  Google Scholar 

  214. 214

    Ortiz, R. M. Osmoregulation in marine mammals. J. Exp. Biol. 204, 1831–1844 (2001).

    CAS  PubMed  Google Scholar 

  215. 215

    Dugbartey, G. J. et al. Renal mitochondrial response to low temperature in non-hibernating and hibernating species. Antioxid. Redox Signal 27, 599–617 (2017).

    CAS  Article  Google Scholar 

  216. 216

    Walford, R. L. & Spindler, S. R. The response to caloric restriction in mammals shows features also common to hibernation: a cross-adaption hypothesis. J. Gerontol. A Biol. Sci. Med. Sci. 52, B179–B183 (1997).

    CAS  Article  Google Scholar 

  217. 217

    Turbilli, C., Bieber, C. & Ruf, T. Hibernation is associated with increased survival and the evolution of slow life histories among mammals. Proc. R. Soc. 278, 3355–3363 (2011).

    Article  Google Scholar 

  218. 218

    Storey, K. B. & Storey, J. M. Metabolic rate depression and biochemical adaptation in anaerobiosis, hibernation and estivation. Quarterly Rev. Biol. 65, 145–174 (1990).

    CAS  Article  Google Scholar 

  219. 219

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  220. 220

    Blackstone, E. & Roth, M. B. Suspended animation-like state protects mice from lethal hypoxia. Shock 27, 370–372 (2007).

    CAS  Article  Google Scholar 

  221. 221

    Shimada, S. et al. Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. Surg. Today 45, 892–903 (2015).

    CAS  Article  Google Scholar 

  222. 222

    Xu, R. et al. Hibernating squirrel muscle activates the endurance exercise pathway despite prolonged immobilization. Exp. Neurol. 247, 392–401 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  223. 223

    Dugbartey, G. J., Bouma, H. R., Strijkstra, A. M., Boerema, A. S. & Henning, R. H. Induction of a torpor-like state by 5′-AMP does not depend on H2S production. PLOS One 21, e01366113 (2015).

    Google Scholar 

  224. 224

    Huang, L. et al. The AMPK agonist PT1 and mTOR Inhibitor 3HOI-BA-01 protect cardiomyocytes after ischemia through induction of autophagy. J. Cardiovasc. Pharmacol. Ther. 21, 70–81 (2016).

    CAS  Article  Google Scholar 

  225. 225

    Ratigan, E. D. & McKay, D. B. Exploring principles of hibernation for organ preservation. Transpl. Rewiews 30, 13–19 (2016).

    Article  Google Scholar 

  226. 226

    Harlow, H. J., Lohuis, T., Beck, T. D. I. & Iaizzo, P. A. Muscle strength in overwintering bears. Nature 409, 997 (2001).

    CAS  Article  Google Scholar 

  227. 227

    Nelson, R., Wahner, H. W., Jones, J. D., Ellefson, R. D. & Zollman, P. E. Metabolism of bears before, during, and after winter sleep. Am. J. Physiol. 224, 491–496 (1973).

    CAS  Article  Google Scholar 

  228. 228

    Lin, D. C., Hershey, J. D., Mattoon, J. S. & Robbins, C. T. Skeletal muscles of hibernating brown bears are unusually resistant to effects of denervation. J. Exp. Biol. 215, 2081–2087 (2012).

    Article  Google Scholar 

  229. 229

    Fuster, G., Busquets, S., Almendro, V., Lopez-Soriano, F. J. & Argilés, J.M. Antiproteolytic effects of plasma from hibernating bears: a new approach for muscle wasting therapy? Clin. Nutr. 26, 658–661 (2007).

    CAS  Article  Google Scholar 

  230. 230

    Andres-Mateos, E. et al. Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy. EMBO Mol. Med. 5, 80–91 (2013).

    CAS  Article  Google Scholar 

  231. 231

    Ivakine, E. A. & Cohn, R. D. Maintaining skeletal muscle mass: lessons learned from hibernation. Exp. Physiol. 99, 632–637 (2014).

    CAS  Article  Google Scholar 

  232. 232

    Luo, J. et al. Serum glucocorticoid-regulated kinase 1 blocks CKD-Induced muscle wasting via inactivation of FoxO3a and Smad2/3. J. Am. Soc. Nephrol. 27, 2797–2808 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  233. 233

    Chung, N., Park, J. & Lim, K. The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue. J. Exerc. Nutr. Biochem. 21, 39–47 (2017).

    Article  Google Scholar 

  234. 234

    Tran, M. T. et al. PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531, 528–532 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  235. 235

    Gidlund, E. K. et al. Rapidly elevated levels of PGC-1α-b protein in human skeletal muscle after exercise: exploring regulatory factors in a randomized controlled trial. J. Appl. Physiol. 119, 374–384 (2015).

    CAS  Article  Google Scholar 

  236. 236

    Oh, S. et al. Nuclear factor (erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox modulation in skeletal muscles. Sci. Rep. 7, 12902 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. 237

    McGee Lawrence, M. E. et al. Six months of disuse during hibernation does not increase intracortical porosity or decrease cortical bone geometry, strength or mineralization in black bears (Ursus americanus) femurs. J. Biomech. 42, 1378–1383 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  238. 238

    McGee-Lawrence, M. et al. Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation. J. Exp. Biol. 218, 2067–2074 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  239. 239

    Fedorov, V. B. et al. Preservation of bone mass and structure in hibernating black bears (Ursus americanus) through elevated expression of analoic genes. Funct. Integr. Genom. 12, 357–365 (2012).

    CAS  Article  Google Scholar 

  240. 240

    Seger, R. et al. Investigating the mechanisms for maintaing eucalcemia despite immobility and anuria in the hibernating American black bear (Ursus americanus). Bone 49, 1205–1212 (2011).

    CAS  Article  Google Scholar 

  241. 241

    Donahue, S. W. et al. Parathyroid hormone may maintain bone formation in hibernating black bears (Ursus americanus) to prevent disuse osteoporosis. J. Exp. Biol. 209, 1630–1638 (2006).

    Article  Google Scholar 

  242. 242

    Gray, S. K. et al. Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice. Bone 51, 578–585 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  243. 243

    Ibánez, L. et al. Effects of Nrf2 deficiency on bone microarchitecture in an experimental model of osteoporosis. Oxid. Med. Cell. Longev. 2014, 726590 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. 244

    Thummuri, D., Naidu, V. G. M. & Chaudhari, P. Carnosic acid attenuates RANKL-induced oxidative stress and osteoclastogenesis via induction of Nrf2 and suppression of NF-κB and MAPK signalling. J. Mol. Med. 95, 1065–1076 (2017).

    CAS  Article  Google Scholar 

  245. 245

    Ni, Z. & Storey, K. B. Heme oxygenase expression and Nrf2 signaling during hibernation in ground squirrels. Can. J. Physiol. Pharmacol. 88, 379–387 (2010).

    CAS  Article  Google Scholar 

  246. 246

    Iaizzo, P. A., Laske, T. G., Harlow, H. J., McClay, C. B. & Garshelis, D. L. Wound healing during hibernation by black bears (Ursus americanus) in the wild: elicitation of reduced scar formation. Integr. Zool. 7, 48–60 (2012).

    Article  Google Scholar 

  247. 247

    Barboza, P. S., Farley, S. D. & Robbins, C. T. Whole-body urea cycling and protein turnover during hyperphagia and dormancy in growing bears (Ursus americanus and U. arctos). Canadian J. Zoology 75, 2129–2136 (1997).

    Article  Google Scholar 

  248. 248

    Nelson, R. A., Jones, J. D., Wahner, H. W., McGill, D. B. & Code, C. F. Nitrogen metabolism in bears: urea metabolism in summer starvation and in winter sleep and role of urinary bladder in water and nitrogen conservation. Mayo Clin. Proc. 50, 141–146 (1975).

    CAS  PubMed  Google Scholar 

  249. 249

    Spector, D. A., Deng, J., Coleman, R. & Wade, J. B. The urothelium of a hibernator: the American black bear. Physiol. Rep. 3, e12429 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. 250

    Walser, M. Urea metabolism in chronic renal failure. J. Am. Soc. Nephrol. 9, 1544–1551 (1998).

    CAS  PubMed  Google Scholar 

  251. 251

    Ahlquist, D. A., Nelson, R. A., Steiger, D. L., Jones, J. D. & Ellefson, R. D. Glycerol metabolism in the hibernating black bear. J. Comp. Physiol. 155, 75–79 (1984).

    CAS  Article  Google Scholar 

  252. 252

    Nelson, R. A., Beck, T. D. I. & Steiger, D. L. Ratio of serum urea to serum creatinine in wild black bears. Science 226, 841–842 (1984).

    CAS  Article  Google Scholar 

  253. 253

    Nakagawa, T., Lomb, D. J., Haigis, M. C. & Guarente, L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560–570 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  254. 254

    Van Tighem, K. Food and Diet. The Get Bear Smart Society

  255. 255

    Carlson, S. M. Synchronous timing of food resources triggers bears to switch from salmon to berries. Proc. Natl Acad. Sci. USA 114, 10309–10311 (2017).

    CAS  Article  Google Scholar 

  256. 256

    Lattanzio, V., Lattanzio, V. M. T. & Cardinali, A. in Phytochemistry: Advances in Research. (ed Imperato, F.) 23–67 (Research Signpost, 2006).

    Google Scholar 

  257. 257

    Overall, J. et al. Metabolic effects of berries with structurally diverse anthocyanins. Int. J. Mol. Sci. 15, E422 (2017).

    Article  CAS  Google Scholar 

  258. 258

    Durbin, S. M. et al. Resveratrol supplementation preserves long bone mass, microstructure, and strength in hindlimb-suspended old male rats. J. Bone Miner. Metab. 32, 38–47 (2014).

    CAS  Article  Google Scholar 

  259. 259

    Lee, S. G. et al. Relationship between oxidative stress and bone mass in obesity and effects of berry supplementation on bone remodeling in obese male mice: an exploratory study. J. Med. Food 18, 476–482 (2015).

    CAS  Article  Google Scholar 

  260. 260

    Moriwaki, S. et al. Delphinidin, one of the major anthocyanidins, prevents bone loss through the inhibition of excessive osteoclastogenesis in osteoporosis model mice. PLOS One 13, e97177 (2014).

    Article  CAS  Google Scholar 

  261. 261

    Murata, M. et al. Delphinidin prevents muscle atrophy and upregulates miR-23a expression. J. Agr. Food Chem. 65, 45–50 (2017).

    CAS  Article  Google Scholar 

  262. 262

    Alvarado, J. L. et al. Delphinidin-rich maqui berry extract (Delphinol®) lowers fasting and postprandial glycemia and insulinemia in prediabetic individuals during oral glucose tolerance Tests. Biomed. Res. Int. 2016, 9070537 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. 263

    Ali, B. H. et al. Effect of aqueous extract and anthocyanins of calyces of Hibiscus sabdariffa (Malvaceae) in rats with adenine-induced chronic kidney disease. J. Pharm. Pharmacol. 69, 1219–1229 (2017).

    CAS  Article  Google Scholar 

  264. 264

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  265. 265

    Zhu, Y. et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–659 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  266. 266

    Chang, X. Y. et al. Quercetin attenuates vascular calcification through suppressed oxidative stress in adenine-induced chronic renal failure rats. Biomed. Res. Int. 2017, 5716204 (2017).

    PubMed  PubMed Central  Google Scholar 

  267. 267

    Momken, I. et al. Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J. 10, 3646–3660 (2011).

    Article  CAS  Google Scholar 

  268. 268

    Cheng, K. H. et al. Resveratrol ameliorates metabolic disordes and muscle wasting in streptozotocin-induced diabetic rats. Am. J. Physiol. Endocrinol. Metab. 301, E853–E863 (2011).

    Article  CAS  Google Scholar 

  269. 269

    Sen, C. K., Khanna, S., Gordillo, G., Bagchi, D., Bagchi, M. & Roy, S. Oxygen, oxidants, and antioxidants in wound healing: an emerging paradigm. Ann. NY Acad. Sci. 957, 239–249 (2002).

    CAS  Article  Google Scholar 

  270. 270

    Basu, A. et al. Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome. J. Nutr. 140, 1582–1587 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  271. 271

    Erlund, I. et al. Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol. Am. J. Clin. Nutr. 87, 323–331 (2008).

    CAS  Article  Google Scholar 

  272. 272

    Stull, A. J., Cash, K. C., Johnson, W. D., Champagne, C. M. & Cefalu, W. T. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J. Nutr. 140, 1764–1768 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  273. 273

    Cassidy, A. et al. High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women. Circulation 127, 188–196 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  274. 274

    Wang, X., Rybczynski, N., Harington, C.R., White, S.C. & Tedford, R.H. A basal ursine bear (Protarctos abstrusus) from the pliocene high arctic reveals eurasian affinities and a diet rich in fermentable sugars. Sci. Rep. 7, 17722 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. 275

    Reiter, R. J. et al. Melatonin in edible plants (phytomelatonin): identification, concentrations, bioavailability and proposed functions. World Rev. Nutr. Diet 97, 211–230 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. 276

    Pedruzzi, L. M. et al. Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2. J. Nephrol. 28, 495–501 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  277. 277

    Himmelfarb, J., Stenvinkel, P., Ikizler, T. A. & Hakim, R. M. The elephant of uremia: oxidative stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 62, 1524–1538 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  278. 278

    Noel, S., Hamad, A. R. & Rabb, H. Reviving the promise of transcription factor Nrf2-based therapeutics for kidney diseases. Kidney Int. 88, 1217–1218 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  279. 279

    Axelsson, A. S. et al. Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci. Transl. Med. 9, eeah4477 (2017).

    Article  CAS  Google Scholar 

  280. 280

    Sun, W. et al. Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Sci. Rep. 6, 34246 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  281. 281

    Ali, B. H. et al. Curcumin ameliorates kidney function and oxidative stress in experimental chronic kidney disease. Bas. Clin. Pharmacol. Toxicol. 122, 65–73 (2018).

    CAS  Article  Google Scholar 

  282. 282

    Han, C. W. et al. Ethanol extract of Alismatis Rhizoma reduces acute lung inflammation by suppressing NF-κB and activating Nrf2. J. Ethnopharmacol 146, 402–410 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  283. 283

    Wondrak, G. T. et al. The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules 15, 3338–3355 (2010).

    CAS  Article  Google Scholar 

  284. 284

    Esgalhado, M., Stenvinkel, P. & Mafra, D. Nonpharmacologic strategies to modulate nuclear factor eryhroid 2-related factor 2 pathway in chronic kidney disease. J. Ren. Nutr. 27, 282–291 (2017).

    CAS  Article  Google Scholar 

  285. 285

    Kwon, J. S. et al. Sulforaphane inhibits restenosis by suppressing inflammation and the proliferation of vascular smooth muscle cells. Atherosclerosis 225, 41–49 (2012).

    CAS  Article  Google Scholar 

  286. 286

    Juurlink, B. H. Dietary Nrf2 activators inhibit atherogenic processes. Atherosclerosis 225, 29–33 (2012).

    CAS  Article  Google Scholar 

  287. 287

    Pomatto, L. C. D. et al. The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress in Drosophila melanogaster. Aging 9, 1153–1185 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  288. 288

    de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  289. 289

    O'Mealey, G. B. et al. PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. J. Cell Sci. 130, 3467–3480 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  290. 290

    Vaziri, N. D. et al. Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease. Free Radic. Biol. Med. 86, 374–381 (2015).

    CAS  Article  Google Scholar 

  291. 291

    Tebay, L. E. et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med. 88, 108–146 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


The authors thank the Scandinavian Brown Bear Project (in particular, O. Fröbert, J. E. Swenson, S. Brunberg, J. M. Arnemo and A. Zedrosser). P.S.'s research benefits from support from the Swedish Medical Research Council, the Heart and Lung Foundation, Njurfonden and EU-funded INTRICARE projects. R.J.J. and M.L. benefit from research support from the Veterans Administration (BX002586), Department of Defense (PR130106), US National Institutes of Health (NIH) (DK108859 and DK109408), La Isla Foundation, Solidaridad and the Danone Research Foundation. M.K. is supported by the Japan Agency for Medical Research and Development (AMED) Core Research for Evolutionary Medical Science and Technology (CREST), AMED, and the Japan Society for the Promotion of Science (16H05302, 16K15470). W.A.'s research has benefited from the grant 'Polyunsaturated fatty acids and seasonal acclimatization' (30061-B25).

Author information




P.S. and R.J.J. launched the idea of studying renal biomimetics. P.S., J.P., M.K., M.L., W.A., T.R., P.G.S. and R.J.J. researched the literature, discussed the content of the article and wrote the text. All authors reviewed or edited the article before submission.

Corresponding author

Correspondence to Peter Stenvinkel.

Ethics declarations

Competing interests

P. S. received grants and honoraria from Baxter, Bayer, Astra Zeneca, Bristol-Myers Squibb, Pfizer, Akeiba and Corvidia. M.K. has received grants and honoraria from Bayer, Astellas, Bristol-Myers Squibb and Kissei Pharmaceuticals. R.J.J. has grants from the US National Institutes of Health (NIH), Department of Defense and the Veteran's Administration. He is also a member of Colorado Research Partners, LLC, which is developing inhibitors of fructose metabolism. The other authors declare no competing interests.

Supplementary information

Supplementary information tables

Supplementary information S1–S5 (table) (PDF 409 kb)

PowerPoint slides


Uraemic phenotype

Phenotype that includes several physical characteristics, such as vascular stiffness, sarcopenia, frailty, osteoporosis and left ventricular hypertrophy.

Chronic tubulointerstitial fibrosis

Diseases that affect the physiology of non-glomerular structures (tubules and/or the interstitium) in the kidney.

Glomerular haemodynamics

The regulation of efferent and afferent glomerular arteriolar resistance required to maintain a stable glomerular filtration rate.

Urinary specific gravity

Test that compares the density of urine to that of water.

N-Nitroso compounds

Compounds found in processed meat that are formed endogenously from the intake of nitrite and nitrate.

Nutrigenomic compounds

Bioactive nutrients that have an effect on or interact with the genome. Nutrigenomics also encompasses the effect of genetic variations on the absorption, metabolism, elimination or biological effects of various nutrients.

Telomere attrition

Telomeres are the protective endcaps of chromosomes. Attrition, or shortening, of telomeres is a form of tumour suppression and may be due to inflammation and oxidative stress as well as exposure to infectious agents, resulting in limited stem cell function, regeneration and organ maintenance during ageing.

Uraemic milieu

Toxic internal milieu in patients with uraemia that is characterized by accumulation of uraemic toxins and waste products that promote inflammation, oxidative stress, carbonylation, calcification and endothelial dysfunction.

Senescent cells

Cellular senescence is an irreversible cell cycle arrest mechanism that acts to protect against cancer. Senescent cells also have a role in complex biological processes, such as development, tissue repair and age-related disorders.


Abnormally elevated carbon dioxide (CO2) levels in the blood.

High-molecular-weight hyaluronan

A high-molecular-weight polysaccharide found in the extracellular matrix, especially in soft connective tissues.

Antagonistic pleiotropy

Scenarios in which one gene contributes to multiple traits, whereby at least one of these traits is beneficial and at least one is detrimental to the organism's health.

Phosphate appetite

A well-documented behaviour in animals that is induced by phosphate deficiency, which is especially common among herbivores.

Protein–energy wasting

A process characterized by a decline in body protein mass and energy reserves, including muscle and fat wasting and loss of visceral proteins. Protein energy wasting is often associated with inflammation and is a strong predictor of mortality.

Caloric restriction

A reduction in calorie intake without incurring malnutrition or a reduction in essential nutrients. In a variety of species, such yeast, fish, rodents and dogs, calorie restriction has been shown to slow the biological ageing process.


Sirtuins (or NAD+-dependent histone deacetylases) are a class of proteins that possess deacylase activity and regulate important biological pathways and cellular processes, including ageing, inflammation, transcription and apoptosis. Sirtuin agonists include pterostilbene and resveratrol.

Trans-sulfuration pathway

A metabolic pathway that involves the interconversion of homocysteine and cysteine via the intermediate cystathionine.


A post-translational modification that increases the catalytic activity of proteins. Physiological actions of sulfhydration include the regulation of endoplasmic reticulum stress signalling, inflammation and vascular tension.

One-carbon methyl donor units

DNA methylation influences the expression of some genes and depends upon the availability of methyl groups. Dietary methyl groups are derived from food sources that contain methionine, one-carbon units, choline or betaine (a choline metabolite).


A state of reduced body temperature and metabolic rate in animals that enables them to survive periods of reduced food availability.

Circadian clock

The circadian clock regulates the internal and external activities of organisms, such as sleep and changes in metabolism, based on the day–night cycle.


The science of timing drugs according to the circadian clock. This approach is used in various clinical conditions, such as cancer, hypertension, seasonal affective disorder and bipolar disorder.

Renal lobulation

Carnivores and most small mammals have smooth-surfaced and uni-pyramidal kidneys, whereas primates and Suidae (hogs and pigs) have a smooth-surfaced and multi-pyramidal kidney system. Large terrestrial mammals have multi-lobulated and multi-pyramidal kidneys to keep the proximal convoluted tubules short. Most marine mammals and bears have each lobe separated into renules (reniculated kidney system).

Therapeutic hypothermia

(also known as targeted temperature management). The induction of mild hypothermia (32–35 °C) after cardiac arrest for neuroprotection.

Sedentary behaviour

A type of behaviour that is characterized by an energy expenditure ≤1.5 metabolic equivalents while in a lying, reclining or sitting posture. Typical sedentary behaviours include watching TV, computer work, driving and reading.


Loss of nerve supply to a part of the body, which can be due to multiple causes, such as surgery, physical injury, chemical toxicity or diseases.

Disuse atrophy

A type of muscle atrophy that occurs when a muscle is less active than usual. Disuse atrophy is a common feature in chronic debilitating diseases and immobility.

Mechanical unloading

A mechanical manoeuvre or therapy that decreases tissue growth and regeneration. Whereas mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, mechanical unloading in microgravity causes reduced tissue regeneration via stem cell tissue progenitors.


The maintenance of normal and constant serum calcium levels.


Blueberries comprise all blue-coloured berries of the Vaccinium genus, of which the most common is bilberries. Blueberries have a low glycaemic index and are a rich source of fibres, vitamin K, manganese, >15 different anthocyanins (especially delphinidin and malvidin), quercetin, myricetin and resveratrol.


Anthocyanins (>600 molecular structures) belong to a class of molecules called flavonoids that are universal plant colourants responsible for the red, purple and blue colours in many fruits, berries, vegetables and flowers. Due to their contribution in multiple physiological activities, the consumption of these molecules is believed to have a substantial role in preventing lifestyle-related diseases.

Senolytic effects

Senolytic compounds selectively induce the death of senescent cells.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stenvinkel, P., Painer, J., Kuro-o, M. et al. Novel treatment strategies for chronic kidney disease: insights from the animal kingdom. Nat Rev Nephrol 14, 265–284 (2018).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing