Biological Process of Aging

Theme Leader :
Ikuroh Ohsawa, Ph.D.
Researcher :
Yasunori Fujita, Ph.D., Masumi Iketani, Ph.D.

Oxidative stress, Mitochondria, Hydrogen molecule, Neurodegenerative disease, clk-1, lifespan, Coenzyme Q

1. 1.Molecular Hydrogen Medicine
2. 2.Protective effects of natural foods on brain function
3. 3.Analysis of clk-1 gene function in mammalian aging

1. Molecular Hydrogen Medicine
We have previously reported that hydrogen molecule (H₂) selectively reduces toxic reactive oxygen species and ameliorates oxidative stress-induced injuries in vivo. Inhalation of hydrogen gas has been demonstrated to limit the infarct volume of the brain, heart and liver by reducing ischemia/reperfusion (I/R) injury and ameliorate transplant injuries. H₂-loaded eye drops also protect retinal I/R injury. Moreover, consumption of water with dissolved H₂ (hydrogen water) prevents stress-induced cognitive decline, degeneration of dopaminergic neurons and allergic reaction. We further reported that hydrogen therapy attenuates irradiation-induced lung damage. Precise mechanisms underlying many effects of H₂ are under investigation.
2. Protective effects of natural foods on brain function
Since elderly psychiatric disorder increases now, we started new research of natural food's effects on stress-related psychiatric disorder. Recently, we reported that oral administration of inosine produces antidepressant-like effects.
3. Analysis of clk-1 gene function in mammalian aging
We focused on clk-1 gene, a gerontogene identified in nematode, to elucidate the mechanisms of aging through investigating the relationship between metabolic rate or ultradian rhythm and lifespan. Because the clk-1 gene product is the synthetase of coenzyme Q (CoQ) that is an electron transporter in mitochondrial respiratory chain and the major source of ROS as well. We have previously generated clk-1 deficient mice that lack CoQ and clk-1 transgenic mice that have reduced level of CoQ. We investigate in the current study by the use of these mice whether lifespan correlates with the metabolic rate or ultradian rhythm and ROS production. Recently, we reported that exogenous administration of CoQ rescues slow growth and heartbeat through the restoration of mitochondrial function in clk-1-deficient mouse embryos.

1. 1.Takahashi K, Ohsawa I, Shirasawa T, Takahashi M. (2017) Optic atrophy 1 mediates coenzyme Q-responsive regulation of respiratory complex IV activity in brain mitochondria. Exp Gerontol. 98, 217-223
2. 2.Murakami Y, Ito M, Ohsawa I. (2017) Molecular hydrogen protects against oxidative stress-induced SH-SY5Y neuroblastoma cell death through the process of mitohormesis. PLoS One. 12, e0176992
3. 3.Nishimaki K, Asada T, Ohsawa I, Nakajima E, Ikejima C, Yokota T, Kamimura N, Ohta S. (2017) Effects of molecular hydrogen assessed by an animal model and a randomized clinical study on mild cognitive impairment. Curr Alzheimer Res. doi: 10.2174/1567205014666171106145017
4. 4.Iketani M, Ohshiro J, Urushibara T, Takahashi M, Arai T, Kawaguchi H, Ohsawa I. (2017) Preadministration of Hydrogen-Rich Water Protects Against Lipopolysaccharide-Induced Sepsis and Attenuates Liver injury. Shock. 48, 85-93
5. 5.Iketani M, Ohsawa I. (2017) Molecular Hydrogen as a Neuroprotective Agent. Curr Neuropharmacol. 15, 324-331
6. 6.Hamanoue M, Morioka K, Ohsawa I, Ohsawa K, Kobayashi M, Tsuburaya K, Akasaka Y, Mikami T, Ogata T, Takamatsu K. (2016) Cell-permeable p38 MAP kinase promotes migration of adult neural stem/progenitor cells. Sci Rep. 6, 24279
7. 7.Ishigaki M, Iketani M, Sugaya M, Takahashi M, Tanaka M, Hattori S, Ohsawa I. (2016) STED super-resolution imaging of mitochondria labeled with TMRM in living cells. Mitochondrion. 28, 79-87
8. 8.Takahashi K, Ohsawa I, Shirasawa T, Takahashi M. (2016) Early-onset motor impairment and increased accumulation of phosphorylated α-synuclein in the motor cortex of normal aging mice are ameliorated by coenzyme Q. Exp Gerontol. 81, 65-75
9. 9.Igarashi T, Ohsawa I, Kobayashi M, Igarashi T, Suzuki H, Iketani M, Takahashi H. (2016) Hydrogen prevents corneal endothelial damage in phacoemulsification cataract surgery. Sci Rep. 6, 31190
10. 10.Shimada S, Wakayama K, Fukai M, Shimamura T, Ishikawa T, Fukumori D, Shibata M, Yamashita K, Kimura T, Todo S, Ohsawa I, Taketomi A. (2016) Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver. Artif Organs. 40, 1128-1136
11. 11.Nakata K, Yamashita N, Noda Y, Ohsawa I. (2015) Stimulation of human damaged sperm motility with hydrogen molecule. Med Gas Res. 5, 2
12. 12.Nakashima Y, Ohsawa I, Nishimaki K, Kumamoto S, Maruyama I, Suzuki Y, Ohta S. (2014) Preventive effects of Chlorella on skeletal muscle atrophy in muscle-specific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice. BMC Complement Altern Med. 14, 390
13. 13.Takahashi K, Noda Y, Ohsawa I, Shirasawa T, Takahashi M. (2014) Extended lifespan, reduced body size and leg skeletal muscle mass, and decreased mitochondrial function in clk-1 transgenic mice. Exp Gerontol. 58, 146-153
14. 14.Muto J, Lee H, Lee H, Uwaya A, Park J, Nakajima S, Nagata K, Ohno M, Ohsawa I, Mikami T. (2014) Oral administration of inosine produces antidepressant-like effects in mice. Sci Rep. 4, 4199
15. 15.Sasaki T, Mogi S, Kaneko T, Kojima H, Katoh S, Sano A, Kojima S. (2014) Relationship between tissue hydroxyl radical and oxidatively modified macromolecule levels. Geriatr Gerontol Int. 14, 498-507
16. 16.Tanisawa K, Mikami E, Fuku N, Honda Y, Honda S, Ohsawa I, et al. (2013) Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes. BMC Genomics 14, 248
17. 17.Iio A, Ito M, Itoh T, Terazawa R, Fujita Y, Nozawa Y, Ohsawa I, Ohno K, Ito M. (2013) Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells. Med Gas Res 3, 6
18. 18.Higashi M, Ohsawa I, Oda F, Yamada Y, Kawana S, Iida K, Mitsuishi T. (2013) Histamine H1-receptor antagonistic drug olopatadine suppresses TSLP in atopic dermatitis model mice. Allergol Int. 62, 137-138
19. 19.Mitsuishi T, Ohsawa I, Kato T, Egawa N, Kiyono T. (2013) Molecular cloning and characterisation of a novel type of human papillomavirus 160 isolated from a flat wart of an immunocompetent patient. PLoS One. 8, e79592
20. 20.Sasaki, T., Tahara, S., Shinkai, T., Kuramoto, K., Matsumoto, S., Yanabe, M., Takagi, S., Kondo, H., and Kaneko, K. (2013) Lifespan extension in the spontaneous dwarf rat and enhanced resistance to hyperoxia-induced mortality. Exp. Gerontol., 48, 457-463
21. 21.Takahashi K, Takahashi M. (2013) Exogenous administration of coenzyme Q10 restores mitochondrial oxygen consumption in the aged mouse brain. Mechanisms of Aging and Development, 134, 580-586
22. 22.Hoshi H, Hao W, Fujita Y, Funayama A, Miyauchi Y, Hashimoto K, Miyamoto K, Iwasaki R, Sato Y, Kobayashi T, Miyamoto H, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Kitagawa K, Nakayama KI, Kawamoto T, Sano M, Fukuda K, Ohsawa I, Ohta S, Morioka H, Matsumoto M, Chiba K, Toyama Y, Miyamoto T. (2012) Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. J Bone Miner Res. 27, 2015-2023
23. 23.Takahashi, M., Shimizu, T., Shirasawa, T. (2012) Reversal of slow growth and heartbeat through restoration of mitochondrial functions in clk-1-deficient mouse embryos by exogenous administration of coenzyme Q10. Exp. Gerontol. 47, 425-431
24. 24.Takahashi, M., Ogawara, M., Shimizu, T., Shirasawa, T. (2012) Restoration of the behavioral rates and lifespan in clk-1 mutant nematodes in response to exogenous CoQ10. Exp. Gerontol. 47, 276-279
25. 25.Terasaki, Y., Ohsawa, I., Terasaki, M., Takahashi, M., Kunugi, S., Dedong, K., Urushiyama, H., Amenomori, S., Kaneko-Togashi, M., Kuwahara, N., Ishikawa, A., Kamimura, N., Ohta, S., Fukuda, Y. (2011) Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am. J. Physiol. Lung Cell Mol. Physiol. 301, L415-426
26. 26.Kamimura, N., Nishimaki, K., Ohsawa, I., Ohta, S. (2011) Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity. 19, 1396-1403
27. 27.Mitsuishi, T., Kabashima, K., Tanizaki, H., Ohsawa, I., Oda, F., Yamada, Y., Halifu, Y., Kawana, S., Kato, T., Iida, K. (2011) Specific substance of Maruyama (SSM) suppresses immune responses in atopic dermatitis-like skin lesions in DS-Nh mice by modulating dendritic cell functions. J. Dermatol. Sci. 63, 184-190
28. 28.Wu, I.-C., Ohsawa, I., Fuku, N., and Tanaka, M. (2010). Metabolic analysis of 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Anal. N.Y. Academy Sci. 1201, 111-120.
29. 29.Wolf, AM., Asoh, S., Hiranuma, H., Ohsawa, I., Iio, K., Satou, A., Ishikura, M., and Ohta, S. (2010). Astaxanthin protects mitochondrial redox state and functional integrity against oxidative stress. J. Nutr. Biochem. 21, 381-389.
30. 30.Mitsuishi, T., Iwabu, Y., Tokunaga, K., Sata, T., Kaneko, T., Ohara, K., Ohsawa, I., Oda, F., Yamada, Y., Kawana, S., Ozaki, K., Nakatake, M., and Yamada, O. (2010). Combined analysis of cell growth and apoptosis-regulating proteins in HPVs associated anogenital tumors. BMC Cancer 10:118, doi:10.1186/1471-2407-10-118.
31. 31.Nakajima, S., Ohsawa, I., Ohta, S., Ohno, M., and Mikami, T. (2010). Regular voluntary exercise cures stress-induced impairment of cognitive function and cell proliferation accompanied by increases in cerebral IGF-1 and GST activity in mice. Behav. Brain Res. 211, 178-184.
32. 32.Oharazawa, H., Igarashi, T., Yokota, T., Fujii, H., Suzuki, H., Machide, M., Takahashi, H., Ohta, S., and Ohsawa, I. (2010). Rapid Diffusion of Hydrogen Protects the Retina: Administration to the Eye of Hydrogen-Containing Saline in Retinal Ischemia-Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 51, 487-492.
33. 33.Takahashi, M. and Shirasawa, T. (2010). Functions of the gerontogene clk-1 in mammals. Biomedical Gerontology 34, 25-31
34. 34.Endo, J., Sano, M., Katayama, T., Hishiki, T., Shinmura, K., Morizane, S., Matsuhashi, T., Katsumata, Y., Zhang, Y., Ito, H., Nagahata, Y., Marchitti, S., Nishimaki, K., Wolf, A.M., Nakanishi, H., Hattori, F., Vasiliou, V., Adachi, T., Ohsawa, I., Taguchi, R., Hirabayashi, Y., Ohta, S., Suematsu, M., Ogawa, S., and Fukuda, K. (2009). Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Circ Res. 105, 1118-1127.
35. 35.Nakashima, Y., Ohsawa, I., Konishi, F., Hasegawa, T., Kumamoto, S., Suzuki, Y., and Ohta, S. (2009). Preventive effects of Chlorella on cognitive decline in age-dependent dementia model mice. Neurosci. Lett. 464, 193-198.
36. 36.Suzuki, Y., Sano, M., Hayashida, K., Ohsawa, I., Ohta, S., and Fukuda, K. (2009). Are the effects of -glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett. 583, 2157-2159.
37. 37.Nakajima, S., Ohsawa, I., Nagata, K., Ohta, S., Ohno, M., Ijichi, T., and Mikami, T. (2009). Oral supplementation with melon superoxide dismutase extract promotes antioxidant defences in the brain and prevents stress-induced impairment of spatial memory. Behav. Brain Res. 200, 15-21.
38. 38.Fu, Y., Ito, M., Fujita, Y., Ito, M., Ichihara, M., Masuda, A., Suzuki, Y., Maesawa, S., Kajita, Y., Hirayama, M., Ohsawa, I., Ohta, S., and Ohno, K. (2009). Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. Neurosci. Lett. 453, 81-85.
39. 39.Nagata, K., Nakashima-Kamimura, N., Mikami, T., Ohsawa, I., and Ohta, S. (2009). Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsycopharmacology. 34, 501-508.
40. 40.Murakami, Y., Ohsawa, I., Kasahara, T., and Ohta, S. (2009). Cytoprotective role of mitochondrial amyloid β peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde. Neurobiol. Aging. 30, 325-329.
41. 41.Harita, Y., Kurihara, H., Kosako, H., Tezuka, T., Sekine, T., Igarashi, T., Ohsawa, I., Ohta, S., and Hattori, S. (2009). Phosphorylation of nephrin triggers Ca2+ signaling by recruitment and activation of phospholipase C-γ1. J. Biol. Chem. 284, 8951-8962.
42. 42.Nakashima-Kamimura, N., Mori, T., Ohsawa, I., Asoh, S., and Ohta, S. (2009). Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother. Pharmacol. 64, 753-761
43. 43.Ohsawa, I., Nishimaki, K., Murakami, Y., Suzuki, Y., Ishikawa, M., and Ohta, S. (2008). Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial ALDH2 activity. J. Neurosci. 28, 6239-6249.
44. 44.Wolf, A.M., Asoh, S., Ohsawa, I., and Ohta, S. (2008). Imaging mitochondrial redox environment and oxidative stress using a redox-sensitive fluorescent protein. J. Nippon Med. Sch. 75, 66-67.
45. 45.Katsura, K.I., Takahashi, K., Asoh, S., Watanabe, M., Sakurazawa, M., Ohsawa, I., Mori, T., Igarashi, H., Ohkubo, S., Katayama, Y., and Ohta, S. (2008). Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat. J. Neurochem. 106, 258-270.
46. 46.Watanabe, M., Katsura, K.I., Ohsawa, I., Mizukoshi, G., Takahashi, K., Asoh, S., Ohta, S., and Katayama, Y. (2008). Involvement of mitoK(ATP) channel in protective mechanisms of cerebral ischemic tolerance. Brain Res. 1238, 199-207.
47. 47.Hayashida, K., Sano, M., Ohsawa, I., Shinmura, K., Tamaki, K., Kimura, K., Endo, J., Katayama, T., Kawamura, A., Kohsaka, S., Makino, S., Ohta, S., Ogawa, S., and Fukuda, K. (2008). Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem. Biophys. Res. Commun. 373, 30-35.
48. 48.Ohsawa, I., Nishimaki, K., Yamagata, K., Ishikawa, M., and Ohta, S. (2008). Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem. Biophys. Res. Commun. 377, 1195-1198.
49. 49.Kogiku, M., Ohsawa, I., Matsumoto, K., Sugisaki, Y., Takahashi, H., Teramoto, A., and Ohta, S. (2008). Prognosis of glioma patients by combined immunostaining for survivin, Ki-67 and epidermal growth factor receptor. J. Clin. Neurosci. 15, 1198-1203.
50. 50.Takahashi, M., Shimizu, T., Moriizumi, E. & Shirasawa, T. (2008). Clk-1 deficiency induces apoptosis associated with mitochondrial dysfunction in mouse embryos. Mech Ageing Dev 129, 291-8.
51. 51.Kim, J., Takahashi, M., Shimizu, T., Shirasawa, T., Kajita, M., Kanayama, A. & Miyamoto, Y. (2008). Effects of a potent antioxidant, platinum nanoparticle, on the lifespan of Caenorhabditis elegans. Mech Ageing Dev 129, 322-31.
52. 52.Fukuda, K., Asoh, S., Ishikawa, M., Yamamoto.Y., Ohsawa, I., and Ohta.S. (2007). Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem. Biophys. Res. Commun. 361, 670-674
53. 53.Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., Katsura, K.-I., Katayama, Y., Asoh, S., and Ohta, S. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 13, 688-694.