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Molecular Regulation of Aging


Theme Leader :
Akihito Ishigami, Ph.D.
Associate Researcher :
Tomoko Funakoshi, Ph.D.
Adjunct Researcher :
Setsuko Handa, Yuka Takino, M.S.


aging, aging regulation, aging biomarker, antioxidant, ascorbic acid, senescence marker protein-30 (SMP30), gluconolactonase, vitamin C, reactive oxygen species, life span, Peptidylarginine deiminase (PAD), citrullinated protein, Alzheimer's disease, chronic obstructive pulmonary disease (COPD)

Major Research Titles

  1. 1.Vitamin C and aging
  2. 2.Vitamin C and chronic obstructive pulmonary disease (COPD)
  3. 3.Biomarkers of aging and their clinical applications
  4. 4.Citrullinated protein and Alzheimer's disease


Humans gradually deteriorate physiologically with aging as multiple biological events foster changes in the expression of critical molecules and thereby promote organic breakdown. The aim of our research group is early detection of these destructive factors by developing methodologies to analyze the relevant genes and proteins, then precisely controlling their activities.
We have discovered that the biomolecule SMP30, which acts to strengthen cellular resistance to both internal and external bodily injury, decreases in quantity and function with aging. Therefore, SMP30 is expected to become extremely useful as a biomarker of aging. Similarly, citrullinated protein has an important physiological purpose by forming the cornified layer of skin that covers the human body. Despite this beneficial function, citrullinated protein also has a negative side, because our recent research has shown that this protein's accumulation in the brain is a possible cause of Alzheimer's disease.
The aging continuum is a thread to which many biomolecules are bound; both environmental and hereditary factors contribute such molecules to mutually complex interactions. Our research is devoted to untying that thread precisely and usefully in the expectation of contributing to humanity the capacity for satisfying and healthful longevity.


  1. 1. Nishijima K, Ohno T, Amano A, Kishimoto Y, Kondo Y, Ishigami A, Tanaka S. : Bone Degeneration and Its Recovery in SMP30/GNL-Knockout Mice. J Nutr Health Aging. 2017;21(5):573-578.
  2. 2. Jang B, Jeon YC, Shin HY, Lee YJ, Kim H, Kondo Y, Ishigami A, Kim YS, Choi EK. : Myelin Basic Protein Citrullination, a Hallmark of Central Nervous System Demyelination, Assessed by Novel Monoclonal Antibodies in Prion Diseases. Mol Neurobiol. 2017 May 3.
  3. 3. Nakabo S, Hashimoto M, Ito S, Furu M, Ito H, Fujii T, Yoshifuji H, Imura Y, Nakashima R, Murakami K, Kuramoto N, Tanaka M, Satoh J, Ishigami A, Morita S, Mimori T, Ohmura K. : Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies. Rheumatology (Oxford). 2017 Apr 7.
  4. 4. Takahashi K, Yanai S, Shimokado K, Ishigami A. : Coffee consumption in aged mice increases energy production and decreases hepatic mTOR levels. Nutrition. 2017 Jun;38:1-8.
  5. 5. Takigawa M, Masutomi H, Kishimoto Y, Shimazaki Y, Hamano Y, Kondo Y, Arai T, Lee J, Ishii T, Mori Y, Ishigami A. : Time-dependent alterations of vancomycin-induced nephrotoxicity in mice. Biol Pharm Bull. (in press)
  6. 6. Amano A, Kondo Y, Noda Y, Ohta M, Kawanishi N, Machida S, Mitsuhashi K, Senmaru T, Fukui M, Takaoka O, Mori T, Kitawaki J, Ono M, Saibara T, Obayashi H, Ishigami A. : Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase-knockout mice. Arch Biochem Biophys. 622, 47-58 (2017) Mar 21. pii: S0003-9861(17)30177-7.
  7. 7. Takahashi K, Takisawa S, Shimokado K, Kono N, Arai H, Ishigami A. : Age-related changes of vitamin E: α-tocopherol levels in plasma and various tissues of mice and hepatic α-tocopherol transfer protein. Eur J Nutr. 2017 Apr;56(3):1317-1327.
  8. 8. Sato Y, Uchida E, Aoki H, Hanamura T, Nagamine K, Kato H, Koizumi T, Ishigami A. : Acerola (Malpighia emarginata DC.) Juice Intake Suppresses UVB-Induced Skin Pigmentation in SMP30/GNL Knockout Hairless Mice. PLoS One. 2017 Jan 23;12(1):e0170438.
  9. 9. Umeda N, Matsumoto I, Tanaka Y, Kawaguchi H, Ebe H, Kagami Y, Ishigami A, Sumida T. : Anti-cyclic citrullinated glucose-6-phosphate isomerase peptide -7 (CCG-7) antibodies were suppressed by biologics treatment and deposited to citrullinated proteins in CD68-positive cells in the RA synovium. Mod Rheumatol. 2017 Jan 4:1-7.
  10. 10. Kunimura Y, Iwata K, Ishigami A, Ozawa H. : Age-related alterations in hypothalamic kisspeptin, neurokinin B, and dynorphin neurons and in pulsatile LH release in female and male rats. Neurobiol Aging. 2017 Feb;50:30-38.
  11. 11. Shuto T, Kamei S, Nohara H, Fujikawa H, Tasaki Y, Sugahara T, Ono T, Matsumoto C, Sakaguchi Y, Maruta K, Nakashima R, Kawakami T, Suico MA, Kondo Y, Ishigami A, Takeo T, Tanaka KI, Watanabe H, Nakagata N, Uchimura K, Kitamura K, Li JD, Kai H. : Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases. Sci Rep. 2016 Dec 16;6:39305.
  12. 12. Koizumi M, Kondo Y, Isaka A, Ishigami A, Suzuki E. : Vitamin C impacts anxiety-like behavior and stress-induced anorexia relative to social environment in SMP30/GNL knockout mice. Nutr Res. 2016 Nov 17. pii: S0271-5317(16)30672-8.
  13. 13. Sase T, Arito M, Onodera H, Omoteyama K, Kurokawa MS, Kagami Y, Ishigami A, Tanaka Y, Kato T. : Hypoxia-induced production of peptidylarginine deiminases and citrullinated proteins in malignant glioma cells. Biochem Biophys Res Commun. 2016 Nov 3. pii: S0006-291X(16)31792-2.
  14. 14. Masutomi H, Kawashima S, Kondo Y, Uchida Y, Jang B, Choi EK, Kim YS, Shimokado K, Ishigami A. : Induction of peptidylarginine deiminase 2 and 3 by dibutyryl cAMP via cAMP-PKA signaling in human astrocytoma U-251MG cells. J Neurosci Res. 2016 Oct 5.
  15. 15. Wizeman JW, Nicholas AP, Ishigami A, Mohan R. : Citrullination of glial intermediate filaments is an early response in retinal injury. Mol Vis. 2016 Sep 26;22:1137-1155.
  16. 16. Lee KM, Lee Y, Chun HJ, Kim AH, Kim JY, Lee JY, Ishigami A, Lee J. : Neuroprotective and anti-inflammatory effects of morin in a murine model of Parkinson's disease. J Neurosci Res. 2016 Oct;94(10):865-78.
  17. 17. Kadowaki S, Shishido T, Sasaki T, Sugai T, Narumi T, Honda Y, Otaki Y, Kinoshita D, Takahashi T, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Watanabe T, Ishigami A, Takeishi Y, Kubota I. : Deficiency of Senescence Marker Protein 30 Exacerbates Cardiac Injury after Ischemia/Reperfusion. Int J Mol Sci. 2016 Apr 11;17(4):542.
  18. 18. Takahashi R, Ishigami A, Kobayashi Y, Nagata K. : Skewing of peritoneal resident macrophages toward M1-like is involved in enhancement of inflammatory responses induced by secondary necrotic neutrophils in aged mice. Cell Immunol. 2016 Jun-Jul;304-305:44-8.
  19. 19. Yamauchi H, Miura S, Owada T, Saitoh S, Machii H, Yamada S, Ishigami A, Takeishi Y. : Senescence marker protein-30 deficiency impairs angiogenesis under ischemia. Free Radic Biol Med. 2016 May;94:66-73. doi: 10.1016/j.freeradbiomed.2016.02.020. Epub 2016 Feb 19.
  20. 20. Takahashi R, Totsuka S, Ishigami A, Kobayashi Y, Nagata K. : Attenuated phagocytosis of secondary necrotic neutrophils by macrophages in aged and SMP30 knockout mice. Geriatr Gerontol Int. 2016 Jan;16(1):135-42.
  21. 21. Kondo Y, Ishigami A. : (REVIEW ARTICLE) Involvement of senescence marker protein-30 in glucose metabolism disorder and nonalchoholic fatty liver disease. Geriatr Gerontol Int. 2016 Mar;16 Suppl 1:4-16. doi: 10.1111/ggi.12722. Review.
  22. 22. Umeda N, Matsumoto I, Kawaguchi H, Kurashima Y, Kondo Y, Tsuboi H, Ogishima H, Suzuki T, Kagami Y, Sakyu T, Ishigami A, Maruyama N, Sumida T. : Prevalence of soluble peptidylarginine deiminase 4 (PAD4) and anti-PAD4 antibodies in autoimmune diseases. Clin Rheumatol. 2016 May;35(5):1181-8.

  23. 23. Kodama, Y., Kishimoto, Y., Muramatsu, Y., Tatebe, J., Yamamoto, Y., Hirota, N., Itoigawa, Y., Atsuta, R., Koike, K., Sato, T., Aizawa, K., Takahashi, K., Morita, T., Homma, S., Seyama, K., Ishigami, A. : Antioxidant nutrients in plasma of Japanese patients with chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome, and bronchial asthma. Clin. Repir. J. (2016) (in press)