Molecular Regulation of Aging

Members

Theme Leader :
Yoshitaka Kondo, Ph.D.
Researcher :
Maki Takami, Ph.D.

Keywords

healthy longevity, aging regulation, nutrition, diet, macronutrient, protein, metabolic health, frailty, dementia, vitamin C, ascorbic acid, senescence marker protein-30 (SMP30), gluconolactonase, antioxidant, epigenetics, DNA demethylation.

Major Research Titles

  1. Nutrition and aging
  2. Aging and vitamin C

Profile

The molecular regulation of aging aims to achieve healthy longevity by unraveling the relationship between nutrition and aging.
A well-balanced diet has long been recommended as a secret to longevity. However, what exactly is a well-balanced diet? Lately, much attention has been paid to the relationship between the caloric ratio of macronutrients (protein, carbohydrates, and fats) and health, aging, and longevity. Recently, we have found that the optimal dietary protein ratio for maintaining metabolic health in mice toward old age is 25%-35%. We are now exploring whether getting the right balance of macronutrients can help prevent problems such as frailty, muscle loss, and dementia, and increase the number of healthy years.
We also focus on the relationship between aging and vitamin C. We have independently generated vitamin C synthesis-deficient mice (SMP30-knockout mice), which cannot synthesize vitamin C like humans, and revealed that long-term vitamin C deficiency shortened the lifespan. Vitamin C is deeply involved in the regulation of gene expression through epigenetics as a cofactor for DNA demethyltransferases. The shortened lifespan caused by vitamin C deficiency may be attributed to epigenetic abnormalities.

References

  1. Kondo Y, Aoki H, Masuda M, Nishi H, Noda Y, Hakuno F, Takahashi SI, Chiba T, Ishigami A. Moderate protein intake percentage in mice for maintaining metabolic health during approach to old age. GeroScience 45(4), 2707-2726, 2023
  2. Sato A, Kondo Y, Ishigami A. The evidence to date: implications of l-ascorbic acid in the pathophysiology of aging. J Physiol Sci 74(1), 29, 2024
  3. Yamaguchi T, Yamamoto Y, Egashira K, Sato A, Kondo Y, Saiki S, Kimura M, Chikazawa T, Yamamoto Y, Ishigami A, Murakami S. Oxidative Stress Inhibits Endotoxin Tolerance and May Affect Periodontitis. J Dent Res 102(3):331-339, 2023
  4. Saga R, Uchida T, Takino Y, Kondo Y, Kobayashi H, Kinoshita M, Saitoh D, Ishigami A, Makishima M. Radiation-induced gastrointestinal syndrome is exacerbated in vitamin C-insufficient SMP30/GNL knockout mice. Nutrition 81, 110931, 2021
  5. Kawahori K, Kondo Y, Yuan X, Kawasaki Y, Hanazawa N, Tsujimoto K, Wada F, Kohda T, Ishigami A, Yamada T, Ogawa Y, Hashimoto K. Ascorbic acid during suckling period is required for proper DNA demethylation in the liver. Sci Rep 10(1), 21228, 2020
  6. Takino Y, Aoki H, Kondo Y, Ishigami A. Acerola (Malpighia emarginata DC.) promotes ascorbic acid uptake into human intestinal Caco-2 cells via enhancing the gene expression of sodium-dependent vitamin C transporter 1. J Nutr Sci Vitaminol 66(4), 296-299, 2020
  7. Ito S, Sairenchi T, Machida T, Takino Y, Kondo Y, Mukai K, Kobashi G, Ishigami A, Senoo T. Reduced aqueous humour ascorbic-acid concentration in women with smaller anterior chamber depth. Sci Rep 9(1), 372, 2019
  8. Amano A, Kondo Y, Noda Y, Ohta M, Kawanishi N, Machida S, Mitsuhasi 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 female aromatase-knockout mice. Arch Biochem Biophys 622, 47-58, 2017
  9. 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 21(5), 573-578, 2017
  10. Kondo Y, Ishigami A. Involvement of senescence marker protein-30 in glucose metabolism disorder and nonalchoholic fatty liver disease. Geriatr Gerontol Int 16 (Suppl. 1), 4-16, 2016
  11. 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 36(12), 1379-1391, 2016
  12. 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 K, Watanabe H, Nakagata N, Uchimura K, Kitamura K, Li J, Kai H. Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases. Sci Rep 6, 39305, 2016
  13. Okada H, Senmaru T, Fukui M, Kondo Y, Ishigami A, Maruyama N, Obayashi H, Yamazaki M, Nakamura N, Hasegawa G. Senescence marker protein-30/gluconolactonase deficiency exacerbates diabetic nephropathy through tubular injury in a mouse model of type 1 diabetes. J Diabetes Investig 6(1), 35-43, 2015
  14. Kondo Y, Sakuma R, Ichisawa M, Ishihara K, Kubo M, Handa S, Mugita H, Maruyama N, Koga H, Ishigami A. Potato chip intake increases ascorbic acid levels and decreases reactive oxygen species in SMP30/GNL knockout mouse tissues. J Agric Food Chem 62 (38), 9286-9295, 2014
  15. Kondo Y, Masutomi H, Noda Y, Ozawa Y, Takahashi T, Handa S, Maruyama N, Shimizu T, Ishigami A. Senescence marker protein-30/Superoxide dismutase 1 double knockout mice exhibits increased oxidative stress and hepatic steatosis. FEBS Open Bio 4, 522-532, 2014
  16. Kondo Y, Hasegawa G, Okada H, Senmaru T, Fukui M, Nakamura N, Sawada M, Kitawaki J, Okanoue T, Kishimoto Y, Amano A, Maruyama N, Obayashi H, Ishigami A. Leprdb/db mice with senescence marker protein-30 knockout (Leprdb/dbSmp30Y/-) exhibit increases in small dense-LDL and severe fatty liver despite being fed a standard diet. PLoS ONE 8(6), e65698, 2013
  17. Kagami Y, Kondo Y, Handa S, Maruyama N, Ishigami A. Senescence marker protein-30 (SMP30)/ gluconolactonase (GNL) expression in the mouse ovary during gestation. Biol Pharm Bull 36(12), 2005-2008, 2013
  18. Kondo Y, Higashi C, Iwama M, Ishihara K, Handa S, Mugita H, Maruyama N, Koga H, Ishigami A. Bioavailability of vitamin C from mashed potatoes and potato chips after oral administration in healthy Japanese men. Brit J Nutr 107(6), 885-892, 2012
  19. Iwama M, Kondo Y, Shimokado K, Maruyama N, Ishigami A. Uric acid levels in tissues and plasma of mice during aging. Biol. Pharm. Bull 35, 1367-1370, 2012
  20. Saito K, Yokoyama T, Yoshida H, Kim H, Shimada H, Yoshida Y, Iwasa H, Shimizu Y, Kondo Y, Handa S, Maruyama N, Ishigami A, Suzuki T. A significant relationship between plasma vitamin C concentration and physical performance among Japanese elderly women : Comparison in healthy Japanese subjects. J Gerontol A Biol Sci Med Sci 67(3), 295-301, 2012
  21. Senmaru T, Yamasaki M, Okada H, Asano M, Fukui M, Nakamura N, Obayashi H, Kondo Y, Maruyama N, Ishigami A, Hasewawa G. Pancreatic insulin release in vitamin C-deficient senescence marker protein-30/gluconolactonase knockout mice. J Clin Biochem Nutr 50(2), 114-118, 2012
  22. Ishikawa Y, Hashizume K, Kishimoto S, Tezuka Y, Nishigori H, Yamamoto N, Kondo Y, Maruyama N, Ishigami A, Kurosaka D. Effect of vitamin C-depletion on UVR-B induced cataract in SMP30/GNL knockout mice. Exp Eye Res 94(1), 85-89, 2012
  23. Uchida E, Kondo Y, Amano A, Aizawa S, Hanamura T, Aoki H, Nagamine K, Koizumi T, Maruyama N, Ishigami A. Absorption and excretion of ascorbic acid alone and in acerola (Malpighia emarginata DC.) juice: Comparison in healthy Japanese subjects. Biol Pharm Bull 34(11), 1744-1747, 2011
  24. Koike K, Kondo Y, Sekiya M, Sato Y, Tobino K, Iwakami S, Goto S, Takahashi K, Maruyama N, Seyama K, Ishigami A. Complete lack of vitamin C intake generates pulmonary emphysema in senescence marker protein-30 knockout mice. Am J Physiol Lung Cell Mol Physiol 298(6), L784-L792, 2010
  25. Maruyama N, Ishigami A, Kondo Y. Pathophysiological significance of senescence marker protein-30. Geriatr Gerontol Int 10 (Suppl. 1), S88-S98, 2010
  26. Hasegawa G, Yamasaki M, Kadono M, Tanaka M, Asano M, Senmaru T, Kondo Y, Fukui M, Obayashi H, Maruyama N, Nakamura N, Ishigami A. Senescence Marker Protein-30/Gluconolactonase deletion worsens glucose tolerance through impairment of acute insulin secretion. Endocrinology 151(2), 529-536, 2010
  27. Kashio A, Amano A, Kondo Y, Sakamoto T, Iwamura H, Suzuki M, Ishigami A, Yamasoba T. Effect of vitamin C depletion on age-related hearing loss in SMP30/GNL knockout mice. Biochem Biophys Res Commun 390(3), 394-398, 2009
  28. Arai KY, Sato Y, Kondo Y, Kudo C, Tsuchiya H, Nomura Y, Ishigami A, Nishiyama T. Effects of vitamin C deficiency on the skin of the senescence marker protein-30 (SMP30) knockout mouse. Biochem Biophys Res Commun 385, 478-483, 2009
  29. Kondo Y, Sasaki T, Sato Y, Amano A, Iwama M, Handa S, Shimada N, Fukuda M, Akita M, Lee J, Jeong KS, Maruyama N, Ishigami A. Vitamin C depletion increases superoxide generation in brains of SMP30/GNL knockout mice. Biochem Biophys Res Commun 377, 291-296, 2008
  30. Sato Y, Kajiyama S, Amano A, Kondo Y, Sasaki T, Handa S, Takahashi R, Fukui M, Hasegawa G, Nakamura N, Fujinawa H, Mori T, Ohta M, Obayashi H, Maruyama N, Ishigami A. Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun 375, 346-350, 2008
  31. Furusawa H, Sato Y, Tanaka Y, Inai Y, Amano A, Iwama M, Kondo Y, Handa S, Murata A, Nishikimi M, Goto S, Maruyama N, Takahashi R, Ishigami A. Vitamin C is not essential for carnitine biosynthesis in vivo: Verification in vitamin C-depleted SMP30/GNL knockout mice. Biol Pharm Bull 31, 1673-1679, 2008
  32. Kondo Y, Inai Y, Sato Y, Handa S, Kubo S, Shimokado K, Goto S, Nishikimi M, Maruyama N., Ishigami A. Senescence marker protein 30 functions as gluconolactonase in L-ascorbic acid biosynthesis, and its knockout mice are prone to scurvy. Proc Nat Acad Sci USA 103, 5723-5728, 2006
  33. Ishigami A, Fujita T, Inoue H, Handa S, Kubo S, Kondo Y, Maruyama N. Senescence Marker Protein-30 (SMP30) induces formation of microvilli and bile canaliculi in Hep G2 cells. Cell & Tissue Res 320, 243-249, 2005
  34. Kondo Y, Ishigami A, Kubo S, Handa S, Gomi K, Hirokawa K, Kajiyama N, Chiba T, Shimokado K, Maruyama N. Senescence marker protein-30 is a unique enzyme that hydrolyzes diisopropyl phosphorofluoridate (DFP) in the liver. FEBS Lett 570, 57-62, 2004
  35. Ishigami A, Kondo Y, Nanba R, Ohsawa T, Handa S, Kubo S, Akita M, Maruyama N. SMP30 deficiency in mice causes an accumulation of neutral lipids and phospholipids in the liver and shortens the life span. Biochem Biophys Res Commun 315, 575-580, 2004
  36. Feng D, Kondo Y, Ishigami A, Kuramoto M, Machida T, Maruyama N. Senescence Marker Protein-30 as a Novel Antiaging Molecule. Ann NY Acad Sci 1019, 360-364, 2004