title: Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.
abstract: Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.
authors: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation Foundation for Biomedical Research and Innovation 2-2 Minatojima- Minamimachi Chuo-ku, Kobe 650-0047 Japan.
authors: Yoko
authors: Y
authors: Nabeshima
authors: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation Foundation for Biomedical Research and Innovation 2-2 Minatojima- Minamimachi Chuo-ku, Kobe 650-0047 Japan.
authors: Miwa
authors: M
authors: Washida
authors: Genetic Strains Research Center, Mammalian Genetics Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors: Masaru
authors: M
authors: Tamura
authors: Genetic Strains Research Center, Mammalian Genetics Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors: Akiteru
authors: A
authors: Maeno
authors: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 190 Longwood Ave, Boston, Massachusetts, USA.
authors: Mutsuko
authors: M
authors: Ohnishi
authors: Genetic Strains Research Center, Mammalian Genetics Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors: Toshihiko
authors: T
authors: Shiroishi
authors: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation Foundation for Biomedical Research and Innovation 2-2 Minatojima- Minamimachi Chuo-ku, Kobe 650-0047 Japan.
authors: Akihiro
authors: A
authors: Imura
authors: 1] Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 190 Longwood Ave, Boston, Massachusetts, USA [2] Department of Applied Oral Sciences, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts, USA.
authors: M Shawkat
authors: MS
authors: Razzaque
authors: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation Foundation for Biomedical Research and Innovation 2-2 Minatojima- Minamimachi Chuo-ku, Kobe 650-0047 Japan.
authors: Yo-ichi
authors: Y
authors: Nabeshima
mesh_terms: D000375:Aging; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D018345:Mice, Knockout; D010641:Phenotype; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D061205:Vascular Calcification / Q000097:blood / Q000188:drug therapy
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C572617:N-1-(hydroxy(3-oxo-2-phenyl-1-cyclopropen-1-yl)methyl)-2-methylpropyl-2-benzenesulfonylamino-4-methylpentanamide; D013449:Sulfonamides; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002154:Calpain; C112682:Capn1 protein, mouse