title: Premature aging in klotho mutant mice: cause or consequence?
abstract: Suitable mammalian models for aging with a wide range of age-associated pathology are desirable to study molecular mechanisms of human aging. Recent studies have identified that fibroblast growth factor 23 (Fgf-23) null mice and klotho hypomorphs could generate multiple premature aging-like features, including shortened lifespan, infertility, kyphosis, atherosclerosis, extensive soft tissue calcifications, skin atrophy, muscle wasting, T cell dysregulation, pulmonary emphysema, osteoporosis/osteopenia, abnormal mineral ion metabolism, and impaired vitamin-D homeostasis. The strikingly similar in vivo phenotypes of two separate genetically altered mouse lines implicate that the premature aging-like features may be partly regulated through a common signaling pathway involving both Fgf-23 and klotho; such speculation is experimentally supported by the observation that Fgf-23 requires klotho as a cofactor to exert its functions. Despite about 2000-fold higher serum levels of Fgf-23 in klotho mutants (compared to wild-type animals), these mice show physical, biochemical and morphological features similar to Fgf-23 null mice, but not as Fgf-23 transgenic mice; these observations suggest that widely encountered premature aging-like features in klotho mutant mice are due to the inability of Fgf-23 to exert its bioactivities in absence of klotho. The results of recent studies showing klotho as a cofactor in Fgf-23 signaling consequently explains that the premature aging-like features in klotho-deficient mice is not a primary cause, rather a consequence of lacking Fgf-23 activity. These understandings will help us to redefine the role of klotho as an aging factor.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Research and Educational Building, 190 Longwood Avenue, Boston, MA 02115, USA. beate_lanske@hsdm.harvard.edu
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: M Shawkat
authors.initials: MS
authors.lastname: Razzaque
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D009154:Mutation; D015398:Signal Transduction
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins