Augmented Wnt signaling in a mammalian model of accelerated aging.
The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.
Liu
Hongjun
H
Cardiology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Fergusson
Maria M
MM
Castilho
Rogerio M
RM
Liu
Jie
J
Cao
Liu
L
Chen
Jichun
J
Malide
Daniela
D
Rovira
Ilsa I
II
Schimel
Daniel
D
Kuo
Calvin J
CJ
Gutkind
J Silvio
JS
Hwang
Paul M
PM
Finkel
Toren
T
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism; D002452:Cell Count; D002460:Cell Line; D048430:Cell Shape; D016922:Cellular Senescence / Q000502:physiology*; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051155:Wnt1 Protein / Q000378:metabolism; D060508:Wnt3 Protein
D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D005966:Glucuronidase; D000090265:Klotho Proteins