Premature aging in klotho mutant mice: Cause or consequence?

Abstract

Suitable mammalian models for aging with 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 2,000 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. Keywords FGF-23; Kotho; Vitamin-D; Calcification; Premature aging Phosphate homeostasisMaintaining phosphate homeostasis is of crucial biological importance, as it regulates fundamental cellular functions and skeletal mineralization; it is also an important component of nucleic acids, biologically active signaling proteins, coenzymes, and lipid bilayer of the cell membranes. Ingested phosphate is mostly absorbed in the small intestine and is either incorporated in cells in organic forms, deposited as a component of bone mineral, or eliminated by the kidney; the rate of renal reabsorption and/or excretion is determined by the specific needs of the body.Roughly 70% of the phosphate is absorbed in the duodenum and jejunum, through a sodiumdependent active transport, a process stimulated by 1,25-dihydroxyvitamin D 3 [1,25 (OH) 2 D 3 ]; besides parathyroid hormone (PTH) and low-phosphate diets can also stimulate Corresponding authors: Tel.

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

“…41 Genetically altered alpha-klotho-knockout mice develop phosphate toxicity as early as at 3 weeks of age, which affects weight gain and the bone maturation process, produces a generalized soft tissue atrophy and results in reduced life span. 1,14,[40][41][42][43][44][45][46] In vivo studies found that phosphate toxicity in alpha-klotho ablated mice is associated with increased renal activity of NaPi2a. However, phosphate Phosphate toxicity RB Brown et al burden was lowered in hyperphosphatemic alpha-klothoknockout mice by generating NaPi2a/alpha-klotho doubleknockout mice, which resulted in prolonged survival.…”

Wnt Signaling and Aging-Related Heart Disorders

“…It should be noted, however, that Klotho protein was shown to inhibit insulin/IGF signaling and mediate FGF23 signaling as a coreceptor for FGF23, and both of these signaling pathways are implicated in the regulation of lifespan and aging-related pathology. 56,57 Thus, the extent to which the increased Wnt activity contributes to premature aging phenotypes in klotho mice is unclear.…”

Development of a Label-free Assay for Sodium-Dependent Phosphate Transporter NaPi-IIb

“…4 This NaPi-IIb transporter is electrogenic and exhibits an Na + :HPO 2-species, and it is responsible for absorbing about 70% of dietary phosphorous in the gut. 5,6 Despite advances in recent years in cellular assay technologies, few assays are available for the study of transporter activity. The most widely used assay format today measures the accumulation of radiolabeled substrates in tissues or cells that express the target transporters.…”