Sci. Aging Knowl. Environ., 3 May 2006
Vol. 2006, Issue 8, p. pe11
[DOI: 10.1126/sageke.2006.8.pe11]

PERSPECTIVES

Toward a Better Understanding of Klotho

Yo-ichi Nabeshima

The author is in the Department of Pathology and Tumor Biology at Kyoto University Graduate School of Medicine, Yoshida Konoe-cho Sakyu-ku, Kyoto 606-8501, Japan. E-mail: nabemr{at}lmls.med.kyoto-u.ac.jp

http://sageke.sciencemag.org/cgi/content/full/2006/8/pe11

Key Words: Klotho • fibroblast growth factor 23 • premature aging • vitamin D • calcium homeostasis • phosphorus homeostasis • insulin/IGF-1 signaling

Introduction

It is well established that processes during the early stages of life, such as development, maturation, and reproduction, are regulated by genetic programs that are evolutionally conserved and precisely coordinated. After the reproductive peak, however, functional deterioration becomes gradually apparent, and this functional decline, defined as aging, continues until the end of life. Is life at later stages genetically programmed or randomly processed? Aging progresses so slowly and aging-associated phenomena are so complicated that researchers face difficulties in studying the molecular mechanisms of this process. However, important findings have come to light through molecular genetic approaches, mainly investigating long-lived mutants of Caenorhabditis elegans, Drosophila, and yeast, short- and long-lived mouse mutants, and premature aging syndromes in humans. Among them, two recently generated mouse models, klotho- and fibroblast growth factor 23 (Fgf23)-deficient mice (1, 2), are useful tools to study a novel signaling pathway responsible for the premature aging-like phenotypes that are exhibited by both mouse mutants.

Klotho mutant mice were originally described as a short-lived mouse model. Such mice have an average life span of about 2 months (versus 2 and a half to 3 years for wild-type mice) and display a variety of aging-related phenotypes, such as (i) arteriosclerosis; (ii) ectopic calcification in various soft tissues, such as lung, kidney, stomach, heart, and skin, which become hardened by calcium deposits; (iii) osteopenia (decreased bone mineral density); (iv) emphysema; (v) uncoordinated movement; (vi) atrophy of the skin; and (vii) severe hyperphosphatemia (high serum concentrations of phosphates) in association with increased concentrations of 1,25(OH)2D3, the active metabolite of vitamin D, which plays an important role in calcium metabolism (1). The gene responsible for these phenotypes was termed klotho (after the Greek goddess who purportedly spun the thread of life), and was shown to encode a type I membrane protein with an extracellular domain that exhibits considerable similarity to beta-glycosidases, enzymes involved with the digestion of sugar moieties of substrates (3). klotho is predominantly expressed in tissues that function in the regulation of calcium homeostasis, including the distal convoluted tubules in the kidney, as well as parathyroid hormone (PTH)-secreting cells and the epithelium of the choroid plexus in the brain (1, 4). Klotho proteins have been predicted to be present on the cell surface of Klotho-expressing cells, because the klotho gene encodes a type 1 membrane protein. However, a large amount of Klotho is detectable in the cytoplasm; its intracellular distribution mostly overlaps the endoplasmic reticulum and Golgi apparatus. In addition, the extracellular domain is cleaved and is secreted into the blood and cerebrospinal fluid. These observations suggest that there are dual functions of Klotho that belong either to its cellular or secreted form.

Surprisingly, an independently established mouse mutant line, namely the Fgf 23 knockout (Fgf23–/–) mouse line, exhibits a premature aging-like phenotype that is quite similar to that of klotho-deficient mice (2, 5). Fgf23 knockout mice develop severe hyperphosphatemia in association with increased concentrations of 1,25(OH)2D3 (2, 5). The opposite phenotype has been reported in transgenic mice that overexpress Fgf23. Such mice exhibit hypophosphatemia as a result of an excessive urinary loss of phosphate (6-8). The phenotype of Fgf23–/– mice is analogous to that of patients with familial tumoral calcinosis with hyperphosphatemia (9), an autosomal recessive disease characterized by ectopic calcifications and elevated serum phosphate concentrations. On the other hand, the transgenic mice mimic the features of patients with autosomal dominant hypophosphatemic rickets/osteomalacia (10), X-linked hypophosphatemia (11), and tumor-induced osteomalacia (12).

Because the ablations of the klotho and Fgf23 genes result in strikingly similar phenotypes, these molecules may play major roles in regulating a common signaling pathway that controls mineral ion homeostasis. In fact, both of them are required for the negative regulation of the 1{alpha}-hydroxylase gene, which encodes a rate-limiting enzyme involved in active vitamin D synthesis.

Klotho as a Cofactor in Fibroblast Growth Factor Signaling

At the American Society for Bone and Mineral Research and the American Society of Nephrology meetings in 2005 (13, 14), Yamashita's group (Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd., Japan) reported that Klotho directly binds to FGF receptor 1c (FGFR1c), which is required for the signal transduction of FGF23. Based on this evidence, Yamashita et al. suggested that Klotho acts as a cofactor of FGFR1c in FGF23 signaling. These researchers also suggested that the striking similarity between the phenotypes of Fgf23–/– and klotho–/– mice might be the consequence of disrupting the common signaling pathway(s) required for the down-regulation of 1{alpha}-hydroxylase and reabsorption of phosphorus in the kidney.

Similarly, Kuro-o's group (University of Texas Southwestern Medical Center at Dallas) reported that Klotho directly binds to multiple FGF receptors and functions as the cofactor not only for FGFR1c but also for other multiple FGFRs in the signal transduction mediated by FGF23 and other FGFs (15). They also suggested that the phenotypes in klotho–/– mice can be divided into two groups, namely (i) the phenotypes overlapping with those observed in Fgf23–/– mice and (ii) the abnormalities that have never been described in Fgf23–/– mice, such as arteriosclerosis, ectopic calcification in extrarenal tissues, skin atrophy, neuronal degeneration, and pulmonary emphysema. As a possible explanation for this observation, they suggested that Klotho affects the signal-transducing activity of multiple FGFs by binding to their receptors as the cofactor. These researchers speculated that the paracrine action of secreted Klotho through its association with FGF receptors on nearby cells might cause these phenotypes.

Klotho might be required for the recognition of FGF23 by a target cell. If this is the case, the FGF23 signal could probably be transduced into the distal convoluted tubule cells where Klotho is expressed. However, because the 1{alpha}-hydroxylase gene, the major target of the FGF23 signal, is preferentially expressed in proximal convoluted tubule cells, it has been speculated that either (i) one or more signal mediators from the distal to the proximal tubule would be required or (ii) some paracrine action of secreted Klotho would be necessary for this signal transduction to occur.

Klotho as an Inhibitor of Insulin/Insulin-Like Growth Factor-1 Signaling

Kuro-o's group also reported that overexpression of Klotho in mice extends life span (by 20 and 30% in females and males, respectively) and inhibits insulin and insulin-like growth factor-1 (IGF-1) signaling. Klotho presumably acts by binding to a putative Klotho receptor that mediates a signal that suppresses the intracellular signals of these hormones (16). Disruption of insulin/IGF-1 signaling extends life span in a variety of organisms (see "One for All" and "Power to the People"). The researchers found that Klotho-mediated inhibition of insulin and IGF-1 signaling is associated with increased resistance to oxidative stress, which potentially contributes to the antiaging properties of Klotho (16, 17). In fact, partial alleviation of the aging-related disorders in klotho-deficient mice was observed by perturbing insulin and IGF-1 signaling (16) (see Kurosu et al. Science article).

What is the Major Cause of the Aging-Like Phenotypes in Klotho-Deficient Mice?

To clarify this complicated situation regarding the function of Klotho, several issues need to be addressed. First, what is the major cause of the premature aging-like phenotypes in klotho-deficient mice? Two major causes are suggested. One is the overproduction of 1,25(OH)2D3, which is accompanied by impaired regulation of calcium and phosphorus homeostasis (5, 18). The other is increased oxidative stress induced by the deficiency of Klotho-mediated inhibition of insulin and IGF-1 signaling (16, 17). In KL(klotho)–/– IRS-1 (Insulin Receptor Substrate-1)+/– mice, life-span extension (such that half of male and female mice live until 120 to 130 days after birth) and amelioration of many age-related phenotypes of klotho-deficient mice have been observed. However, the observed amelioration of the klotho phenotypes is only partial, because the life span of KL–/– IRS-1+/– mice is not as long as that of klotho–/– mice rescued by a vitamin D-deficient diet (18) (see below). Therefore, it is likely that the contribution of oxidative stress is limited in the klotho-deficient phenotypes.

In contrast, increased vitamin D activity and elevated concentrations of calcium and phosphorus ions cause almost all phenotypes observed in both klotho–/– and Fgf23–/– mice, because normalization of vitamin D activity, either (i) by dietary restriction (a regimen in which klotho–/– mice are fed a vitamin D-deficient diet) (18) or (ii) by genetic ablation of 1{alpha}-hydroxylase in klotho–/– mice (resulting in klotho–/– 1{alpha}-hydroxylase–/– mice) (19) or in Fgf23–/– mice (Fgf23–/– 1{alpha}-hydroxylase–/– mice) (5) can substantially rescue the premature aging-like phenotypes of these mice, including arteriosclerosis, ectopic calcifications in various soft tissues, osteopenia, skin atrophy, emphysema, and hypogonadism, thus resulting in prolonged survival in both mutants. Most important, when fed with a vitamin D-deficient diet, almost all male and female klotho knockout mice survive for more than 6 months without displaying obvious abnormalities (18). Thus, the life span of klotho–/– mice fed a vitamin D-deficient diet is much longer than that of KL–/– IRS-1+/– mice. Furthermore, the reduced blood glucose and insulin concentrations observed in klotho-deficient mice can be strikingly improved in both male and female klotho knockout mice when they are fed a vitamin D-deficient diet, suggesting that the impaired glucose metabolism in klotho-deficient mice is a secondary effect caused by the increased vitamin D activity (18). In addition, because adipose tissues, an important tissue for the regulation of glucose metabolism, are also affected in klotho–/– mice (such that adipose tissues are scarcely observed at 3 to 4 weeks of age), impaired glucose metabolism in klotho-deficient mice should be investigated more carefully.

Calcium Homeostasis

In vivo genetic manipulation studies suggest that either klotho or Fgf23 deficiencies result in premature aging-like disorders as a result of both the increase in vitamin D activity and the abnormal regulation of calcium and phosphorus homeostasis. As mentioned earlier, the involvement of Klotho in the regulation of calcium homeostasis is consistent with its predominant expression in the distal convoluted tubules in the kidney, the parathyroid glands, and the choroid plexus in the brain, all of which are indispensable for the regulation of calcium homeostasis. However, such a tissue distribution appears to be inconsistent with the proposed hypothesis that Klotho is involved in insulin and IGF-1 signaling. (Major tissues related to glucose metabolism are skeletal muscles, liver, adipose tissues, and pancreas.) Briefly, the parathyroid glands play a key role in calcium homeostasis by monitoring the concentrations of extracellular calcium ions and thereby secreting appropriate levels of PTH to maintain a normal calcium concentration (20). Based on the genetic evidence and biochemical data discussed earlier, Klotho, in combination with FGF23, functions in the distal convoluted tubules to regulate the production of 1,25(OH)2D3, a major hormonal determinant of intestinal calcium absorption. Furthermore, in many respects, the choroid plexus functions as the "kidney of the brain" (21). Indeed, its main function is to produce cerebrospinal fluid, which is secreted across the choroid plexus epithelium in a process that involves the unidirectional transport of ions and the movement of water by osmosis.

Although klotho–/– mice rescued by diet or genetic manipulation can survive for more than 6 months and are healthy in appearance, another systemic abnormality in addition to the vitamin D hyperactivation appears to be involved in the symptoms observed in klotho–/– mice, because those mutant mice are still slightly defective compared with wild type. The most likely cause may be the imbalance of calcium homeostasis in klotho–/– mice. We have demonstrated that Klotho has weak beta-glucuronidase activity (22), and Chang et al. have reported that Klotho activates the transient receptor potential ion channel TRPV5 by hydrolyzing the extracellular N-linked oligosaccharide of this receptor (23) (see Chang et al. Science article). TRPV5, Klotho, and calbindin-D28K (the vitamin D-sensitive intracellular Ca2+ transporting protein) are exclusively coexpressed in the distal convoluted tubule cells, which form the nephron segments responsible for the active and regulated transepithelial Ca2+ reabsorption in the kidney. This finding suggests the importance of these Klotho/TRPV5/calbindin-D28K positive cells and the substantial biological roles of Klotho and TRPV5 proteins in Ca2+ homeostasis regulation. Consistently, mice lacking TRPV5 (24) display diminished renal Ca2+ reabsorption, causing severe hypercalciuria (excessive urinary calcium excretion) and compensatory hyperabsorption of dietary Ca2+ in the intestines. Therefore, it has been speculated that klotho deficiency may result in the down-regulation of TRPV5 and impair calcium balance, even when the overproduction of vitamin D is rescued by diet or genetic manipulation.

Klotho Distribution

The second important issue for understanding the function of Klotho is to determine how widely the secreted Klotho protein is distributed in vivo. It is well known that multiple FGF receptors are simultaneously expressed in a wide variety of cell types and that insulin- and IGF-1-mediated signals are also transduced in widely ranging cells. If Klotho acts through multiple FGF receptors and the putative Klotho receptor in a paracrine fashion, the extracellular Klotho protein bound on the cell surface should be detected in many tissues. Despite many intensive efforts to date, there has been no evidence for the binding of Klotho to the surface of Klotho-nonexpressing cells in vivo. This rather puzzling fact gives us an insight into how Klotho interacts with its putative receptor and multiple FGFRs. Several explanations are likely for this contradictory finding. A "quick touch and go" mechanism, or an unstable interaction between Klotho and receptors may explain the difficulty of detecting Klotho on the cell surface. If this is the case, can Klotho indeed function as a cofactor of FGFRs and transduce the signal as the ligand of its putative receptor? Another explanation could be that the amounts of Klotho are too small to be detected. However, this explanation may not be consistent with the reported serum Klotho concentration, which is around 100 pM. Compared with the concentrations of other hormones and signal-mediating proteins, 100 pM is in fact a very high concentration. Incidentally, serum FGF23 concentrations are around 1 pM (25), which is 1/100th as much as the reported Klotho concentration. This puzzling issue will be clarified shortly, because we have successfully established a reliable assay (an enzyme-linked immunosorbent assay) system that will allow us to measure serum Klotho concentrations more accurately in healthy and disease conditions.

Klotho Interactions

The third issue to clarify is how Klotho interacts with multiple proteins. On the basis of binding assays with iodized Klotho, Kuro-o's group has suggested the existence of a putative Klotho receptor protein on the surface of cultured cells (16). Assuming that Klotho binds to a subset of FGF receptors as well as a putative Klotho receptor, important questions are (i) whether the FGF receptors and the putative Klotho receptor might share a common molecular structure and (ii) whether these receptors bind to different regions of a single Klotho molecule. Once this putative Klotho receptor is identified, we could address questions regarding its properties, including (i) its distribution in vivo, (ii) the expression and regulation of its gene, (iii) its response to different serum glucose concentrations, and (iv) its possible effect on insulin and IGF-1 signaling. Further studies on Klotho and its putative receptor should reveal the answers to these questions in the near future.

Klotho Knockout Mice: A Model for Natural Aging?

The last issue to discuss is whether the klotho knockout mouse is an appropriate model to study the process of natural aging. Based on physical, behavioral, morphological, and biochemical analyses of klotho knockout mice, the loss of Klotho is directly associated with premature aging-like phenotypes, and such phenotypes are the consequence of hyperactive vitamin D-mediated processes. Thus, klotho knockout mice can be considered as a "disease model with premature aging symptoms." The process of premature aging in this model, however, is clearly different from the natural aging process, which is influenced by many factors, including the slow and progressive accumulation of oxidative stress, insulin and IGF-1 signals, caloric intake, and environment. Care is needed in interpreting symptoms and phenotypes observed in klotho knockout mice, especially in terms of the analysis of the natural aging process.

The Many Roles of Klotho

Since the discovery of Klotho in 1997, the molecular function of Klotho has not been precisely determined, but recent reports suggest three different roles for this protein: (i) a cofactor for the FGF receptor 1c in FGF23 signaling, which down-regulates the expression of 1{alpha}-hydroxylase in the kidney; (ii) a hormone that interferes with intracellular signaling of insulin and IGF-1; and (iii) a beta-glucuronidase that activates the ion channel TRPV5 by trimming its sugar moiety, leading to the up-regulation of Ca2+ reabsorption in the kidney. Notably, our recent investigations have unveiled a fourth molecular function of Klotho in calcium homeostasis regulation. The concentration of serum calcium is under stringent control defined by the reabsorption in the kidney, the absorption in the intestine, and the resorption from bone, which are largely regulated by PTH synthesized in the parathyroid gland and by 1,25-(OH)2D3 produced in the kidney nephron. In recent years, we have been focusing on the cell-autonomous function of Klotho. It should be noted that the PTH secretion in response to low calcium stimuli is blunted in klotho–/– mice, indicating that Klotho is required for the immediate secretion of PTH (26). Together with our previous results (18), we hypothesize that Klotho is necessary for both the rapid tuning of Ca2+ concentration through PTH secretion and the FGF23/1,25(OH)2D3-mediated adjustment of minerals. In this regard, Klotho might play a pivotal role in the regulation of calcium homeostasis at various phases, although this hypothesis should be further investigated in the light of related findings. Given that all these findings are correct, how can we reconcile four different functions of Klotho? Is there any common mechanism? To answer this question, further in vivo studies will be required to examine the physiological actions of Klotho. It will also be of great importance to better understand the fundamental molecular mechanism(s) underlying the pleiotropic actions of Klotho for possible therapeutics against aging-associated complications.


May 3, 2006
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Citation: Y.-i. Nabeshima, Toward a Better Understanding of Klotho. Sci. Aging Knowl. Environ. 2006 (8), pe11 (2006).




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