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Klotho, Spinning the Thread of Life:
an Anti-Ageing Gene
Antonis S. Manolis, MD
ABSTRACT
Klotho, named after the ancient Greek goddess Klotho, the spinner (of life), is an ag-
ing suppressor or longevity-related gene, discovered in 1997. A defect in the Klotho
gene expression in mice leads to phenotypes resembling human premature or acceler-
ated aging syndromes, with a short lifespan, infertility, arteriosclerosis, skin atrophy,
osteoporosis and emphysema, while Klotho overexpression is associated with extend-
ed longevity. The Klotho gene encodes a transmembrane protein expressed mainly
in the kidney, the parathyroid gland and the choroid plexus. The Klotho protein has
multiple regulating functions, can serve as a useful biomarker and may have potential
therapeutic applications, and thus an emerging role in reno-cardio-vascular disease,
which is briefly explored in this overview.
According to ancient Greek mythology, Klotho or Clotho (in Greek: Κλωθώ),
the Spinner, is the youngest of the 3 Fates or Moires: Klotho who spins, Lachesis who
measures, and Atropos who cuts the thread of life. Klotho was in charge of spinning
the thread of human life. She also made critical decisions, as to when a person was to
be born, saved or die, thus in essence controlling people’s lives. Klotho is also the name
given to an aging suppressor or longevity-related gene, discovered in 1997.
1-3
A defect in
the Klotho gene expression in mice leads to phenotypes resembling human premature
or accelerated aging syndromes, with a short lifespan, infertility, arteriosclerosis, skin
atrophy, osteoporosis and emphysema, while Klotho overexpression is associated with
extended longevity. Klotho knock-out mice develop osteopenia and vascular or other
ectopic calcifications, similar to those seen in chronic kidney disease (CKD). They also
have shorter lifespan and senescent changes in many other organs and tissues, includ-
ing the heart, lungs, muscles, skin, thymus, gonads, hearing, and motor neurons. The
Klotho gene encodes a (130-kDa) single-pass transmembrane protein expressed mainly
in the kidney, the parathyroid gland and the choroid plexus,
4
and to a lesser extent in
placenta, prostate and small intestine. The Klotho protein has multiple (pleiotropic)
regulating functions with an emerging role in cardiorenal disease.
5
There are two separate forms of Klotho protein, membrane (beta) Klotho and
secreted (alpha) Klotho.
2,3
Membrane Klotho forms a complex with fibroblast growth
factor (FGF) receptors and functions as an obligate co-receptor for FGF-23, a bone-
derived hormone (the major phosphatonin) that induces phosphate excretion into
urine. Mice lacking Klotho or FGF-23 not only develop phosphate retention but are
EDITORIAL
First Department of Cardiology,
Evagelismos General Hospital of
Athens, Athens, Greece
HOSPITAL CHRONICLES 2012, 7(3): 129–132
Correspondence to:
Antonis S. Manolis, MD, First
Department of Cardiology,
Evagelismos Hospital, Athens,
Greece; e-mail: asm@otenet.gr
Manuscript received June 24, 2012;
revised manuscript received and
accepted June 30, 2012
KEY WORDS: klotho gene; klotho
protein; ageing; longevity; chronic
kidney disease; fibroblast growth factor;
phosphatemia; vascular calcification;
cardiovascular disease
AbbreviAtions
CKD = chronic kidney disease
FGF = fibroblast growth factor
Conflict of Interest: none declared
130
HOSPITAL CHRONICLES 7(3), 2012
also afflicted by a premature-aging syndrome, pointing to
a link between phosphate metabolism and aging. Secreted
α-Klotho functions as a humoral factor that regulates activ-
ity of multiple glycoproteins on the cell surface, including
ion channels and growth factor receptors such as insulin/
insulin-like growth factor-1 receptors, and inhibits acute
kidney injury, vascular calcification, renal fibrosis, and cancer
metastasis in an FGF-23-independent manner. The activity
of this extracellular domain of Klotho increases the expres-
sion of antioxidant enzymes and provides cell and organism
resistance to oxidative stress.
Klotho is expressed in areas involved with calcium regula-
tion, predominantly in the kidney distal convoluted tubules, but
also in the brain choroid plexus (which produces cerebrospinal
fluid) and the parathyroid gland. Klotho acts as a cofactor for
interaction of FGF23 with FGF R1. This interaction negatively
regulates 1αhydroxylase, the rate limiting enzyme in the syn-
thesis of 1,25(OH)2D3 (vitamin D). Klotho deficient mice
show severe hyperphosphatemia and ectopic calcification of
soft tissues due to excess vitamin D. Although the klotho gene
was first reported as having anti-ageing properties in mice,
human Klotho gene polymorphisms have been linked with
reduced longevity.
Chronic kidney disease (CKD) has been suggested as a
state of Klotho deficiency in the kidney, plasma, and urine.
6,7
Secreted Klotho protein has FGF-23- independent phospha-
turic and calcium-conserving effects via its paracrine action
on the proximal and distal tubules, respectively.
8
On the other
hand, Klotho deficiency causes phosphate retention and ac-
celerated ageing. As Klotho declines in CKD, it causes FGF-
23 resistance and induces FGF-23 and parathyroid hormone
increases, and hypovitaminosis D. Klotho downregulation
appears to be an early biomarker for kidney dysfunction and
mineral dysregulation, may play a pathogenetic role in the
progression of CKD, and it may also be responsible for vas-
cular calcification, which is one of the principal complications
of CKD. The anti-calcification effect of Klotho may possibly
be related to a phosphaturic action, the preservation of glo-
merular filtration rate (GFR), and a direct effect on soft tissues
including the vascular smooth muscle. Thus, in clinical practice,
Klotho can serve as an early and sensitive biomarker of CKD.
Maintaining normal phosphate levels with use of phosphate
binders in patients with CKD with declining Klotho expression
is expected to ameliorate mineral and vascular derangements.
Furthermore, Klotho replacement therapy or manipulation of
up-regulation of endogenous Klotho may slow progression of
CKD and also prevent and/or reverse its complications.
7
Fibroblast growth factor 23 (FGF-23) is a recently dis-
covered secretory hormone, mainly produced by osteocytes,
with main functions the inhibition of renal tubular phosphate
reabsorption and the suppression of circulating vitamin D
levels by decreasing synthesis and enhancing catabolism of
vitamin D.
9-11
FGF-23 participates in the bone/kidney axis that
protects the organism from excess vitamin D and coordinates
renal phosphate handling with bone mineralization/turnover.
Abnormalities of FGF-23 production underlie many inherited
and acquired disorders of phosphate homeostasis. Recent
studies have shown that the function of FGF-23 is dependent
on interaction with Klotho, as an obligate co-receptor, which
binds FGF-23 and then activates FGF receptors.
10
These
proteins appear responsible for maintaining mineral-ion
homeostasis, but also regulate cell survival, proliferation and
vitamin D metabolism. Hereditary disorders that exhibit high
serum FGF-23 levels are associated with phosphate wasting
and impaired bone mineralization, whereas defects in either
FGF-23 or Klotho are associated with phosphate retention
and a premature-aging syndrome.
3
The aging-like pheno-
types in Klotho-deficient or FGF-23-deficient mice can be
managed by targeting and treating hyperphosphatemia with
dietary or genetic manipulation, suggesting a novel concept
that phosphate retention accelerates aging, as seen in CKD.
Interestingly, a recent study indicated that elevated FGF-23
levels were independently of klotho associated with left ven-
tricular hypertrophy (LVH) in a large, racially diverse CKD
cohort.
12
In addition to FGF-23, there are other endocrine
FGFs that have been recognized as hormones that regulate a
variety of metabolic processes. FGF-19 is secreted from the
intestine during food intake and acts on liver to suppress bile
acid synthesis. FGF-21 is secreted from the liver during fasting
and acts on adipose tissue to promote lipolysis and responses
to fasting. One critical feature of endocrine FGFs is that they
require the Klotho gene family of transmembrane proteins
as coreceptors to bind their related FGF receptors and exert
their biological actions.
Klotho is an antiageing protein that confers resistance to
oxidative stress and several pathological conditions predis-
posing to cardiovascular-renal damage.
5
Klotho is essential
in calcium-phosphate metabolism and the maintenance of
vascular integrity; it offers cardiorenal protection. Reduced
levels of soluble Klotho are detected in the early stages of
cardiovascular-renal disease; thus, Klotho might be consid-
ered as a useful biomarker that predicts atherosclerosis and
vascular calcification.
In a cohort of 804 adults of >65 years of the InCHIANTI
study, a longitudinal population-based study of aging in Tus-
cany, Italy, plasma Klotho was an independent predictor of
all cause mortality, with participants in the lowest tertile of
plasma klotho (<575 pg/mL) having an increased risk of death
compared with participants in the highest tertile of plasma
klotho (>763 pg/mL; hazards ratio 1.78).
13
The same authors
reported similar findings in a larger cohort of 1023 individuals,
aged 24-102 years, whereby higher plasma klotho concentra-
tions were independently associated with a lower likelihood
of having cardiovascular disease.
14
In a recent study,
15
thoracic aorta specimens from 44 pa-
tients who underwent elective cardiac surgery, and thrombus
KLOTHO, THE ANTI-AGEING GENE
131
material from 2 patients with acute coronary syndrome, were
tested for FGF-23-Klotho system expression. It was found
that human vascular tissue expresses members of the FGF23-
Klotho system, indicating that it can be a direct target organ
for FGF-23. In addition, Klotho expression was detected in
occlusive coronary thrombi. These findings suggest a putative
role of FGF23-Klotho axis in human vascular pathophysiol-
ogy and cardiovascular disease. Another most recent study
reported endogenous Klotho expression in human arteries, in
vivo, and in human aortic smooth muscle cells, in vitro.
16
The
authors maintained that vascular Klotho deficiency in CKD,
promoted by chronic metabolic stress factors found in CKD,
may be a possible explanation for accelerated vascular aging
with calcification observed in these patients. They also showed
that high levels of FGF-23 in CKD cannot be vasculoprotective
because Klotho/FGF-receptor deficiency mediates resistance
and that vitamin D receptor activator therapy mediates vas-
cular protection by enhancing vascular Klotho expression and
rendering vascular cells FGF-23 responsive.
The potential use of FGF-23 – Klotho as an antiageing
therapy is tempting; however, there is also lurking risk.
10
Al-
though increased serum levels of active vitamin D are clearly
responsible for several ageing-like phenotypes, including tis-
sue atrophy, moderate production of active vitamin D is still
essential for normal bone mineralization. Also, vitamin D
deficiency has been linked to increased risk in development
of various forms of cancer or other diseases such as multiple
sclerosis, diabetes mellitus, rheumatoid arthritis, osteoarthritis,
hypertension, and stroke. Therefore, it is clear that a balance
of moderate levels of systemic active vitamin D is essential for
maintaining overall health and longevity. Nevertheless, Klotho
pathways remain as potential targets for anti-ageing interven-
tions and reno-cardiovascular regulation and homeostasis.
5,17
Prevention of Klotho decline and supplementation of Klotho
can be a novel therapeutic strategy for many age-related
diseases.
18,19
In a recent animal study, it was demonstrated
that the administration of a vitamin D analogue and/or an
angiotensin receptor blocker (olmesartan) improved chronic
renal failure and up-regulated the klotho gene in the kidney.
20
In particular, the combination therapy of the 2 drugs provided
the most effective renal protection.
Although the seminal discovery of Klotho, the anti-ageing
gene, may not have still increased our longevity, however, it
has shed new light into our understanding of the role of the
Klotho protein and mineral homeostasis in the pathogenesis
of reno-cardio-vascular disease (Fig. 1). Our task still remains
to unravel more secrets of function and potential therapeutic
applications for this spinner of life in future studies.
9
Ageing/DM/HTN ↓Klotho CKD (Klotho deficiency state)
(chronic stress factors: TNF-α,
disordered mineral levels/uremia)
PTH/vitD ↑Klotho ↑ROS
↓NO
↑Inflammation
↑FGF-23 FGF Resistance Phosphatemia Endothelial dysfunction
+Klotho
Vascular calcification
Phosphaturia LVH
Reno-Cardio-Vascular Disease
Ageing Syndrome ↓Longevity
(Osteoporosis / arteriosclerosis, (e.g. InCHIANTI study)
ectopic calcifications / skin atrophy)
Figure 1. Putative role of Klotho involvement in reno-cardio-vascular disease. CKD = chronic
kidney disease; DM = diabetes mellitus; FGF = fibroblast growth factor; HTN = hypertension;
LVH = left ventricular hypertrophy; NO = nitric oxide; PTH = parathyroid hormone; ROS =
reactive oxygen species; vitD = vitamin D
FIGURE 1. Putative role of Klotho involvement in reno-cardio-vascular disease. CKD = chronic kidney disease; DM = diabetes
mellitus; FGF = fibroblast growth factor; HTN = hypertension; LVH = left ventricular hypertrophy; NO = nitric oxide; PTH =
parathyroid hormone; ROS = reactive oxygen species; vitD = vitamin D.
132
HOSPITAL CHRONICLES 7(3), 2012
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