Since its discovery in 1997 the Klotho gene has been known to be involved with longevity.  I came across a recent news article describing research linking expression of the gene to reduction in hypertension, and this led me to look into what is known about the gene.  As reported here, Klotho appears to have a lot of interesting properties.

“The Klotho gene codes for a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. Its discovery was documented in 1997 by Kuro-o et al.^[1] The name of the gene comes from Klotho or Clotho, one of the Moirae, or Fates, in Greek mythology(ref).”  In mice at least the Klotho protein acts like a hormone.  It circulates through the blood and binds to cells.

The newly-reported publication is Klotho Gene Delivery Prevents the Progression of Spontaneous Hypertension and Renal Damage.  “Researchers, led by principal investigator Zhongjie Sun, tested the effect of an anti-aging gene called Klotho on reducing hypertension. They found that by increasing the expression of the gene in laboratory models, they not only stopped blood pressure from continuing to rise, but succeeded in lowering it. Perhaps most impressive was the complete reversal of kidney damage, which is associated with prolonged high blood pressure and often leads to kidney failure(ref).”  The experiment was on laboratory rats where the gene was delivered by a virus vector.  “This is the first study showing that a decline in Klotho protein level may be involved in the progression of hypertension and kidney damage, Sun said. With age, the Klotho level decreases while the prevalence of hypertension increases. —  Researchers used one injection of the Klotho gene in hypertensive research models and were able to markedly reduce blood pressure by the second week. It continued to decline steadily for the length of the project – 12 weeks. The Klotho gene was delivered with a safe viral vector that is currently used for gene therapy. The virus is already approved by the U.S. Food and Drug Administration for use in humans(ref).”  Of course, it is hoped that the research will at some point lead to a Klotho therapy for humans for hypertension and associated kidney damage.

Studies relating Klotho to aging started to appear soon after its discovery.  Most of these are based on working with rats or mice.  Some of the earlier publications related deficiency of Klotho to classical indicators of aging.  The 1977 publication Mutation of the mouse Klotho gene leads to a syndrome resembling ageing states “A defect in Klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. —  The Klotho gene product may function as part of a signaling pathway that regulates ageing in vivo and morbidity in age-related diseases.” 

The 2002 publication Association of human aging with a functional variant of Klotho concludes “These results suggest that the KL-VS allele influences the trafficking and catalytic activity of Klotho, and that variation in Klotho function contributes to heterogeneity in the onset and severity of human age-related phenotypes.”  The study suggested that one of the aging mechanisms that may be accelerated by insufficient expression of Klotho is the buildup of advanced glycation endproducts (AGEs). “Multiple models of aging invoke accelerated or excessive posttranslational modification of proteins including glycation. Resultant advanced glycation end-products (AGEs) elicit a wide range of responses that have been proposed to contribute to many age related phenotypes, including atherosclerosis, Alzheimer’s disease, diabetic complications, and microvascular changes (29). It is possible that the proposed glycosidase activity of Klotho retards the accumulation of AGEs.” Note that Tissue Glycation is an important theory of aging discussed in my treatise.

Research articles implicate low levels of Klotho expression with endothelial dysfunction, pulmonary emphysema,  impairment of osteoblast and osteoclast differentiation, cognition impairment and other disease processes in mouse models.

The 2004 paper Klotho is a serum factor related to human aging looks at Klotho protein in human serum in 112 individuals.  “ The population aged from 0 to 91 years screened by ELISA revealed that the level of serum KL declined while age increased, though each individual level was variable and that the trend of decreasing in serum KL had no difference in sex. – Conclusion: Our data suggest that KL is a serum factor related to human aging.”

Klotho’s actions and the channels it works through are complex.  From the 2006 paper Toward a better understanding of Klotho: “Suggested functions of Klotho are (i) a fundamental regulator of calcium homeostasis, namely, a cofactor for the fibroblast growth factor (FGF) receptor 1c in FGF23 signaling and a regulator of parathyroid hormone secretion; (ii) a hormone that interferes with the intracellular signaling of insulin and insulin-like growth factor-1 (IGF-1); and (iii) a beta-glucuronidase that activates the transient receptor potential ion channel TRPV5 by trimming its sugar moiety.”   

As to how Klotho may impact on longevity: a) I have already mentioned its actions in averting tissue glycation, b) the IGF-1 pathway has long been known to be associated with longevity and is that affected by calorie restriction, and c) Klotho promotes the body’s antioxidant defenses.

Klotho expression is also important for averting premature aging due to overexpression of Vitamin D.  The mechanism is associated with its function in regulating FGF23.  (YES my reader friends, in animal model experiments, overexpression of vitamin D leads to premature aging.  I will cover that issue in a separate blog post).  The 2002 publication Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system states “These observations suggest that Klotho may participate in a negative regulatory circuit of the vitamin D endocrine system, through the regulation of 1alpha-hydroxylase gene expression.” The 2008 paper FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis states “We show that the signal transduction pathways initiated by FGF-23-Klotho prevent tissue atrophy by stimulating proliferation and preventing apoptosis caused by excessive systemic vitamin D. Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1alpha-hydroxylase expression and phosphoinositide-3 kinase-dependent inhibition of caspase activity.”

A number of other papers also deal with the involvement of Klotho and FGF23 in vitamin D mediated premature aging, for example Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process concludes “our data support a new model of interactions among Fgf-23, vitamin D, and Klotho, a gene described as being associated with premature aging process.”  

Besides Klotho defects being implicated in disease processes there is some evidence that overexpression of Klotho could be life-extending.  For example, the 2005 paper Suppression of Aging in Mice by the Hormone Klotho states “Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.” The point is reinforced in several other publications.

The link of Klotho to insulin is further reinforced by a 2007 study that involved comparing the expression of genes in young and old brains(ref).  “They observed that the levels of Klotho in the brain showed a striking decrease with aging. The association between Klotho and aging prompted Abraham’s group to investigate the regulation of Klotho further. These studies lead to the observation that secretion of Klotho is regulated by insulin. — To their surprise, they found that insulin, a hormone usually associated with diabetes, increases significantly the levels of secreted Klotho. The reason this finding is important is because excess insulin has been previously implicated in a biochemical pathway that is associated with a decreased life span and elevated oxidative stress. — In addition, this observation provides a potentially pivotal link between Klotho and sugar metabolism, and raises an intriguing relationship between Klotho and type II diabetes, commonly known as late onset diabetes. The authors are proposing a novel mechanism of action for Klotho whereby insulin increases Klotho secretion, i.e., activity, and in turn, the secreted Klotho inhibits insulin’s actions in the cell, which are known to be detrimental when insulin is in excess(ref).”

One viewpoint is that Klotho derives much of its anti-aging capability from the protein acting “by increasing the cell’s ability to detoxify harmful reactive oxygen species (ref).  “Using cultured cells and transgenic mice, the researchers showed that Klotho increases resistance to oxidative stress.   “Increased longevity is always associated with increased resistance to oxidative stress,” explains Kuro-o (the man who discovered Klotho). “Oxidative stress causes the accumulation of oxidative damage to important biological macromolecules such as DNA, lipids, and proteins that would result in functional deterioration of the cell, which eventually causes aging(ref).”  Of course, this viewpoint is consistent with the classical Oxidative Damage theory of aging.

A 2007 report is entitled Obesity May Be Associated With A Relative Of Anti-aging Gene, Klotho.  Differences in how to interpret results with Klotho knockout mice has also engendered controversy about its anti-aging capacities such as described in a blog article I found entitled Controversial Klotho in cancer.

Despite that it has been studied for over a dozen years, the exact anti-aging mechanisms of Klotho still are not clearly identified.  The 2008 paper Klotho as a regulator of oxidative stress and senescence states “The Klotho gene functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice. — The secreted Klotho protein can regulate multiple growth factor signaling pathways, including insulin/IGF-1 and Wnt, and the activity of multiple ion channels. Klotho protein also protects cells and tissues from oxidative stress, yet the precise mechanism underlying these activities remains to be determined. Thus, understanding of Klotho protein function is expected to provide new insights into the molecular basis for aging, phosphate/vitamin D metabolism, cancer and stem cell biology.”                          

As time goes on we will doubtlessly be hearing more about Klotho.