Daniel Piątek, Emilia Migryt, Kamila Tuzim, Joanna Szydełko, *Anna Boguszewska-Czubara
Klotho protein protects against aging and nicotine-induced chronic cellular stress
Department of Medical Chemistry, Medical University in Lublin, Poland
From 1997, when Klotho protein was first discovered and named “the anti-aging hormone”, scientists have been thoroughly investigating its biological properties. This protein plays an important role in numerous metabolic pathways that contribute to slower ageing processes. The prevalence of neurodegenerative diseases, impairment of cognitive functions and chronic stress increases with age. Additional factors, such as nicotine, rosiglitazone, statins, blood-pressure lowering drugs, calcitriol, magnesium, chronic psychosocial stress and aerobic exercises have an influence on Klotho protein plasma concentration. The research on proteins that increase Klotho plasma levels is important because of broad range of biological processes in which Klotho is engaged. Further studies on this substance could result in new possibilities of treatment for several common diseases.
The KL gene is located on the long arm of human chromosome 13. Its product protein was discovered in 1997 and it immediately became of interest to many scientists due to its involvement in the mechanisms of ageing. The name of the protein is a reference to the Greek mythology, as Clotho was the youngest of the Three Moirai. She was responsible for spinning the thread of life from her distaff onto her spindle. By naming the protein after her, scientists wanted to emphasize the unique role of the protein. Soon after the discovery of the involvement of Klotho in ageing processes, it occurred that it is also involved in other vital processes and its effects are truly pleiotropic. From a biochemical point of view, Klotho is a novel β-glucuronidase, capable of activating the TRPV5 ion channel (1, 2). Thanks to the use of specific antibodies, it became possible to detect the secreted form of Klotho in the cerebrospinal fluid and serum (1). There are two forms of this protein: transmembrane (130kDa) and secretory (65kDa). They are synthesized in varying organs, but both have an ability to create oligomer complexes (1, 2). Transmembrane form is mainly produced by the brain (specifically, by the choroid plexus) and by the kidneys. The highest quantities of the secretory form are observed in the plasma and in the cerebrospinal fluid (3). The two forms have different functions. The transmembrane form is the co-receptor for fibroblast growth factor (FGF23) and the secretory form interacts with ion channels, transporters and receptors for growth factors (2). Among others, Klotho regulates the functions of the endothelium and the production of nitric oxide by the endothelium. It also affects many intracellular signaling pathways, including p53/p21 pathway, Wnt pathway, cAMP and protein kinase C pathway (2).
Klotho protein as ageing hormone
A mutation in the KL gene may cause faster progression of symptoms associated with senility, such as shorter life expectancy, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema (4). As only some organs are able to produce the Klotho protein, researchers aimed to find target structures for Klotho in different human tissues. The results confirmed that Klotho protein functions as a humoral factor in cerebrospinal fluid and is engaged in hormonal regulation network (5). Recent studies have also underlined the role of the insulin and insulin-like growth factor (IGF) signaling pathway as one of the most important metabolic routes for the lifespan regulation. It has been discovered that even slight alterations weakening the insulin/IGF-1 signaling pathway can extend the lifespan of Caenorhabditis elegans even over two times (6). The Klotho protein suppresses intracellular pathways induced by insulin/IGF1 and finally enables the animals to remain active and young for a longer time (7). A relationship between Klotho serum levels and activities of daily living (ADL) in older people has been investigated. Lower levels of Klotho protein have been associated with ADL disability in elderly people (8). Furthermore, it has been suggested that the Klotho protein can be used as predictor of all-cause mortality (8, 9). Because the study has been conducted on a relatively small group, further research is required to verify if the concentration of Klotho protein may indeed be used as prognostic factor of ADL disability or mortality. The ageing process is strictly related to the overproduction of free radicals and impairment of cytoprotective mechanisms. It is probable that the Klotho protein owns the ability to prolong lifespan due to its capability of reducing oxidative stress (10). Some studies have indicated an increased expression of manganese superoxide dismutase as a result of activation FoxO – forkhead box transcription factors – in mice with high Klotho protein levels (10). Dismutase degrades free radicals and protects against small cellular damages, consequently, increasing the lifespan.
Klotho protein in neurological diseases
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