Monday, July 12, 2010

Klotho more than “ninphae”



        
    

 

From Greek mythology “Klotho” was one of three Moirae. She is responsible for spinning the thread of human life, so that she mades major decisons when a person is born. She controls who born through his life she also decide who has to be saved or put to death.

Two other sisters , Lachesis and Atropos, are responsible of human destiny and influence their misery and suffering.

Clotho assisted Hermes to create the alphabet, and forced the goddess Afrodite into making love with other gods, killed the Titan Typhon with poison fruits and persuaded Zeus to kill Asclepius with a bolt of lightning.

As you know Asclepius, the Roman Esculapius, is the god of Medicine and Healing. Asclepius has a daughter Epione ( Goddess of soothin of pain) and he his the father of : Hygieia (Hygiene), Panacea (Universal Remedy), Aceso (Goddess of Healing process), Leso or Laso (Goddess of recuperation from illness), Aglaea or Aglaia (Shining one, splendor, brillant, Healthy Glow) wife of Hephaesto and mother of Eucleia (good repute), Eupheme (Acclaim), Euthenia (Prosperity), Philophrosyne (Welcome).

The rod of Asclepius, a snake-entwined staff, remains a symbol of medicine today, also if sometimes a staff with two snakes (the caduceus) is mistakenly used instead.

He was one of the Apollo’s sons.

Asklepios

Asclepius

God of Medicine

Is KLOTHO, an anti-ageing hormone ?

The KLOTHO gene was identified serendipitously through a hypomorphic allele that results in severe early degenerative changes and short lifespan ( Nature 1997). The homozygous mutant animals develop normally until 3 weeks of age, then exhibit severe growth retardation, osteoporosis, ectopic calcification, aterosclerosis, emphysema and atrophy of the skin, thymus, testes and ovaries, and die at an average age of 61 days.

KLOTHO prolong lifespan at least in part by inhibiting insulin-IGF-1 signalling. KLOTHO may be secreted by KIDNEY cells blocking both IGF-1 and Insulin receptor action at adipocytes and target tissue levels.

clip_image002

Levels of calcium and phosphate are elevated in KLOTHO deficient mice, demonstrating that this protein has a role in calcium and phoshate homeostasis. The altered calcium and phoshate levels are due to elevated 1,25 OH Vitamin D3 levels, which result from increased expression of 1alfa hydroxylase gene activity at kidney level.

Normalization of 1,25 OH Vitamin D3 with a Vitamin D deficient diet partially rescued some of the KLOTHO deficient phenotypes, including slow growth, ectopic calcification and early death. This suggests that the putative pro-ageing effect of KLTHO deficiency is not associated with ageing itself, but rather that the pathology is related to altered Vitamin D metabolism.

FGF23 KO mice share many features with the KLOTHO deficient mouse, including hypercalcemia, hyperphosphatemia, ectopic calcification, hypoglycaemia, infertility, and very short lifespan.

FGF23 is a circulating factor that is produced in the bone and inhibits phosphate transport in renal proximal tubular cells. FGF23 deficiency results in phosphate retention and hyperphosphatemia, constitutively elevated expression of 1 alfa hydroxylase, elevated levels of 1,25 OH Vitamin D3 and hypercalcaemia.

Interestingly without KLOTHO the functions of FGF23 is literally abolished.

Many tissues express FGF Receptors subtypes that interact with the KLOTHO-FGF23 complex, therefore it is possible that KLOTHO exerts his anti-ageing action through the activation of his enzymatic activity i.e. beta glucoronidation.

We know that all steroids enzymes including all lipophilic vitamins such as Vitamin D, with a steroid like structure, can be glucuronized in order to achieve a better hydrophility and flow into the blood vessels. The pool of glucuronide-linked steroids hormones is an inactive quote of hormones, those destiny is in normal condition to be metabolized further into hepatic cells or recycled by endocrine organs.

KLOTHO can hydrolyse STEROID GLUCURONIDES, including estradiol, estrone, estriol and vitamin D so that some effects of KLOTHO can occur through processing of inactive streroid glucuronides to active steroids hormones. Steroid hormones could have a role in the regulation of ageing in mammals.

 

clip_image003

 

References

Arking DE, Krebsova A, Macek M Sr et al. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci USA 2002;99:856-61.

Duce JA, Podvin S, Hollander W et al. Gene profiling analysis implicates klotho as an important contributor to aging changes in brain white matter of rhesus monkey. Glia 2008;56:106-117.

Arking DE, Becker DM, Yanek LR et al. KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet 2003;72:1154-61.

Mitani H, Ishizaka T, Aizawa T et al. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 2002;39:838-43.

Ogata N, Matsumura Y, Shiraki M et al. Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women. Bone 2002;31:37-42.

Yamada Y, Ando F, Niino N et al. Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women. J Mol Med 2005;83:50-7.

Mullin BH, Wilson SG, Islam FM etr al. Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women. Calcif Tissue Int 2005;77:145-51.

Kawano K, Ogata N, Chiano M et al. Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 2002;17:1744-51.

Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51.

Roth GS, Lane MA, Ingram DK et al. Biomarkers of caloric restriction may predict longevity in humans. Science 2002;297:811.

Kurosu H, Yamamoto M, Clark JD et al. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829-33.

Chang Q, Hoefs S, van der Kemp AW et al. The beta glucuronidase Klotho hydrolyzes and activates the TRPV5 channel. Science 2005;310:490-3.

Russell SJ, Kahn CR. Endocrine regulation of aging. Nat Rev Mol Cell Biol 2007;8:681-91.

Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996;273:59-63.

Ingram DK, Cutler RG, Weindruch R et al. Dietary restriction and aging: the initiation of a primate study. J Gerontol 1990;45:B148-B163.

Sohal RS, Argarwal S, Candas M et al. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev 1994;76:215-24.

Lee C-K, Klopp RG, Weindruch R et al. Gene expression profile of aging and its retardation by caloric restriction. Science 1999;285:1390-3.

Kujoth GC, Hiona A, Pugh TD et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2003;309:481-4.

Weindruch R, Sohal RS. Caloric intake and aging. N Engl J Med 1997;337:986-94.

Priè D, Friedlander G. Genetic disorders of renal phosphate transport. N Engl J Med 2010;362:2399-2409.

Who take care about that?

Followers