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Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Life extension factor klotho enhances cognition. Cell Rep. 2014 May 22;7(4):1065-76. Epub 2014 May 10 PubMed.
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Kangwon National University
The klotho gene is predominantly expressed in the kidney and, to a lesser extent, in the brain and reproductive and endocrine organs, and it has been identified as a novel anti-aging factor (Kuro-o et al., 1997; Yang et al., 2010). We have, for the first time, reported memory impairment induced by klotho gene knockout in mice (Nagai et al., 2003). Surprisingly, Dubal et al. demonstrate here a very novel finding (using transgenic mice with systemic overexpression of klotho): that klotho enhances cognition even early in life. Similar to our recent report using klotho mutant mice (Park et al., 2013), they clearly suggest a causal role for NMDARs and their GluN2B subtype in klotho-mediated cognitive enhancement.
Even though the present article shows unexpected findings, we think that klotho mutant mice should still be considered a disease model for premature aging syndromes. The process of premature aging in this model, however, is clearly different from the natural aging process, which is influenced by many factors. Indeed, klotho mutant mice do not reveal some phenotypes usually seen in aged humans, such as brain atrophy with deposition of amyloid or senile plaques (Kuro-o et al., 1997; Anamizu et al., 2005; Nixon et al., 2005). Therefore, it might also be of great importance to better understand the fundamental molecular mechanisms underlying the pleiotropic actions of klotho for possible therapeutics against premature aging- and natural aging-associated complications.
Importantly, the klotho gene has a remarkable renoprotective effect in response to ICR-derived glomerulonephritis in a mouse model, via attenuating mitochondrial oxidative stress (Haruna et al., 2007). In addition, klotho gene expression is decreased in patients suffering chronic kidney disease (Kuro-o, 2009). Clinical data suggests that individuals of all ages with chronic kidney disease are at higher risk for developing dementia and cognitive impairment (Madero et al., 2008). Therefore, it is possible that renopathological changes (in the absence of klotho) are responsible for cognitive impairments in humans.
Nonetheless, we think that multifactorial approaches the authors used to analyze the cognitive function of the klotho gene help us understand the role of this gene in the aging-dependent and aging-independent complications.
Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S, Kawakami E, Kanda N, Matsubara S, Kuro-O M, Nabeshima Y, Nakamura K, Oyanagi K. Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells. Acta Neuropathol. 2005 May;109(5):457-66. PubMed.
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Park SJ, Shin EJ, Min SS, An J, Li Z, Hee Chung Y, Hoon Jeong J, Bach JH, Nah SY, Kim WK, Jang CG, Kim YS, Nabeshima Y, Nabeshima T, Kim HC. Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. Neuropsychopharmacology. 2013 Jul;38(8):1426-37. Epub 2013 Feb 6 PubMed.
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