The focus of our study is to examine how the age suppressor protein, Klotho, is regulated with agingin the brain. When Klotho expression is eliminated, mice develop normally, but age to death by 4months of age. This rapid deterioration is accompanied with a phenotype not unlike what is observedin aged humans (cognitive impairment, atherosclerosis, ectopic calcification, emphysema,osteoporosis, skin atrophy and hair loss, thymic involution, infertility and decreased bone mineraldensity). Elimination of Klotho in mice causes cognitive impairment that is associated with increasedoxidative stress. In contrast, Klotho overexpressing transgenic mice live longer by up to 30% and areresistant to oxidative stress. Our group found that Klotho is downregulated in the aging non-humanprimate, rat and mouse brains Together, these have lead us to hypothesize that Klotho is importantin brain function and its downregulation with age may be the result of oxidative stress which, ifprevented, could ameliorate decline into neurodegenerative disease. The work proposed, examinesregulation of the Klotho promoter and 3'UTR with age and the effect of oxidative damage to theKlotho promoter with age. We will determine whether the high GC content of the Klotho promotermakes it a target for age-related downregulation because of damage that accumulates over timebecause of oxidative stress. This will be done by comparing the oxidation state of the Klothopromoter to that of other genes both in vitro and in post mortem samples from aged rhesus monkeybrain. We will also work to characterize the transcription factors that bind and induce activation of theKlotho promoter. The Klotho promoter does not contain the classical elements for transcriptioninitiation. Understanding what factors are important for Klotho transcription may shed light onsignaling pathways leading to Klotho activation and the role of Klotho in the normal cell. Last, we willdetermine whether Klotho is regulated by microRNAs (miR) and how miR change in the brain withage. MiR bind and regulate translation of mRNA and nothing is known about whether and how miRaffect Klotho processing. Again, understanding the processes that regulate Klotho will enable us tohave a better understanding of the processes that affect Klotho and Klotho's wider role in cellularfunction. The results of this work will add new knowledge on both the anti-aging gene Klotho andelucidate a possible mechanism for how oxidative damage selectively downregulates specific genes.
With a rapidly aging population, increases in age related disorders are anticipated to rise to unprecedented levels in the next 50 years. Understanding the regulation of genes known to effect and be affected by the aging process is critical to developing novel therapies for a range of disorders. The aging suppressor protein, Klotho is decreased in the brain with age and may be a target for therapeutic development against neurodegenerative disorders.
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