The elucidation of molecular mechanisms of aging is essential to fighting against age-related diseases and improving the quality of life of elderly people. The long-term goal of this project is to identify changes at the protein level associated with aging and longevity using animal models. A defect in klotho gene expression leads to a syndrome resembling human aging. In contrast, mice that overexpress Klotho enjoy an extended lifespan, indicating that Klotho is an aging-suppressor gene that can delay aging when overexpressed and accelerate aging when disrupted. Klotho protein functions as a hormone-like substance that inhibits insulin and IGF-1 signaling, consistent with accumulating genetic evidence that inhibition of insulin-like signaling is an evolutionarily conserved mechanism for extending lifespan from worms to mammals. Using mice with different Klotho expression levels and other established mouse models for extended longevity, proteomic changes associated with the acceleration and deceleration of aging will be identified.
The specific aims are to: (i) Identify phosphorylation and modifications of signaling proteins regulated by insulin/IGF-1 signaling in mouse tissues using protein microarray technology. (ii) Identify protein-protein interactions that regulate insulin/IGF-1 signaling and aging. Preliminary data suggest that Klotho, putative Klotho receptor, IGF-1 receptor and other unidentified proteins form a complex on the cell surface, thereby regulating activity of insulin/IGF-1 signaling and eventually aging. The components of this multi-protein complex will be identified using immunoprecipitation and 2-dimensional gel fingerprint analysis followed by mass spectrometry-based protein sequencing. (iii) Develop a new diagnostic method to distinguish aging states of individual animals by profiling serum and tissue proteins using mass spectrometry. Mathematical algorithms will be developed that extract a set of biomarkers to specify different aging states. These studies are expected to provide critical information that promotes a better understanding of the molecular mechanisms of aging and longevity. ? ?
| German, Dwight C; Khobahy, Ida; Pastor, Johanne et al. (2012) Nuclear localization of Klotho in brain: an anti-aging protein. Neurobiol Aging 33:1483.e25-30 |
| Hu, Ming Chang; Shi, Mingjun; Zhang, Jianning et al. (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124-36 |
| Goetz, Regina; Nakada, Yuji; Hu, Ming Chang et al. (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 107:407-12 |
| Hu, Ming-Chang; Shi, Mingjun; Zhang, Jianning et al. (2010) Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int 78:1240-51 |
| Hu, Ming-Chang; Kuro-o, Makoto; Moe, Orson W (2010) Klotho and kidney disease. J Nephrol 23 Suppl 16:S136-44 |
| Hu, Ming Chang; Shi, Mingjun; Zhang, Jianning et al. (2010) Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24:3438-50 |
| Kuro-o, Makoto (2009) Klotho and aging. Biochim Biophys Acta 1790:1049-58 |
| Cha, Seung-Kuy; Ortega, Bernardo; Kurosu, Hiroshi et al. (2008) Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 105:9805-10 |
| German, Dwight C; Gurnani, Prem; Nandi, Animesh et al. (2007) Serum biomarkers for Alzheimer's disease: proteomic discovery. Biomed Pharmacother 61:383-9 |
| Goetz, Regina; Beenken, Andrew; Ibrahimi, Omar A et al. (2007) Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 27:3417-28 |
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