Centenarians, people that live to 100 years of age, are remarkably protected from dementias, despite their advanced age. Understanding factors that protect centenarians from Alzheimer's disease (AD) may provide new leads for successful treatment. Our parent grant application investigates the role of SIRT6 protein in genome maintenance including DNA repair and suppression of LINE1 (L1) transposable elements. We discovered that L1s are activated during aging, especially in the brain, and the cytoplasmic DNA copies of L1s trigger type I interferon response. We hypothesize that the neuroinflammation induced by L1 activity contributes to the development of AD. The goal of Project 3 of the parent program project grant, is focused on the protein SIRT6 role in repressing L1 activity. SIRT6 deficient mice show neurodegeneration, and SIRT6 levels are reduced in patients with AD. Recently, our collaborator Yousin Suh (Albert Einstein), has identified via GWAS coding variants of SIRT6 that are only found in centenarians. Our preliminary data suggest that the centenarian variant of SIRT6 has higher enzymatic activity. Our hypothesis is that centenarian SIRT6 variant is a more powerful repressor of L1 activity leading to reduction of neuroinflammation and protection from AD. Here we propose to test whether centenarian SIRT6 variant has higher activity in silencing L1 elements and then examine whether overexpressing WT or centenarian SIRT6 variants in the brains of AD model mice delays the disease progression. These experiments will serve as a proof of principle that SIRT6 activators may be used as therapeutic target for AD and that small molecule activator compounds developed for SIRT6 can be used in AD treatment.
Centenarians are remarkably resistant to dementias despite the advanced age. We propose to test whether newly discovered centenarian variant of SIRT6 protein protects the brains from Alzheimer's disease (AD) by more efficiently silencing transposable elements and reducing neuroinflammation. These studies will provide a proof of concept whether SIRT6 activation can be a targeted for AD treatment.
| Swovick, Kyle; Welle, Kevin A; Hryhorenko, Jennifer R et al. (2018) Cross-species Comparison of Proteome Turnover Kinetics. Mol Cell Proteomics 17:580-591 |
| Tan, Li; Ke, Zhonghe; Tombline, Gregory et al. (2017) Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSCÂ Reprogramming. Stem Cell Reports 9:1721-1734 |
| Valenzano, Dario Riccardo; Aboobaker, Aziz; Seluanov, Andrei et al. (2017) Non-canonical aging model systems and why we need them. EMBO J 36:959-963 |
| Ke, Zhonghe; Mallik, Pramit; Johnson, Adam B et al. (2017) Translation fidelity coevolves with longevity. Aging Cell 16:988-993 |
| Moskalev, Alexey; Anisimov, Vladimir; Aliper, Aleksander et al. (2017) A review of the biomedical innovations for healthy longevity. Aging (Albany NY) 9:7-25 |
| Tian, Xiao; Seluanov, Andrei; Gorbunova, Vera (2017) Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species. Trends Endocrinol Metab 28:722-734 |
| Gorbunova, Vera; Rezazadeh, Sarallah; Seluanov, Andrei (2016) Dangerous Entrapment for NRF2. Cell 165:1312-1313 |
| Patrick, Alison; Seluanov, Michael; Hwang, Chaewon et al. (2016) Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan. Aging (Albany NY) 8:841-7 |
| Ma, Siming; Upneja, Akhil; Galecki, Andrzej et al. (2016) Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity. Elife 5: |
| Van Meter, Michael; Simon, Matthew; Tombline, Gregory et al. (2016) JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep 16:2641-2650 |
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