We recently showed that SIRT6 is a DNA damage sensor that can recognize Double Strand Breaks (DSB) and initiate the DNA damage response for both homologous recombination and non-homologous end joining. Furthermore, male mice overexpressing SIRT6 display an increased lifespan, suggesting that SIRT6 has critical roles in the regulation of age-related pathologies. SIRT6 knockout mice showed accelerated aging and premature death by three weeks of age, accompanied by metabolic defects, genomic instability, and a progeroid-like phenotype. Particularly, the absence of SIRT6 results in neurodegeneration, heart disease, inflammation, diabetes, and more. In addition, several age-related diseases have been associated with the lack of Sirtuins. For example, Sirtuins play major roles in metabolism and have been implicated in the improvement of CR response in aging. To understand the molecular mechanism of aging, several genes have been studied – specifically, the Sirtuin deacylase and ADP-ribosylase gene family, which are highly conserved proteins with important roles in preventing age-related diseases. Nevertheless, the underlying mechanism is still under debate. The effects of CR are documented in various model organisms including worms, flies, mice and the primate rhesus monkey, suggesting that these effects are translatable into humans. Among the few successful treatments to delay aging, Calorie Restriction (CR) has been proven successful in extending lifespan and alleviate some of the detrimental effects of aging, such as cardiovascular disease, insulin resistance, and increased oxidative damage. Suddenly (in evolutionary terms), aging people have to deal with new health threats and the maintenance of organismal function for longer times, as more persons survive much longer than before. As a result, the mean life expectancy increased from 40-45 years before the modern era to 78.8 nowadays, mostly due to decreased rates of infant mortality, improved medical care, and favorable environmental conditions. Technological advances over the last centuries have drastically changed the environment in which humans evolved. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.ĭuring aging, there is an increase in the incidence of several age-related diseases including neurodegeneration, in which aging itself is the main risk factor. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. In addition, we traced these differences in human and mouse samples of Alzheimer’s and Parkinson’s diseases, healthy aging and calorie restriction (CR). To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer’s patients. Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration.
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