Research Paper Volume 13, Issue 5 pp 6420—6441
Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6
- 1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
- 2 The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
- 3 Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow 121205, Russia
Received: August 24, 2020 Accepted: January 21, 2021 Published: March 9, 2021https://doi.org/10.18632/aging.202755
How to Cite
Copyright: © 2021 Stein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer’s patients. 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 addition, we traced these differences in human and mouse samples of Alzheimer’s and Parkinson’s diseases, healthy aging and calorie restriction (CR). 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. 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. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.