Erichsen, L;
Adjaye, J;
(2022)
Crosstalk between age accumulated DNA-damage and the SIRT1-AKT-GSK3ß axis in urine derived renal progenitor cells.
Aging
, 14
(20)
pp. 8179-8204.
10.18632/aging.204300.
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Abstract
The aging process is manifested by a multitude of inter-linked biological processes. These processes contribute to genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, de-regulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mammalian ortholog of the yeast silent information regulator (Sir2) SIRT1 is a NAD+-dependent class III histone deacetylase and has been recognized to be involved in many of the forementioned processes. Furthermore, the physiological activity of several Sirtuin family members has been connected to the regulation of life span of lower organisms (Caenorhabditis elegans and Drosophila melanogaster) as well as mammals. In the present study, we provide evidence that SIX2-positive urine derived renal progenitor cells-UdRPCs isolated directly from human urine show typical hallmarks of aging. This includes the subsequent transcriptional downregulation of SIRT1 and its downstream targets AKT and GSK3ß with increased donor age. This transcriptional downregulation is accompanied by an increase in DNA damage and transcriptional levels of several cell cycle inhibitors such as P16. We provide evidence that the renal progenitor transcription factor SIX2 binds to the coding sequence of SIRT1. Furthermore, we show that the SIRT1 promoter region is methylation sensitive and becomes methylated during aging, dividing them into SIRT1-high and -low expressing UdRPCs. Our results highlight the importance of SIRT1 in DNA damage repair recognition in UdRPCs and the control of differentiation by regulating the activation of GSK3β through AKT.
| Type: | Article |
|---|---|
| Title: | Crosstalk between age accumulated DNA-damage and the SIRT1-AKT-GSK3ß axis in urine derived renal progenitor cells |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.18632/aging.204300 |
| Publisher version: | https://doi.org/10.18632/aging.204300 |
| Language: | English |
| Additional information: | © 2022 Erichsen and Adjaye. 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. |
| Keywords: | DNA-damage, SIRT1, aging, renal differentiation, Humans, DNA Damage, Proto-Oncogene Proteins c-akt, Sirtuin 1, Stem Cells, Glycogen Synthase Kinase 3 beta, Aging, Promoter Regions, Genetic, DNA Methylation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10179644 |
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