A team of researchers at the Korea Advanced Institute of Science and Technology (KAIST) have used algorithms and simulations to provide insight into the complex mechanism of cellular ageing. With their findings, they present a potential therapeutic strategy for reducing age-related diseases associated with the accumulation of senescent cells.
Using simulations that model molecular interactions they identified an enzyme that could be targeted to reverse a natural ageing process called cellular senescence.
The findings were validated with laboratory experiments on skin cells and skin equivalent tissues, and published in the 8 December 2020 issue of Proceedings of the National Academy of Sciences (PNAS).
“Our research opens the door for a new generation that perceives ageing as a reversible biological phenomenon,” says Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering at KAIST, who led the research with colleagues from KAIST and Amorepacific Corporation in Korea.
Cellular senescence
Cells respond to a variety of factors, such as oxidative stress, DNA damage, and shortening of the telomeres capping the ends of chromosomes, by entering a stable and persistent exit from the cell cycle. This process, called cellular senescence, is important, as it prevents damaged cells from proliferating and turning into cancer cells. But it is also a natural process that contributes to ageing and age-related diseases.
Recent research has shown that cellular senescence can be reversed. But the laboratory approaches used thus far also impair tissue regeneration or have the potential to trigger malignant transformations.
Algorithms
Professor Cho and his colleagues used an innovative strategy to identify molecules that could be targeted for reversing cellular senescence. The team pooled together information from the literature and databases about the molecular processes involved in cellular senescence. To this, they added results from their own research on the molecular processes involved in the proliferation, quiescence (a non-dividing cell that can re-enter the cell cycle) and senescence of skin fibroblasts, a cell type well known for repairing wounds. Using algorithms, they developed a model that simulates the interactions between these molecules. Their analyses allowed them to predict which molecules could be targeted to reverse cell senescence.
PDK1 inhibition
They then investigated one of the molecules, an enzyme called PDK1, in incubated senescent skin fibroblasts and three-dimensional skin equivalent tissue models. They found that blocking PDK1 led to the inhibition of two downstream signalling molecules, which in turn restored the cells’ ability to enter back into the cell cycle. Notably, the cells retained their capacity to regenerate wounded skin without proliferating in a way that could lead to malignant transformation.
The research team recommend investigations are next done in organs and organisms to determine the full effect of PDK1 inhibition. Since the gene that codes for PDK1 is over-expressed in some cancers, the scientists expect that inhibiting it will have both anti-ageing and anti-cancer effects.
Reference
An, S., et al. (2020) Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts. Proceedings of the National Academy of Sciences (PNAS). Volume No. 117. Issue No. 49. pp. 31535-31546. https://doi.org/10.1073/pnas.1920338117
