A new study opens the door for a new generation that perceives aging as a reversible biological phenomenon, thanks to a potential therapeutic strategy presented by the KAIST team. Scientists provided insight into the complex cellular senescence mechanism and presented a novel strategy for reducing age-related diseases associated with senescent cells’ accumulation.
Scientists used computer simulations to model molecular interactions. Through this, they identified an enzyme that could be targeted to reverse a natural aging process called cellular senescence.
Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering at the Korea Advanced Institute of Science and Technology (KAIST) said, “Our research opens the door for a new generation that perceives aging as a reversible biological phenomenon.”
Cells respond to various 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 essential, as it prevents damaged cells from proliferating and turning into cancer cells.
While being equally significant, the process is also responsible for aging and age-related diseases.
A recent study has shown that cellular senescence can be reversed. But the laboratory approaches used thus far also impair tissue regeneration or potentially trigger malignant transformations.
Professor Cho and his colleagues used an innovative strategy to identify molecules 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 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.
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 signaling molecules, which restored the cells’ ability to enter back into the cell cycle. Notably, the cells retained their capacity to regenerate wounded skin without increasing in a way that could lead to malignant transformation.
Scientists suggested that the examinations are next done in organs and organisms to decide the full impact of PDK1 Inhibition. Since the gene that codes for PDK1 is overexpressed in some cancers, the scientists expect that restraining it will have anti-aging and anti-cancer effects.
- Sugyun An et al., Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts, Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1920338117