Systems Biology Opens a New Path to Reverse Cell Aging

Professor Kwang-Hyun Cho’s team discovered that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores cell cycle entry, resulting in restored skin regeneration capacity. These findings provide insight into a potential therapeutic strategy to treat age-related diseases.

Article | Spring 2021

Cellular senescence is defined as a stable, persistent exit from the cell cycle in response to stresses such as telomere shortening, oxidative stress, oncogene activation, and DNA damage. This process is important, as it prevents damaged cells from proliferating and turning into cancer cells. However, senescent cells accumulate in tissues during aging and secrete proinflammatory cytokines, which can contribute to aging and age-related diseases, including cancer. Recent research has shown that cellular senescence can be reversed. However, these attempts to revert cellular senescence in laboratory settings thus far have shown limitations such as impaired tissue regeneration and tumorigenesis.

Professor Kwang-Hyun Cho and his colleagues used a systems biology approach to identify molecules that could be targeted for reversing cellular senescence. The team pooled together information from the literature and network databases to identify the relevant molecules of cellular senescence. Furthermore, they added experimental data on the molecular processes involved in the proliferation, quiescence (a non-dividing cell that can re-enter the cell cycle) and senescence of human dermal fibroblasts. 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 (mTOR and NF-κB), 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 scientists plan to further investigate the effect of PDK1 inhibition at the organ and organism levels. Since the gene that codes for PDK1 is overexpressed in some cancers, the scientists expect that inhibiting it will have both anti-aging and anti-cancer effects.

These findings provide insight into the complex mechanism of cellular senescence and present a potential therapeutic strategy for reducing age-related diseases associated with the accumulation of senescent cells.