Korean scientists changed end-of-life human skin cells back into a state in which they can reenter the cell cycle, a process they say could be used to stop or reverse symptoms of aging and cancer.
Researchers from Korean university KAIST and cosmetics conglomerate Amorepacific triggered the anti-aging effects by inhibiting metabolism-regulating enzyme PDK1, which they identified in simulations of molecule interactions within these cells. Their findings were published in Proceedings of the National Academy of Sciences.
While attempts to slow and reverse the effects of human aging have a long and frequently dubious history, the PNAS paper built upon recent findings on cell aging. Cells leave the cell cycle and stop dividing after reaching a limit on mitosis or experiencing DNA damage, oxidative stress or other pressures. Entering this “senescence” stage prevents damaged cells from becoming cancerous, but senescent cells also secrete inflammatory signals and contribute to aging-related symptoms and diseases, such as a shorter lifespan, neurodegenerative diseases and cancer.
Cellular senescence was long thought to be irreversible, but research published in 2003 and expanded upon in 2018 showed that through external tinkering, some senescent cells can escape their terminal state and its effects. Animal tests have found that removing senescent cells reverses aging effects such as osteoarthritis and the buildup of plaque in arteries.
Kwang-Hyun Cho, who designed and co-authored the study, has previously reverted cancerous colon cells into healthy states and was motivated to bring a similar approach to anti-aging research.
“Throughout my study on cancer systems biology, I realized that aging is the most strong oncogenic factor, so we would be able to expand our health span if (we) can revert aging,” said Cho, a professor of bioengineering at KAIST, which was formerly named Korea Advanced Institute of Science and Technology.
Cho and his colleagues built a computer model that simulated how numerous molecules in human skin cells interact with each other as senescence takes hold. The model showed that the inhibition of three proteins caused at least 30% of cells to change from senescence to quiescence — a state in which cells don’t divide but can reenter the cell cycle. Suppressing PDK1, an enzyme involved in metabolism within mitochondria, was found to have the largest state-reversing effect because of its involvement in multiple positive feedback loops related to senescence.
The researchers then applied PDK1 inhibitors to live senescent human skin cells, which appeared to be successfully reversed into quiescence and regain their full functionality. The inhibitors “eliminated hallmarks of cellular senescence, restored the proliferation of the cells in response to growth factors, and restored skin regeneration capacity,” the researchers wrote.
Previous animal studies that reversed cellular senescence claimed it could come with harmful side effects, such as leading to malignant tumor cells or impairing immune responses. In contrast, the KAIST and Amorepacific scientists claimed that inhibiting PDK1 not only won’t cause cancer but may even prevent it: The enzyme is abundantly present in many tumors, and its inhibition has been targeted in some potential cancer treatments.
“This is the first discovery of showing that aged senescent human cells can be safely reverted back to the young healthy quiescent cellular state without any risk of inducing ... a cancerous cellular state,” Cho said.
The study was funded by KAIST, Amorepacific and two research institutes under the South Korean government.
The researchers said that while they expect PDK1 inhibition to have both antiaging and tumor-suppressing effects, the treatment should be tested at the organ and organism scales. It also remains to be seen whether its effects vary based on cell type or cause of entering senescence.
Cho said he may begin a startup company to further develop PDK1 inhibitors to tap into the “huge implication” of his research and create a de-aging treatment that doesn’t raise the risk of cancer.
“If we can develop a safe drug for inhibition of PDK1 then we can greatly enhance our quality of life by delaying any possibility of oncogenesis in our body,” he said.
The article, “Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts,” was published Dec. 8 in Proceedings of the National Academy of Sciences. The authors of the study were Sugyan An, Jungsoo Kang, Soobeom Lee and Kwang-Hyun Cho, KAIST; Si-Young Cho, Hyung-Su Kim, Dae-Jin Min and EuiDong Son, Amorepacific Corporation. The lead author was Kwang-Hyun Cho.