Fight Aging!

Cells become senescent in response to damage, signaling of other senescent cells, or on reaching the Hayflick limit to cell replication. Senescent cells cease to replicate, secrete a potent mix of inflammatory signals, and near all self-destruct or are destroyed by the immune system. Unfortunately, some escape this fate, and so senescent cells accumulate with age to cause chronic inflammation, tissue remodeling, and age-related disease. A few years ago, researchers discovered a way to adjust splicing factors to reverse cellular senescence, allowing cells to replicate once again. Here, another approach is outlined, which may or may not work via similar underlying mechanisms. I remain of the mind that this isn't a useful path to therapy, as a significant fraction of senescent cells become senescent for a good reason, in that they are damaged and potentially cancerous. It is better, I think, to focus on selective destruction via senolytic therapies rather than attempts to rehabilitate senescent cells.

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 aging 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.

Researchers 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.

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 scientists recommend investigations are next carried out in organs and organisms to determine the full effect of PDK1 inhibition. 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.

Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=11111