Alterations in the levels and behaviors of splicing factors have gained more attention of late in the study of aging, particularly in the context of the increased numbers of senescent cells present in aged tissues. Researchers here report on an exploration of some of the connections that exist between splicing factors, cellular senescence, and a number of proteins already known to undergo age-associated changes in their gene expression.
Aging is at root the consequence of numerous forms of molecular damage, but every tissue is a dynamic system in which any given change leads to countless chains of consequences: altered signaling, altered mechanisms, a complex dance of interlocking feedback loops. Tracing these paths is an enormous task, and building a full map is far beyond the present capacity of the research community. It will require decades to make even modest inroads into thin slices of cellular biochemistry - just look at the history of sirtuin research for an example of such a lengthy and narrowly focused research effort.
Waiting for full understanding before taking action is not the right strategy in the matter of aging. We do not have the luxury of time. Given that the molecular damage that causes aging has been identified with a high degree of confidence, the right path is to repair this damage and then see whether benefits result. As efforts related to the selective destruction of senescent cells have demonstrated in recent years, the beneficial outcomes will be very clear and the effect sizes large and reliable if the target is in fact a significant cause of aging.
A study has found that certain genes and pathways that regulate splicing factors - a group of proteins in our body that tell our genes how to behave - play a key role in the ageing process. Significantly, the team found that disrupting these genetic processes could reverse signs of ageing in cells. Aged, or senescent, cells are thought to represent a driver of the ageing process and other groups have shown that if such cells are removed in animal models, many features of ageing can be corrected. This new work found that stopping the activity of the pathways ERK and AKT, which communicate signals from outside the cell to the genes, reduced the number of senescent cells in in cultures grown in the laboratory. Furthermore, they found the same effects from knocking out the activity of just two genes controlled by these pathways - FOXO1 and ETV6.
The ERK and AKT pathways are repeatedly activated throughout life, through aspects of ageing including DNA damage and the chronic inflammation of ageing. The research suggests that this activation may hinder the activity of splicing factors that tell genes how to behave. This, in turn, could lead to a build-up of senescent cells - those which have deteriorated or stopped dividing as they age. To stop the activity of the ERK and AKT pathways, the study used inhibitors which are already used as cancer drugs in clinics. When the pathways were disrupted, the team observed an increase in splicing factors, meaning better communication between protein and genes. They also noted a reduction in the number of senescent cells. Researchers saw a reversal of many of the features of senescent cells that have been linked to the ageing process.