Ageing is a dramatic public health issue in the face of the current demographic changes: the proportion of 60 and over in the world's population will almost double by 2050. In this context, a new discovery has just broadened scientific knowledge. Researchers shed light on the mechanisms of senescence, by identifying a key protein associated with ageing.

Currently, most of older people die of noncommunicable diseases such as heart disease, cancer and diabetes, rather than infectious or parasitic diseases, even in developing countries. A better understanding of the fundamental mechanisms that lead to ageing will pave the way towards ultimately healthier ageing, which is a major socioeconomic issue for the coming decades.

Senescence, which is a process that limits proliferation of damaged cells in response to various types of stress, has been associated to ageing. Accumulation of senescent cells in tissues may contribute to organ degeneration and age-related diseases. As a result, clearance of these cells has been associated with slower ageing and longer healthspan in animal models.

Scientists demonstrated that progressive depletion of a protein drives proliferating cells into irreversible ageing. Moreover, such a depletion is a very early trigger, and therefore a determinant of cellular ageing, or senescence.

This factor, called CSB is involved in Cockayne syndrome, a disease affecting about one in every 200,000 people in European countries. The absence of CSB protein or its dysfunction causes early ageing, photosensitivity, progressive neurological disorders and intellectual deficit in patients with Cockayne syndrome. "We had previously shown that the absence or impairment of CSB is also responsible for dysfunction of mitochondria, the power plant of cells" says the senior author. "This new study reveals the very same alterations in replicative senescence, a process strictly linked to physiological ageing" says the author.

The importance of the present discovery is that it shows that a factor that was considered to be stable in normal cells is instead progressively depleted when they proliferate. When this happens, the cell is irreparably committed to the dead end of senescence.

CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response.

Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53- independent manner. This activity of CSB is independent of its role in the repair of UVinduced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress.

Moreover, a molecule previously identified by these researchers as being able to reverse the defects of Cockayne syndrome patient cells, is also able to attenuate the commitment of normal cells to senescence.

"These studies demonstrate an important link between the [pathological] accelerated ageing process and normal aging, and also expose the CSB protein as a key factor against cellular ageing" concludes the senior author.

https://www.pasteur.fr/en/research-journal/news/institut-pasteur-team-identifies-key-protein-linked-ageing

https://www.nature.com/articles/s41467-019-13314-y

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcsb-promoter&filter=22