The cholesterol biosynthetic pathway induces cellular senescence · Inserm, Science for Health

What molecular mechanisms cause our cells to invade? Senescence, this cellular condition associated with the aging of tissues and organs and certain diseases? A research team in Lyon Insert has just shown that the cholesterol biosynthetic pathway is involved in this phenomenon. His work highlights multiple mediators and questions the potential benefit of preventive or therapeutic targeted treatment in pathologies associated with senescence.

Cell senescence is one of the central mechanisms of aging. This process causes cells to permanently stop reproducing and some of their functions in response to stress, internal damage, or even biological signals such as: the shortening of the ends of their chromosomes. Throughout life, the accumulation of senescent cells in the body favors aging and related diseases: cardiovascular disease, dementia, vision loss, etc. Suffice it to say that the mechanisms that control senescence control the length of life in good health regulate. Several molecules involved in this phenomenon have already been identified, such as the p53 protein, which is known to block the ability of cells to divide. However, the pathways further upstream that lead to the activation of p53 in particular are still poorly understood. The work of Dorian Ziegler at the Lyon Cancer Research Center under the leadership of David Bernard and Inserm researcher Nadine Martin is now providing new data. To explore these pathways, the researchers started from an observation: senescent cells exhibit changes in lipid metabolism that lead to an accumulation of fatty acids and cholesterol. In addition, through previous work it was possible to identify two proteins – MVK and PMVK – that intervene in particular in a pathway involved in the cellular synthesis of cholesterol, the mevalonate pathway, and their activation the entry of cells accelerated into senescence.

A cascade of events

Based on this information, the researchers first examined the effect of modulating the activity of the mevalonate signaling pathway on the aging of cells in culture. They found that reducing the activity of this signaling pathway delayed cell aging. The scientists then inactivated the first enzyme involved in each of the processes controlled by the mevalonate pathway (in particular, the first enzyme involved in cholesterol biosynthesis) and simultaneously activated PMVK to trigger the senescence process. Result: If the first link in the chain that leads to cholesterol synthesis is inhibited, the cells do not enter senescence. “ The blockade is not complete, but very significant and does not make us doubt the role of the cholesterol biosynthetic pathway in senescence. However, it is possible that other mechanisms contribute. », explains Nadine Martin. In order to further decipher the molecular mechanism involved, the Lyons team became interested in ERRα, a protein that plays an important role in regulating the synthesis of various cellular components, whose activity is stimulated by cholesterol and which is involved in the activation of p53 mentioned above. The researchers found that the ERRα protein was activated in senescent cells but was no longer activated when the cholesterol synthesis pathway was inhibited, suggesting a cause-and-effect relationship between the two. To verify the role of ERRαThe team even went so far as to observe the level of senescence of liver cells altered by a high-fat diet in mice lacking ERRα. Result: Without ERRα, the cells do not enter senescence.

A potential therapeutic interest

In summary, the p53 protein – which is directly involved in senescence – is activated (at least partially) by ERRα, itself activated by cholesterol, whose synthesis pathway is stimulated by the mevalonate pathway. Beyond a better understanding of the mechanisms associated with senescence, these results may also have therapeutic interest. “ Several drugs already on the market inhibit the mevalonate signaling pathway: Statins prescribed for hypercholesterolemia or even bisphosphonates are indicated for osteoporosisexplains David Bernard. According to this new study, the beneficial effects of these drugs could be achieved by reducing the mechanisms of senescence. In general, inhibiting the onset of senescence through treatments could perhaps help combat age-related diseases. If our work does not allow us to answer these questions, it opens the door to new considerations and avenues of research. », he concludes.

David Bernard leads the team Senescence Cellular, cancer and aging