An increase in glycerol kinase (GK) enzyme activity on its own is capable of halting cell proliferation and initiating a programme of senescence. The blue staining of the cells is a biomarker of senescence. This image shows cells overexpressing the GK enzyme. © Khaled Tighanimine/team Mario Pende.

Cell senescence is a physiological process that has been associated in many studies with age-related diseases. Yet the biological mechanisms of senescence and how it could constitute a relevant therapeutic target in fighting these diseases remain poorly understood. In a new study published in Nature Metabolism, scientists from Inserm, Université Paris Cité and CNRS at the Necker Enfants Malades Institute have identified metabolic modifications, i.e. changes in how energy is used by the cells, associated with senescence. This study also suggests that these metabolic changes, which lead to the accumulation of fat in the cells, could be a promising therapeutic target in age-related diseases.

Cell senescence is a physiological process in which a cell’s functions change and it irreversibly ceases to divide. It is induced by acute or chronic exposure of the body to physiological stress signals (such as damage caused to DNA, ageing, oncogenesis[1], etc.).  While it is now well established that the accumulation of senescent cells in the body contributes to age-related diseases, its role in the initiation of these diseases and the various underlying mechanisms involved is not yet fully understood.

To increase knowledge on the subject, Inserm researcher Mario Pende and his colleagues have for several years, and particularly as part of the AgeMed scientific programme (see box), studied the metabolic changes that occur in cells during the process of senescence.

Senescence is characterised by inflammation and metabolic reprogramming – i.e. by a change in how the cells use energy.

‘Understanding the metabolic changes that occur in the cells during ageing is therefore key, as this could open up new avenues for targeting senescence and reaping health benefits,’ explains Pende.

In their new study, the scientists started by using approaches from the fields of transcriptomics (analysis of all RNA molecules resulting from genome transcription) and metabolomics (analysis of metabolites – small organic compounds derived from the body) to study these changes in vitro, in senescent cells subjected to various stresses.

Combining these different methods enabled them to identify a distinct metabolic ‘signature’ associated with senescence. In the senescent cells, they observed an accumulation of several metabolites: lactate, alpha-ketoglutarate, glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN). These accumulations result from changes in the activity of certain enzymes (including one called glycerol kinase). These findings were then confirmed in other cell types and in animal models.

‘Combined with other measurements, this metabolic signature can be used as a biomarker of cell ageing, enabling it to be monitored over an individual’s lifetime,’ emphasises Pende.

In the second part of the study, the scientists also sought to modulate the metabolic changes they had observed, to see if they could reduce the harmful effects of senescence on health. Using molecules that inhibit glycerol kinase activity, they saw a reduction in senescence-related inflammation along with decreased fat accumulation in the cells (triglycerides).

‘While we were unable to restart the cell cycle and encourage the senescent cells to multiply again, we clearly observed a reduction in the inflammatory markers associated with the senescence process. All in all, our findings therefore indicate that regulating the metabolic change observed in senescent cells could be a promising strategy for targeting cell senescence in age-related diseases,’ concludes Pende.

 

[1] The conversion of a normal cell into a cancer cell

Inserm Transfert has filed a patent for this research.

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