Role of the GCP signalling pathway in ageing identified

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With increasing life expectancy, old age is becoming an ever larger part of the human lifespan. During ageing, the way cells function changes, which sometimes has drastic consequences for the body. A recent study published in the journal "Nature Aging", led by Josef Penninger, Professor of Personalised Medicine at MedUni Vienna, reveals the crucial role of a previously unknown lipid metabolic pathway in ageing, in particular its impact on muscle health and glucose control.

Against the background of the question of how the increase in years of life affects the metabolic processes of cells, the research team led by first author Domagoj Cikes (IMBA - Institute of Molecular Biotechnology, Austrian Academy of Sciences) and study leader Josef Penninger ( Department of Laboratory Medicine, MedUni Vienna) investigated in particular genes that are associated with fat metabolism and are dysregulated during ageing. They focussed in particular on those genes that are dysregulated in the skeletal muscles. As the body’s largest organ, this fulfils important functions throughout life: Among other things, muscles serve as metabolic reservoirs for blood sugar and thus control vital processes. Specifically, the researchers focussed on the lipid glycerophosphocholine (GPC) and the enzyme that hydrolyses GPC, glycerophosphocholine phosphodiesterase 1 (GPCPD1). The physiological function of this metabolic pathway was previously unknown. Now Josef Penninger’s team has discovered that its dynamics reflect the ageing process almost perfectly: At a younger age, this pathway functions better, and larger amounts of the enzyme and smaller amounts of the substrate it breaks down, glycerophosphocholine (GPC), are present in muscle tissue. In older age, fewer enzymes that break down GPC are present, so the amount of GPC substrate increases.

These observations led the researchers to ask how these changes are related to ageing. In the search for answers, a mouse model with a mutated enzyme revealed an astonishing effect on glucose homeostasis: GPC accumulated in the muscle and the mice became severely glucose intolerant, as glucose entry into the muscle tissue was severely inhibited. "This observation is extremely interesting, as a key feature of ageing is that the muscles can no longer absorb glucose as well as they did when we were younger, which in turn triggers a cascade of other health problems," says Domagoj Cikes, explaining the significance of the findings. Several chronic diseases of ageing are associated with high glucose levels, including inflammation, stiffening of blood vessels, diabetes and retinal dysfunction - all of which occur after this initial disruption of glucose homeostasis.
"As GPC levels also correlate well with biological age, it could be a good biomarker for biological age," says Josef Penninger with regard to future research that will investigate how the GPC signalling pathway can be influenced to minimise the consequences of ageing. (Source IMBA)

Publication: Nature Aging

Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism
Domagoj Cikes1, Michael Leutner, Shane J.F. Cronin, Maria Novatchkova, Lorenz Pfleger, Radka Klepochová, Benjamin Lair, Marlène Lac, Camille Bergoglio, Nathalie Viguerie, Gerhard Dürnberger, Elisabeth Roitinger, Eric Rullman, Thomas Gustafsson, Astrid Hagelkruys, Geneviève Tavernier, Virginie Bourlier, Claude Knauf, Michael Krebs, Alexandra Kautzky-Willer, Cedric Moro, Martin Krssak, Michael Orthofer, Josef M. Penninger
doi: 10.1038/s43587’023 -00551-6
’023 -00551-6