Staying young – from the cells up

Canadian scientists discover a new enzymatic complex that can stop cells from aging, opening the way to possible new therapies.

Researchers at Université de Montréal and McGill University have discovered a new multi-enzyme complex that reprograms metabolism and overcomes cellular senescence.

Longevity.Technology: Cellular senescence is a defence against the formation of tumours as it limits cells’ ability to divide, but cancer cells are able to circumvent this defence and how they do this is poorly understood. Senescent cells cause inflammation, pump out toxic SASP and play a role in aging. They accumulate with age, and if we could prevent this accumulation, we could delay or even prevent age-related diseases. The more we understand about the pathways involved in senescence and aging, the further we progress our healthy life extension goals.

In their study, published in Molecular Cell, the researchers show that an enzyme complex named HTC (hydride transfer complex) can inhibit cells from aging [1].

“HTC protects cells from hypoxia, a lack of oxygen that normally leads to their death,” said senior author Gerardo Ferbeyre, an UdeM biochemistry professor and principal scientist at the CRCHUM, the university’s affiliated teaching hospital research centre [2].

“Importantly, HTC can be hijacked by certain cancer cells to improve their metabolism, resist to a hypoxic environment and proliferate,” said Ferbeyre, who made the discovery with Sebastian Igelmann, a PhD student in his lab and first author of the study [2].

HTC is made up of three enzymes: pyruvate carboxylase, malate dehydrogenase 1 and malic enzyme 1. They were all highly expressed in samples from a prostate cancer mouse model generated at the University of Veterinary Medicine Vienna, in Austria, and in tissue samples from prostate cancer patients.

“Most interestingly, inhibition of these enzymes stopped the growth of prostate cancer cells, suggesting that HTC could be a key target to develop new therapeutics for a variety of cancers, including prostate cancer,” said Ferbeyre.

Most key metabolic cycles were identified more than 50 years ago, but HTC remained hidden to researchers. “We found it by performing state-of-the art metabolomic analysis, the study of chemical processes of cell metabolism,” said co-author Ivan Topisirovic, a McGill researcher and medical professor [2].

The scientists were able to assemble the enzyme complex from purified proteins and obtain biophysical data about its composition. Their next step will be to generate a detailed high-resolution structure of the enzyme complex in order to design drugs able to modulate its functions, and we should see benefits that go beyond cancer, hopefully modulating the pathways that end in senescence.

[1] https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00695-X
[2] https://www.chumontreal.qc.ca/en/crchum/nouvelles/staying-young-cells

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