Aspects of the ageing of human cells can be reversed by new compounds developed at the University of Exeter, research shows. The findings raise the possibility of future treatments not only for blood vessels — which become stiffer as they age, raising the risk of problems including heart attacks and strokes — but also for other cells.

In a laboratory study of endothelial cells — which line the inside of blood vessels — researchers tested compounds designed to target mitochondria.

In the samples used in the study, the number of senescent cells (older cells that have deteriorated and stopped dividing) was reduced by up to 50%.The Exeter team also identified two splicing factors (a component of cells) that play a key role in when and how endothelial cells become senescent.

Cellular senescence is a key driver of ageing, influenced by age-related changes to the regulation of alternative splicing. Hydrogen sulfide (H2S) has similarly been described to influence senescence, but the pathways by which it accomplishes this are unclear.

Anti-degenerative Drugs

Professor Lorna Harries, of the University of Exeter Medical School, said the goal was to help people stay healthier for longer;

“The compounds developed at Exeter have the potential to tweak the mechanisms by which this ageing of cells happens. We used to think age-related diseases like cancer, dementia and diabetes each had a unique cause, but they actually track back to one or two common mechanisms.

This research focuses on one of these mechanisms, and the findings with our compounds have potentially opened up the way for new therapeutic approaches in the future. This may well be the basis for a new generation of anti-degenerative drugs."

Splicing Factors

Each one of our genes is capable of making more than one product, and splicing factors are the genes that make the decision about which of these products are made.

Using novel chemicals, the researchers were able to very specifically target two splicing factors (SRSF2 or HNRNPD) that play a key role in determining how and why our cells change with advancing age.

“Nearly half of the aged cells we tested showed signs of rejuvenating into young cell models,"

said Professor Harries.

[caption id=“attachment_96830” align=“aligncenter” width=“680”]H2S donor treatments affect splicing factor transcript expression. H2S donor treatments affect splicing factor transcript expression.
Credit: Eva Latorre et al, CC-BY[/caption]

The researchers tested three different compounds, all developed at the University of Exeter, and found each produced a 40-50% drop in the number of senescent blood vessel cells.

The compounds in question — AP39, AP123 and RT01 — have been designed by the Exeter team to selectively deliver minute quantities of the gas hydrogen sulfide to the mitochondria in cells and help the old or damaged cells to generate the ‘energy’ needed for survival and to reduce senescence.

Alternative Fuel

The results showed a reduction in levels of senescent cells, as measured by a reduction in levels of the biochemical senescence marker SA-β-Gal, with similar decreases in level of CDKN2A transcripts, a molecular marker of senescence.

“Our compounds provide mitochondria in cells with an alternative fuel to help them function properly. Many disease states can essentially be viewed as accelerated ageing, and keeping mitochondria healthy helps either prevent or, in many cases using animal models, reverse this. Our current study shows that splicing factors play a key role in determining how our compounds work,"

said Professor Matt Whiteman, also from the University of Exeter.

Funding for the work was provided by the Dunhill Medical Trust, the Medical Research Council, UK, and the Brian Ridge Scholarship.

Latorre E, Torregrossa R, Wood ME, Whiteman M, Harries LW Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2 Aging 2018; 10:1666-1681.

Top Image: Eva Latorre

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