A new way to rejuvenate old cells in the laboratory, making them not only look younger, but start to behave more like young cells, has been discovered by researchers at the Universities of Exeter and Brighton.
A team led Professor Lorna Harries, Professor of Molecular Genetics at the University of Exeter, has discovered a new way to rejuvenate inactive senescent cells. Within hours of treatment the older cells started to divide, and had longer telomeres – the ‘caps’ on the chromosomes which shorten as we age.
This discovery, funded by the Dunhill Medical Trust, builds on earlier findings from the Exeter group that showed that a class of genes called splicing factors are progressively switched off as we age. The University of Exeter research team, working with Professor Richard Faragher and Dr Elizabeth Ostler from the University of Brighton, found that splicing factors can be switched back on with chemicals, making senescent cells not only look physically younger, but start to behave more like young cells and start dividing.
The researchers applied compounds called reversatrol analogues, chemicals based on a substance naturally found in red wine, dark chocolate, red grapes and blueberries, to cells in culture. The chemicals caused splicing factors, which are progressively switched off as we age to be switched back on. Within hours, the cells looked younger and started to rejuvenate, behaving like young cells and dividing.
The discovery has the potential to lead to therapies which could help people age better, without experiencing some of the degenerative effects of getting old. Most people by the age of 85 have experienced some kind of chronic illness, and as people get older they are more prone to stroke, heart disease and cancer.
Professor Harries said: “This is a first step in trying to make people live normal lifespans, but with health for their entire life. Our data suggests that using chemicals to switch back on the major class of genes that are switched off as we age might provide a means to restore function to old cells.”
Dr Eva Latorre, Research Associate at the University of Exeter, who carried out the experiments was surprised by the extent and rapidity of the changes in the cells.
“When I saw some of the cells in the culture dish rejuvenating I couldn’t believe it. These old cells were looking like young cells. It was like magic,” she said. “I repeated the experiments several times and in each case the cells rejuvenated. I am very excited by the implications and potential for this research.”
Professor Harries added: “This demonstrates that when you treat old cells with molecules that restore the levels of the splicing factors, the cells regain some features of youth. They are able to grow, and their telomeres – the caps on the ends of the chromosomes that shorten as we age – are now longer, as they are in young cells. Far more research is needed now to establish the true potential for these sort of approaches to address the degenerative effects of aging. ”
Professor Richard Faragher of the University of Brighton, will today argue for more research into the degenerative effects of ageing in a debate into whether science should be used to extend people’s lifespans.
Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.
Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.
This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.
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