Modifying gene expression for healthy ageing
Weaker bones, impaired immune functions and increased susceptibility to disease are just some of the many consequences of ageing, but the precise genetic and molecular processes involved are not clearly understood. Ground-breaking EU-funded research is attempting to determine why and how we age, potentially leading to new treatments and dietary guidelines to slow down the process.
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The key to understanding ageing could lie in determining how genetic factors affect adult stem cells, which are essential for the life-long maintenance and regeneration of organs and tissues. Clinical and experimental studies have shown that the functional capacity of adult stem cells to regenerate organs declines as we age, but why this occurs at different speeds in different individuals remains unclear.
“We’re assuming that some of the genetic factors that either speed up ageing or slow it down affect stem cells,” says Karl Lenhard Rudolph, scientific director of the Leibniz Institute on Aging Fritz Lipmann Institute (FLI) in Germany. “In other words, by changing the ways our stem cells function, the genes we inherit can decide how fast we age.”
Rudolph, one of the world’s leading researchers in the field of ageing, is attempting to establish the connection between genetic factors and the functional capacity of stem cells with the StemCellGerontoGenes project, supported by a grant from the European Research Council (ERC).
Over five years, Rudolph and his team are studying the hematopoietic stem cells that underpin the formation of blood cells as well as stem cells involved in intestinal and muscular regeneration. Using reverse genetic screens with RNA interference to inhibit gene expression, the researchers are able to analyse how turning on or off a gene impacts stem cell activity. RNA or ribonucleic acid is one of the three major biological macromolecules, along with DNA and proteins, essential for all known forms of life.
The StemCellGerontoGenes team has already identified several interesting mechanisms which could lead to further research and potentially new treatments for some of the effects of ageing.
They found that the PER2 gene, which is commonly associated with the circadian rhythms of biological activity over a 24-hour cycle, is activated in ageing and damaged hematopoietic stem cells, affecting lymphoid cells in particular. As a consequence, the number of these white blood cells of the immune system is reduced, resulting in increased susceptibility to bacterial infection. Tests showed that turning off the PER2 gene in ageing mice improved their immune response against bacterial infections.
Gauging the impact of dietary changes on healthy ageing
Diet is another much-discussed issue in relation to health and ageing. Research on invertebrate organisms has shown that a calorie-restricted diet can increase the lifespan of flies and worms, while positive effects from calorie restriction on health parameters have also been observed in mice and non-human primates. However, the effects on lifespan were not clear in the primate studies, which suggested that reducing calorie intake may have both positive and adverse effects during ageing. The StemCellGerontoGenes team therefore looked at the role of calorie restriction in slowing the ageing of hematopoietic stem cells in mice.
The team found that calorie restriction dialled back stem cell cycle activity, putting the hematopoietic stem cells into a kind of dormant state thought to be important to slowing the ageing process. Conversely, reducing calorie intake also compromised the capacity of hematopoietic stem cells to produce lymphocytes cells of the adaptive immune system essential in protecting against infections. Accordingly, mice on calorie-restricted diets displayed a heightened risk of chronic bacterial infection.
“The data provides some very interesting leads that point towards the impact of nutrition on stem cell ageing and the immune system. Our data demonstrates that contrary to popular belief a reduction in calorie intake has negative effects that may outweigh the positive effects,” Rudolph says. “Clearly more research needs to be conducted to translate these findings into human practice. If we succeed in separating the positive and negative effects of calorie restriction and the genetic pathways that influence stem cell ageing, we may be able to define therapeutic approaches.”
Further work will be carried out over the coming years to refine and verify the initial results, which Rudolph says would not have been possible without long-term ERC support, which has enabled the researchers to run time-consuming and costly experiments.
“We do not necessarily believe that our results will eventually extend human lifespan, we are instead more interested in improving healthy lifespan by deciphering the molecular pathways that govern the fitness of stem cells. The improved fitness of stem cells should in turn allow a longer maintenance of different organ systems and improved health in old age,” Rudolph says.