Weill Cornell Medicine researchers have uncovered the mechanism by which a gene linked to long lifespans in humans, called the forkhead box protein O3 (FOXO3) gene, prevents the development of new neurons.
'This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons.' said senior author Dr Ji-hye Paik from Weill Cornell Medicine, New York. 'If new cells were made in such stressful conditions they would be killed. It's better for stem cells to remain dormant and wait until the stress is gone to produce neurons.'
Published in Nature Communications, the research team studied how brain stem cells reacted to oxidative stress, which is known to damage cells, proteins and DNA, and also contribute to the ageing process. The scientists further investigated FOXO3 gene expression, to identify the pathway responsible. They found that following oxidative stress, which can be caused by poor diets, obesity, exposure to radiation, pollution, as well as other factors, the FOXO3 gene is modified, which results in the FOXO3 protein turning on stress response genes in the nucleus of stem cells.
This stress response leads to a reduction in a specific nutrient, s-adenosylmethionine (SAM), and subsequently a particular protein, lamin, protects the DNA in the stem cell nucleus. Finally, a type-I interferon (IFN-1) immune response is triggered, which causes the stem cell to stop producing new neurons until the danger has passed.
'Without SAM, lamin can't form this strong barrier and DNA starts leaking out.' explained Dr Paik.
Interestingly, genetic variants of FOXO3 are more common in humans over 100 years old, indicating that a longer lifespan may be associated with a surplus of brain stem cells, which are required for learning and memory. These results could also explain why exercise, which increases FOXO3 production, and dietary restrictions which reduce systemic SAM levels, are linked with longevity.
However, although increasing FOXO3 production may appear attractive as a therapeutic for age-associated diseases, 'It could be a double-edged sword.' said Dr Paik. 'Over activating FOXO3 could be very harmful. We don't want to keep this on all the time.'
Future work will continue to explore whether temporary modulation of the pathway could provide long-term health benefits.