As people age, their immune systems deteriorate. This makes them more susceptible to infections, and can mean that vaccines are less effective.
This new research shows that immune cells in older people have damaged DNA, a hallmark of ageing. Targeting this DNA damage could be a key way to rejuvenate immune systems in older people and therefore increase healthspan.
mTOR inhibitors, such as rapamycin, are drugs which target an important enzyme in cells called mTOR which becomes more active during ageing. Such drugs have been shown to increase lifespan in many organisms including yeast, flies and mice. They also improve immune responses to vaccination in older people. Dr Loren Kell, with Professors Ghada Alsaleh, Lynne Cox, and Katja Simon, hypothesised that rapamycin could be used to directly alleviate DNA damage.
To test this, the group exposed human T cells in the lab to a DNA-damaging agent that killed 80% of the cells after 24 hours. If cells were instead treated with rapamycin at the same time as exposure to DNA damage, 60% were still alive at 24 hours – 3 times more than without rapamycin. The presence of rapamycin appeared to reduce the DNA damage in the T cells. Professor Cox said “The cells showed less DNA damage even after only 4 hours – it’s a very fast response. We don’t yet know whether rapamycin is blocking damage formation or helping cells to repair the damage more quickly and efficiently, so this research opens up a whole new area of study to identify the mechanism of protection”.
The researchers then tested the effects of rapamycin on immune cells in people, in collaboration with Professor Philip Atherton’s team at the University of Nottingham. One group of older adults were given a low dose of rapamycin every day for 4 months, and one group took a dummy pill instead (a placebo). The people who took rapamycin were found to have significantly less evidence of DNA damage and cell ageing in their immune cells, compared to participants in the placebo group.
The study, published in Aging Cell, found that not only does rapamycin protect against DNA damage if given at the same time that cells are exposed to damaging agents, but it appears to help even if given in advance. Professor Alsaleh said “Regardless of whether rapamycin is given before, during, or after DNA damage occurs, we observe a consistent protective response. These findings uncover a previously unrecognised role of mTOR inhibition in directly protecting the genome, offering new insight into the biological basis of rapamycin’s effects on ageing. This suggests that rapamycin, or other mTOR inhibitors, may have broader relevance in contexts involving DNA damage, including healthy ageing, clinical radiation exposure, and exposure to cosmic radiation during space travel”.
On the impact of her research, Dr Kell said “Our findings provide a new understanding for why rapamycin and other mTOR inhibitors have such promising anti-ageing potential in the immune system and more widely across the body. Since DNA damage is a central driver of immune system ageing, our study supports future endeavours to identify more strategies that can improve DNA stability during ageing. On a personal level, I am thrilled that a large part of my PhD work is now published and open to the greater research community.”
Senior author Professor Katja Simon said “The publication is a result of a collaboration between three experts across the University of Oxford - Lynne Cox on DNA damage (Biochemistry), Ghada Alsaleh on ageing (NDORMS) and Katja Simon, a T cell immunologist (NDORMS). We obtained funding for a PhD project and completed this exciting piece of work with high translational potential together.”