The GILZ Protein: A Target to Restore the Ageing Immune System?

One of the key processes that contributes to ageing is the decline of the immune system. The adaptive immune system – the highly specific T cells and B cells that constitute the body’s most powerful weapon against pathogens – becomes less capable of recognising and responding to threats. At the same time the innate, inflammatory wing of the immune system becomes chronically overactive.

The second process, often termed inflammageing, contributes to and drives many age-related diseases. This has been known for some time, but we still don’t have a good understanding of what causes this background inflammation. This study reports how inflammageing in white cells called macrophages may be caused by the loss of a protein called GILZ, which is in turn due to the decline of the stress hormone cortisol.

We know that GILZ plays a key role in our immune system, for example it’s involved in switching off the macrophage inflammatory response. So we put forward the hypothesis that loss of GILZ contributes to macrophage-mediated inflammation in older individuals,’ explains Jessica Hoppstädter. Her data shows that a lower cortisol level causes macrophages to produce less GILZ, which in turn means that the macrophages simply continue to release inflammatory signaling molecules. The team found that GILZ levels are indeed lower in older subjects. To find out whether that in itself was enough to cause an inflammatory response, Hoppstädter genetically deactivated the GILZ protein. The data confirmed Hoppstädter’s conjecture: the macrophages were activated and there was a resulting increase in chronic inflammatory processes.

Could GILZ and other proteins be targeted to slow or halt inflammageing entirely? The ability to slow inflammageing could massively reduce the incidence of age-related diseases. However, developing a compound that can boost GILZ will be challenging due to its complex interactions.

A substance able to arrest the progress of age-related inflammatory processes or impede macrophage aging is still a long way off. ‘All of these projects are still very much in the realm of basic research. The GILZ protein operates within an extensive network of complex biochemical interrelationships and it can have both beneficial and deleterious effects. A huge amount of work still needs to be done before we have a medically effective drug,’ says Alexandra K. Kiemer. The phenomenon of human aging remains immensely complex, but the work of the Saarbrücken scientists has moved us one small step further to a better understanding of why and how we age.

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