Understanding how dietary zinc and inflammation impact healthy ageing in the brain

Our bodies need zinc to function but many older people do not have enough zinc in their bodies because of poor diet and because as we age the ability of our body to absorb zinc decreases. Zinc is a very important nutrient for the immune system. We have shown that not enough zinc can cause immune cells to become 'inflammatory'. The process of inflammation is one of our body's defences that help us to fight infection and to repair injured tissue. However, too much inflammation, or inflammation that occurs without an infection or injury, can affect the health of your body and your brain. We know that as you get older your background level of inflammation increases and this inflammation accelerates the aging process. We think that the inflammation that contributes to ageing is caused, at least in part, by reduced levels of zinc in the body. Thus, as people grow older, they take up less zinc, and this leads to inflammation which affects our brains. My aim is to discover that the effects of ageing on the brain are caused by inflammation which is activated by reduced levels of zinc. If I am right, then we may be able to prevent the age related decline in mental ability in older people by increasing their zinc levels and/or blocking the specific inflammation that occurs. Thus the ultimate aim would be to prolong the health-span of old people.

Inflammation is an essential host response to infection and injury, however, as we age our basal level of inflammation increases which contributes to the ageing process. This is referred to as "inflamm-aging". At the heart of inflamm-aging research is an attempt to understand the regulation of the pattern recognition receptor (PRR) NLRP3 (NACHT, LRR and PYD domains-containing protein 3) which is strongly implicated in inflammatory ageing. Diet, particularly micronutrient composition, has been well established to affect inflammatory processes. Zinc is an essential micronutrient and zinc deficiency affects up to 2 billion people worldwide, and is common in aged individuals. We have recently reported that zinc depletion of macrophages activates the NLRP3 inflammasome in vitro and that a zinc deficient diet accelerates a mouse model of Alzheimer's disease. This project is therefore investigating how zinc deficiency leads to inflammation, and whether this can accelerate the aging process.
The pathways which lead to zinc deficiency induced inflammation will be investigated using RNAi and pharmacological inhibitors in macrophages activated with damage associated molecular pattern (DAMPs) and zinc chelating agents. To investigate the role of zinc deficiency and NLRP3 activation in age related cognitive decline, groups of 3 month old senescence accelerated mouse-prone 8 (SAMP8) and senescence-accelerated-resistant mouse (SAMR1) animals will be placed on zinc deficient and zinc normal diets with or without the addition of the novel NLRP3 inhibitor mefenamic acid. Cognitive/memory performance and inflammatory markers will then be monitored for 6 months. I will also investigate the correlative relationship between zinc levels, inflammatory markers and cognitive decline in human brain and plasma samples. Collectively, these experiments will comprehensively elucidate the mechanisms by which zinc deficiency induces inflamm-aging and age related cognitive decline.

- Who will benefit from this research?
The immediate beneficiaries of this research will be the Faculty here at the University of Manchester. The identification of drug targets (such as NLRP3 or associated proteins in inflamm-aging) will benefit our local commercialisation team (UMI3) and may, in the longer term, provide economic benefits. Beyond this the presentation/publication of papers at conferences and in international high impact peer reviewed journals will benefit the wider scientific community and the universities in general. Clinicians may be informed of new strategies or treatments for the management of inflammatory disease and/or ageing that will ultimately lead to benefits for patients and increase the health-span of the population. The wider public will also benefit from increased understanding of and exposure to science through outreach activities I am involved with. I also participate in careers fairs with local schools benefiting local school children to learn about future careers in science.

- How will they benefit from this research?
Most immediately research from this proposal will help inform researchers in the field and in the scientific community in general about key, up to now, unknown mechanisms of inflammation and ageing. The creative experiments I have designed will inspire other researchers to investigate similar mechanisms and thus our levels of knowledge on these process in general will increase substantially. The new areas of research that our discoveries will open will lead to the recruitment and training of students in this area which will spawn further developments. Many of these future developments will likely involve the identification of targets that may eventually lead to interventions that inhibit inflammation and promote healthy ageing by prolonging health-span. These will inform clinical studies and may lead to new treatments. Due to the nature of this research there is scope for the commercialisation of the discoveries and potential economic benefits to the University and to the economy in general. Inflammation and ageing have a massive impact on human suffering and thus research into these mechanisms has potentially a direct impact on the health and wellbeing of people in the UK and worldwide.