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Neuroendocrine Immune Networks in Ageing

Final Report Summary - NINA (Neuroendocrine Immune Networks in Ageing)

The Challenge of Ageing
With falling birth rates and increased life expectancy Europe is now the oldest continent. Current demographic trends indicate that by the year 2020 almost 1 in 5 of the European population will be aged 65 and over and in the UK 5% of the population will be aged over 85 by the year 2034. This increased life expectancy would be a cause for celebration if it were not for data suggesting that although life expectancy is increasing in the developed world, the period of good health enjoyed by its people (health span) is not keeping pace. As a result, understanding factors that contribute to healthy ageing and developing and validating interventions to promote healthy ageing is now a research priority across Europe and worldwide.

What does the NINA network do?
Although ageing is a complex process, certain body systems that are crucial for health and longevity, namely the Immune, Endocrine and Central Nervous Systems (CNS), stand out as substantial “victims” of ageing. Importantly, these 3 systems have a significant influence upon each others function. NINA is a Marie Curie Initial Training Network that trained 15 early career fellows (13 early stage researchers and 2 experienced researchers), integrating research and training at 10 world class European institutes. NINA focused its research and training activity on the age-related changes that influence the interactions of the brain, immune and endocrine systems to develop a clearer understanding of how these changes in turn impact upon health. Fellows benefited from the combined research and training expertise of the academic partners in the network and this was enhanced by the broad intersectoral experience provided by the involvement of two industrial partners and a non-governmental organisation as an associate partner.
Projects carried out by the partners and fellows in the network include:
1. The effect of sleep duration and quality of immune function in old age;
2. The effect of hormones secreted by adipose tissue (adipokines) on immune function;
3. The effect of the stress of care-giving on immunity in young and older adults;
4. The associations between psychosocial and behavioural factors and the aging of the immune system in adults of working age;
5. Transcriptomic analysis of the hypothalamic paraventricular nucleus (PVN) to identify gene networks involved in central regulation of metabolism and longevity;
6. The effects of feeding habits (hyperphagia) on HPA function and brain neuroplasticity at the different ages in rodents;
7. Determine whether early-life stress in mice can lead to epigenetic programming of the glucocorticoid receptor , a major feedback regulator of the HPA stress axis;
8. Generation of a novel amphibian model to study ageing of the immune system;
9. Investigate the effect of age and gender on sleep and sleep disorders;
10. Use the honey bee as a model to understand the physiological stress effect on brain metabolism;
11. Identify cells involved in development of the thymus and try to regenerate thymus using iPS cells;
12. How does early life stress affect the maturation of the HPI axis regulatory efficiency during development?

What have we found?
1. Hormonal Set points influence longevity and the response to overeating:
Whether hormone balance and metabolism are key influences on longevity and healthspan has been debated in the biogerontology literature for the last century. Previous research in rodents has shown that animals with lower circulating thyroid hormones (TH) exhibit a longer lifespan. This observation is echoed by clinical studies in humans, whereby nonagenarians and their offspring have lower circulating total thyroxine (tT4) and thyroid-stimulating hormone (TSH) concentrations. However, these correlations required further research in order to identify the mechanisms underlying this relationship and to determine if a causal factor exists. Using different strains of laboratory mice with varying levels of thyroid hormones the team at the National Natural History Museum in Paris showed that mice with lower than average serum tT4 were long lived. Furthermore, these mice were resistant to diet-induced obesity (DIO). The team analysed mitochondrial and inflammatory differences in the hypothalamus and found that the long lived, low TH mice were characterised by increased mitochondrial plasticity when on a high fat diet. One secret of a long life may thus be a more adaptable response to varying levels of food intake by the brain, notably the hypothalamus.
2. Early life stress results in epigenetic programming affecting health in later life.
That early life events can affect health in later life is now largely accepted as a result of a wealth of epidemiological studies. What remains unanswered is how these events are programmed in the individual such that they affect the body for decades to come. Research at the Max Plank Institute for Psychiatry in Munich determined whether early-life stress in mice can lead to epigenetic programming of the glucocorticoid receptor (GR, Nr3c1), a major feedback regulator of the hypothalamic-pituitary adrenal (HPA) stress axis. In mammals, DNA methylation typically occurs in a highly tissue- and cell-specific manner making it a challenge to study discrete, small regions of the brain where cellular heterogeneity is high and tissue quantity limited. Therefore, a step-by-step protocol for the investigation of epigenetic programming in the brain was developed that involves the preparation of micropunches from differentially-aged mouse brains from which DNA and RNA can be simultaneously isolated, thus allowing DNA methylation and gene expression analyses in the same sample. These experiments led to the identification of an early-life stress responsive control region at the mouse GR receptor that upon hypermethylation resulted in increased GR expression and subsequently improved regulation of downstream target genes in the PVN.
3. Stress in adult life has negative effects on immunity
It is well established that the HPA axis, one of the major endocrine axes involved in mediating the response to stress, is profoundly affected by age. The ability to produce the stress hormone cortisol does not alter with age, but the production of the counter stress hormone DHEA declines from the age of 30. NINA examined the stress of caregiving in both young adults (caring for children with special needs) and older adults caring for partners with dementia or coping with bereavement. The research focussed on effects on the innate immune system which has received little attention to date. The younger adults were able to maintain immunity in the presence of stress and did not show hyperactivity of the HPA axis, in contrast the older group showed reduced immune cell function (neutrophil superoxide generation). Thus our ability to cope with stress is reduced with age, with consequences for immunity
4. The thymus can be generated using stem cell technology
One of the major factors compromising immunity in old age is the atrophy of the thymus, the organ which produces T lymphocytes which orchestrate the immune systems response to pathogens as well as vaccinations. The thymus starts to shrink in childhood and by middle age produces very few new T cells. One strategy to improve immunity in old age could be to regenerate the thymus in older adults. A team at the University of Birmingham has used a stem cell technique that reprograms adult cells to become pluripotent stem cells (iPS) which can then be induced to differentiate in to any tissue type. They have used iPS to generate a fully functioning thymus in mice, showing that in principal iPS cells could be used to regenerate a key element of the immune system in old age.
5. Sleep is improved by physical activity and poor sleep affects immune cell numbers
It is well established that sleep duration and quality change with age, with older adults sleeping less at night, waking earlier in the morning and having n more disrupted sleep. A study at the University of Birmingham investigated sleep patterns in 200 older adults and looked at lifestyle factors affecting sleep and also examined associations between sleep parameters and immunity. They found that the level of habitual physical activity was associated with sleep latency, how easily the adult fell asleep, with the more active adults going to sleep in a shorter time. The study also showed that adults with shorter sleep had a more pro-inflammatory immune system with higher numbers of neutrophils compared to lymphocytes, a factor that is also a biomarker of a more aged immune system.
In a second sleep study at the University of Lausanne the fellow investigated the effect of age and gender on sleep and sleep disorders and their underlying molecular genetics. Studies of narcolepsy using genome wide association analysis revealed a gene variant rs2859998 in the UBXN2B gene which showed a strong association with the age at onset of excessive daytime sleepiness. Whether the activity of the gene or the gene product changes with age has yet to be determined.

How might our results be useful?
The NINA network has investigated how stress and ageing impact upon three of the body’s master systems: the CNS, endocrine and immune systems and how these communicate to influence health and longevity. The data might have impact in the following ways:
• Determining the endocrine response to feeding in early life, including basal thyroid hormone levels, may identify those more prone to an adverse response to overeating;
• iPS technology may be used to regenerate the thymus and improve vaccination responses and immunity overall in older adults;
• Adjusting the HPA axis, specifically the cortisol:DHEA ratio at times of stress may improve immunity in vulnerable older adults;
• Increased physical activity has benefits for sleep in old age and should be included in lifestyle advice as a health benefit.
• Providing an online tool to assess sleep and health in large populations, often hard to reach by standard approaches.

The project co-ordinator is Prof Janet M Lord and the website address is: http://www.birmingham.ac.uk/research/activity/mds/projects/ii/nina/index.aspx