The number of people aged 65 years and over is expected to rise by over 60% in the next 25 years, which presents an enormous challenge for the healthcare system. Ageing dramatically affects immune function; this phenomenon is known as immunosenescence and partly explains the increased susceptibility for infection in older individuals. Influenza is particularly common in older individuals and is a major cause of death in older people. Vaccination is recommended to protect elderly people against influenza, but immunosenescence also reduces the efficacy of vaccination. It has been estimated that 3050% of older adults fail to mount protective antibody responses after influenza vaccination, representing a considerable waste of resource and a false sense of security for those receiving the vaccinations.

Probiotics have shown promise in the prevention or treatment of several disease states ranging from lactose intolerance, constipation and diarrhoea, alleviation of allergy and even to more chronic systemic diseases, such as cardiovascular disease and cancer. Often they are taken together with prebiotics, which are carbohydrates that provide a food source for the beneficial bacteria when they reach the lower gut. There is particular interest in the positive influences of pre- and probiotics in older people, who are subject to alteration in gut microflora composition as well as immunosenescence. Several studies have demonstrated beneficial effects of specific pre- and probiotics on immune function in older subjects. However, none of these studies have taken into account the agerelated shift in immune cell populations. Furthermore, there is little understanding of the mechanisms underlying these effects. Despite this, probiotics have recently been proposed as prime candidates for 'antiimmunosenescence' therapy. We propose to investigate the impact of a pre- and probiotic mix on the immune response to influenza vaccination in young and older subjects, taking into account the age related shifts in immunity due to immunosenescence. The inclusion of both a young and older group of subjects will allow us to ascertain whether older individuals derive particular benefit from probiotics because of their altered gut microbiota and immune status.

This proposal brings together a unique combination of expertise in nutrition, gut health and immunology to determine the scientific basis for the immunomodulatory effects of pre- and probiotics. The chief investigator, Dr Parveen Yaqoob, has been working in the area of diet, health, ageing and immune function for 18 years. Professor Ian Rowland has been working on the interaction between diet and the gut microbiota and its implications for human health for 30 years. Dr Kieran Tuohy was appointed Lecturer in Food Metabonomics in the Department of Food Biosciences in 2005 and has over ten years experience in the field of gut microbiology and functional foods. Professor Margot Gosney is Director of Clinical Health Sciences, The University of Reading and a clinician working in elderly care at the Royal Berkshire NHS Foundation Trust, Reading. Her research interests include the association between nutrition and health of elderly people, ageing, oncology, dental science for stroke patients, influenza, incontinence, falls and intellectual decline. Dr Sue Todd is a Reader in Medical Statistics at the University of Reading and has over 15 years experience as an applied statistician working in the fields of clinical trials and epidemiology, with particular interest in sequential clinical trials, Data and Safety Monitoring Boards and statistical methods for epidemiology. Professor Richard Aspinall has been working on the hypothesis that age related changes in the T cell arm of the immune system are driven by age associated thymic atrophy. The Chief Investigator and the other project researchers have no direct personal involvement with the funding organisation (BBSRC DRINC) and therefore there are no conflicts of interest. The results of this study will also contribute to the PhD thesis of two postgraduate students.

Healthy volunteers (60 young \[1835y\] and 60 older \[6585y\]) will be randomly assigned to either a pre-and probiotic mix or to placebo (a maltodextrin/milk mix) for 8 weeks in total. The probiotic strain will be Bifidobacterium longum bv. infantis CCUG 52486 (10\^8 10\^9 live bacteria per day), which was originally isolated from healthy elderly subjects, and which has been demonstrated to have particular ecological fitness and antipathogenic effects in vitro. A suitable prebiotic (8g/day) will be selected on the basis of ability to promote optimal growth and survival of this probiotic (inulin, fructooligosaccharides \[FOS\], galactooligosaccharides\[GOS\] and xylooligosaccharides\[XOS\] will be tested). The pre- and probiotic mix and placebo sachet will be manufactured and packaged in the University of Reading pilot plant, and tested by Reading Scientific Services Limited for safety. This project will assess vaccine efficacy on the basis of both specific antibody titre and cellular responsiveness.

Participants will be required to visit the Department of Food and Nutritional Sciences on 5 occasions once for screening and 4 times during the study (0, 4, 6 and 8 weeks). The screening visit will involve a detailed medical history and several assessments to be conducted by a Research Nurse, making the visit approximately 2 hours duration. The study visits will be shorter (approximately 1 hour), involving a discussion of the study, identifying any problems or concerns and collection of biological samples. Blood (150ml), saliva and faecal samples will be collected at baseline and after 4 weeks of supplementation. After this sampling, subjects will receive an influenza vaccination (Solvay Pharmaceuticals) and further samples will be collected 2 and 4 weeks after vaccination.