== Microbial translocation was higher in old monkeys despite lifelong environmental and dietary equivalence and good health. monkeys, and immunoglobulin therapy was not effective in reducing MT markers or improving metabolic health. We interpret these findings to suggest that ageing may lead to lower control over colonization at the mucosal surface, and reduced clearance of pathogens resulting in MT and inflammation. Leaky gut in ageing, which is not readily rescued by innate immune support with immunoglobulin, primes the liver for negative consequences of high fat, high sugar diets. == Introduction == There is loss of gastrointestinal (GI) mucosal barrier function (described as leaky gut in lay terms) with age in invertebrates, animals, and people13. A leaky GI mucosa allows greater translocation of microbial antigens (microbial translocation; MT) into the intestinal wall and portal circulation, inciting inflammation locally and remotely4. MT is potentially important in driving metabolic health, as there is evidence linking bacterial endotoxemia to the accumulation of ectopic fat57, which is an important driver of insulin resistance8. Although intestinal leakiness occurs with advancing age across multiple species, it has only recently been additionally documented as an important mediator Sarsasapogenin of lifespan, at least in invertebrates2. Trends in microbiomes of aged animal models or people have not been consistently observed9,10. Clinical studies have repeatedly demonstrated geographic, dietary, and medication effects on the microbiome, making generalizations about age difficult. Most studies evaluate the fecal microbiome, which represents a catch-all approach for estimation of colonic contents and may not represent location-specific microbiomes. The microbiome in close association with the mucosal surface may differ, and may be a small sub-population of the general microbiome that cannot be captured with gross fecal Sarsasapogenin analysis11,12. Differences may be attributed to effects of the intestinal epithelial cells, which are constantly interacting with the microbiome. The mucosa contributes to host defense through several mechanisms, with immune competence being closely related to mucosal barrier function12,13. It is well appreciated in human and non-human primates that the elderly experience immunosenescence1416, and Rabbit Polyclonal to GAS1 currently there are no approved therapeutic strategies that target immunosenescence, specifically MT, or have indications for ageing, although prebiotics and probiotics are commonly used over the counter strategies. Age-related increases in leakiness are difficult to assess in human clinical trial settings as age, diet, and environmental factors in people typically change concomitantly. In the current series of studies we aimed to survey the structural and functional changes of the gut with ageing, using a relevant non-human primate model that is not confounded by medications or dietary influences17,18. We hypothesized that the GI barrier defects that we have observed in older monkeys10may be improved with oral dosing with serum bovine immunoglobulins (SBI) which is a clinically utilized non-absorbable dietary protein product that consists of multiple immunoglobulin classes from a large pool of bovine donors. It thus captures immunoglobulin types generated from a wide range of pathogens. These immunoglobulins enable some direct binding of pathogens and their toxins, whereas the Fc region of the protein interacts with immune cells that support intestinal Sarsasapogenin homeostasis to reduce inflammatory stimuli and MT19. It is believed that its predominant effect is enhancement of intestinal barrier integrity rather than endotoxin binding to reduce MT20. We report herein that age-related leaky gut occurs with age and that Western diet challenge does not further augment leakiness, but does lead to exaggerated declines in health. Our data suggests that adequate colonic physical barrier elements and innate immune responses to MT are present in old monkeys, and thus it may not be surprising that additional oral immunoglobulin therapy was not effective in reversing leaky gut or improving health. The microbiome profile was similar across ages, and not considered to be a major driver for loss of mucosal barrier function. Age-related adaptive immunosenescence should be investigated like a mechanism and target for improving gut function in the Sarsasapogenin older population. == Results == An overview of studies and the monkey organizations are depicted in Fig.1. == Number 1. == Overview of monkey cohorts.