function.6 Cellular Aging There are well-established mechanisms of cellular aging that have been described in human and animal models.7 These include acquisition of genetic errors, oxidant damage, the presence of replicative “clocks,” and alteration in metabolic signal pathways involved in cellular growth and repair. The concept of antagonistic pleiotropy, with expression of genes that enhance early survival and function but are disadvantageous later in life, has been used to explain the association between aging and development of cancer. Many of these models explain aging in non-GI tissues; however, it is important to point out that some questions remain. For example, errors in replication of DNA form the basis of models of fibroblast aging. The assumption that a certain number of replicative cycles will result in genetic errors cannot be translated to the human small bowel. Small bowel function, including appropriate secretion and error-free mucosal replacement, seems to be preserved with age. Some areas of the GI tract do seem to be sensitive to the effects of aging, such as the propensity of the colon to develop adenomas and colon cancer with age. Immunobiology of Aging Aging affects the immune system in several ways. Aged individuals are less able to mount an immune response to a new immunogenic stimulus (such as a vaccine). This may reflect a loss of immunocompetent B cells from the marrow or lymphatic tissue.8 Immunosuppressive/cytotoxic T-cell numbers are also preferentially increased in rodent models of aging,9 resulting in T-cell replicative senescence and reduced cellular immunity.10 The latter is responsible for the well-characterized tendency of older patients to demonstrate lower rates of effective immunization with tuberculin injection and cutaneous anergy to antigens such as Candida. Neurodegenerative Disease Neurodegenerative disease in the central nervous system is a major cause of morbidity and mortality worldwide in the aged population. The likelihood of developing dementia, such as Alzheimer’s disease, increases steeply beyond the age of 65 years.11 Approximately 5% of individuals aged 65 years show signs of memory impairment and other cognitive loss associated with dementia; however, the percentage increases to 40% by 85 years of age. Direct costs of dementia include treatment of the underlying disease and complications associated with dementia, such as aspiration and falls. Indirect costs include lost income and productivity of family members that care for demented relatives.12 Aging is a risk factor for development of other neurodegenerative diseases in the central nervous system, such as Parkinson’s disease, and peripheral neuropathies such as autonomic and sensory neuropathy. Age-related autonomic neuropathy results in impaired coordination of swallowing, gastric emptying, and colonic motility that can result in overt disease. More importantly, it seems to render aged individuals susceptible to superimposed effects of medications or diseases such as diabetes, with resultant severe impairment in function.13 Autonomic and sensory neuropathy is also implicated in the decreased visceral responses to inflammation and peritonitis observed in older patients. Serious events such as bowel perforation and other inflammatory conditions are often misdiagnosed or delayed in diagnosis due to a lack of overt peritoneal sensory responses such as guarding or rigidity. Aging of the GI Tract: Specific Issues