Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment.

BACKGROUND: Association of Alzheimer's Disease (AD) with Type 2 Diabetes (T2D) has been well established. Cyclo(His-Pro) plus zinc (Cyclo-Z) treatment ameliorated diabetes in rats and similar improvements have been seen in human patients. Treatment of amyloid precursor protein (APP) transgenic mice with Cyclo-Z exhibited memory improvements and significantly reduced Aß-40 and Aß-42 protein levels in the brain tissues of the mice. SCOPE OF REVIEW: Metabolic relationship between AD and T2D will be described with particular attention to insulin sensitivity and Aß degradation in brain and plasma tissues. Mechanistic effect of insulin degrading enzyme (IDE) in decreasing blood glucose and brain Aß levels will be elucidated. Cyclo-Z effects on these biochemical parameters will be discussed. MAJOR CONCLUSION: Stimulation of IDE synthesis is effective for the clinical treatment of metabolic diseases including AD and T2D. GENERAL SIGNIFICANCE: Cyclo-Z might be the effective treatment of AD and T2D by stimulating IDE synthesis.

Host resistance and immune responses in advanced age.

Immunosenescence results in populating immune tissues with less functional T cells, and perhaps B cells dendritic cells, that do not function well and produce more type 2 cytokines and fewer type 1 cytokines. Impaired immunity, distinct from immunosenescence, correlates more with disease burden than chronologic age. Older adults who have chronic diseases or chronic infections are more susceptible to common infections and have poor vaccine responses. Understanding specific mechanisms and targeting interventions are dependent on research to resolve the relationship between frailty-associated impaired immunity and the role of chronic infection versus immunosenescence in developing impaired immunity.

Comorbidity is a better predictor of impaired immunity than chronological age in older adults.

OBJECTIVES: To determine whether high level of comorbidity, measured using a standardized instrument, can predict impaired immunity in older adults. SETTING: Geriatric outpatient Clinic and Nursing Home Care Unit of Veterans Affairs Greater Los Angeles Healthcare System. PARTICIPANTS: Fifteen men aged 51 to 95 with varying levels of chronic illness. MEASUREMENTS: Disease burden was measured using the Cumulative Illness Rating Scale (CIRS) and immunity using proliferation of T cells induced by phytohemagglutinin (PHA) and production of interleukin (IL)-12, a proinflammatory cytokine that promotes T helper cell-dependent immune response, and IL-10, a cytokine that inhibits T helper cell-dependent immune response, in response to mitogenic stimulation of peripheral blood mononuclear cells. RESULTS: With increasing comorbidity (increase in CIRS score) in older adults, there is a proportional decrease in immune response (decrease in T cell proliferation and IL-12 production and increase in IL-10 production in response to PHA stimulation). Neither immune response nor CIRS score was significantly correlated with chronological age in this sample of older adults with varying degrees of chronic illness. CONCLUSION: This study demonstrates that the level of comorbidity correlates with the magnitude of immune response in older adults and suggests that the CIRS could be used to determine the magnitude of impaired immunity in older adults with different specific illnesses and different levels of severity.

Immune dysfunction in the elderly and its reversal by antihistamines.

The decline in immunity seen in the elderly is a significant contributor to disease burden. This decline has largely been attributed to alterations in T cell immunity and contributes to an overall increased risk and severity of infection in the elderly. A key component of T cell immunity involves antigen presentation, an event where an antigen is processed and presented to specific immune cells for destruction. This event has been found to be crucial to immune function. Recent research has focused on a key antigen presenting cell (APC), the dendritic cell (DC), and changes within its function associated with aging. DCs are considered to be the most professional APCs, and are responsible for the initiation and outcome of effector T cells and their resultant immune response. DCs capture antigens and undergo a maturation process and polarize into either type 1 dendritic cells (DC1) or type 2 dendritic cells (DC2), based upon their ability to favor a T helper1 (Th1) or T helper 2 (Th2) T cell response, respectively. Evidence suggests that in normal healthy adults, a Th1 type response predominates, and in frail elders, a Th2 response predominates. It has been proposed that this change from a predominately Th1 type to a predominate Th2 type response is a possible mechanism for age-associated immune dysfunction. In addition, recent research has focused on how histamine, an inflammatory mediator, promotes a Th2 response. Histamine has also been shown to polarize human DCs into Th2 cell-promoting effector DCs or DC2s. This has been shown to occur via interaction with the H2 receptor. Therefore, we theorize that use of an H2 selective antihistamine will reverse this polarization back to a Th1 type response and therefore improve immune function of the frail elderly.

The frail elderly: role of dendritic cells in the susceptibility of infection.

The decline in immunity in the elderly has largely been attributed to impairment of T cell mechanisms. This seems reasonable since the thymus involutes with age, so that the number of naïve cells to respond to new foreign antigens also declines. However, little is known about how aging affects antigen-presenting cells (APC) that are responsible for the initiation and outcome of effector T cell immune responses. This review focuses on the age-related alterations of a key APC, the dendritic cell (DC). Recent findings suggest that interleukin-10, a key cytokine that can suppress cell mediated immunity and maturation of DC subsets, is elevated in the very healthy elderly. However, production of IL-12, required for the initiation of T cell immune responses, declines in frail elderly along with DC antigen presenting function. These findings suggest that shifts in IL-10 and IL-12 may not only directly influence immune response but may also alter the balance and maturation of DC subsets. Finally, study of immunologic differences between the very healthy and frail elderly may reveal important changes in DC function and regulation influenced by age and/or environment (disease, nutrition, medications, etc.).