Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors.

Studies of the diminished mitogen-induced proliferative response of T lymphocytes from older subjects show that aging must result in some defect(s) in the intracellular events required for transition from the G0 or quiescent state through the prereplicative interval and into the first S phase of the cell cycle. This conclusion is supported by observations of diminished inducibility of the lymphokine IL-2 and its receptor during aging. The current study demonstrates that decreased proliferative response to phytohemagglutinin (PHA) is also paralleled by decreased induction during the prereplicative interval of two of the most strongly enhanced proteins in mitogen-activated T cells: HSP90 and P73, which are also members of the heat-shock protein family. Diminished induction of HSP90 and P73 is observed in lymphocytes from older subjects (mean age 75), regardless of differences in health status of the subject populations. These results suggest that in vivo aging of human T cells results in a general defect in the induction of gene products required for transition from quiescence into the S phase of the cell cycle and that diminished T cell proliferation in advanced age is not due to a specific, "intrinsically immunologic" defect in induction of IL-2 and the IL-2 receptor.

Cutaneous-delayed hypersensitivity in nursing home and geriatric clinic patients. Implications for the tuberculin test.

Cutaneous-delayed hypersensitivity was studied by one and two-step Mantoux-type skin tests to four standard antigens in 33 elderly nursing home residents, 34 geriatric clinic patients, and 20 healthy young adult controls. Demographic and anthropometric data were collected to determine the effects of nutrition and other variables on cutaneous-delayed hypersensitivity. Anergy (a lack of response greater than 5 mm of induration when read at 48 hours) to any of the four antigens occurred in 34% of nursing home residents, 17% of geriatric clinic patients, and none of the healthy young adults. Mean and maximal responses were less in the nursing home residents than the clinic patients or controls, even if anergic individuals were excluded from analysis, suggesting both a qualitative and quantitative decline in cell-mediated immune function in this elderly population. Repeat testing with each antigen for which there was a negative initial response revealed a "booster" affect of 7 to 19% and occurred as commonly in the healthy young adults as in the nursing home residents or geriatric clinic patients. The mumps antigen elicited strong responses in the healthy young adults, but weak reactions in the nursing home residents. An unexpectedly high prevalence of positive tuberculin (PPD) responses occurred in the nursing home residents, suggesting recent exposure. Analysis of anthropometric and demographic characteristics show that neither nutritional status nor age alone can account for differences in cutaneous-delayed hypersensitivity observed between populations. Cutaneous-delayed hypersensitivity may vary widely between elderly populations and have important practical implications for the tuberculin test.

Expression of the human T cell antigen receptor complex in advanced age.

Several studies of T cell-associated surface marker expression in older subjects "with no evidence of diseases known to affect immune function" have suggested that diminished expression of the constant portion (CD3) of the human T cell antigen-receptor complex (CD3/Ti) may be associated with aging. To determine if there is a decrease with age in expression of this complex, we determined the percent of cells positive for WT31, an antibody that recognizes a constant epitope on Ti alpha-beta heterodimers, CD3, CD4 and CD8 by immunofluorescence on peripheral blood lymphocytes from young controls (19-31 years), and 2 well characterized populations of older donors (greater than 69 years). The first group of older donors had no history of chronic or recent acute illness and saw a physician only for routine medical care. The second group was selected from patients seen in a geriatrics clinic for diagnoses that included osteoarthritis and cardiopulmonary disorders. There were no significant differences in the percent of cells positive with WT31, or with antibodies to CD4 and CD8 between young adults and the 2 groups of older donors. The clinic subjects showed a consistent decrease in percent of CD3+ lymphocytes in peripheral blood mononuclear cells compared to young adults (5-10% reduction) with less difference between the healthy older subjects and young adults. In the clinic subjects this reduction appears to be due to a decrease in CD3+, WT31-lymphocytes. These cells represent about 5-6% of the total T cell population in the young and healthy older group and are known to express CD3 in combination with Ti gamma-delta dimers. We show here that these cells are about equally distributed in high and low density lymphocytes after Percoll fractionation. We conclude that significant quantitative reduction in expression of the CD3/Ti antigen-receptor complex on human T cells is not a feature of the primary aging process and cannot account for diminished in vitro proliferative response of healthy subjects with age. However, diminished abundance of T cells expressing products of the Ti gamma-chain in less healthy older subjects may predispose to or result from diseases not usually associated with altered immune function.

Lymphocyte proliferative response to PHA and anti-CD3/Ti monoclonal antibodies, T cell surface marker expression, and serum IL-2 receptor levels as biomarkers of age and health.

Alteration of T cell surface marker expression with a decrease of CD3 positive cells relative to the number of CD4 and CD8 positive cells, diminished in vitro proliferative response to mitogenic stimuli like PHA and antibodies to the CD3/Ti complex, and increase in serum IL-2 receptor levels, are among the changes in immunologic parameters that have been associated with advanced age. To distinguish between effects of the primary aging process and diseases of aging not known to be directly related to immune function, we investigated these variables in two well characterized populations of elderly donors (greater than 70 years) and a young adult control group (less than 35 years). The first group of older donors reported no evidence of significant chronic or recent acute illness and saw a physician only for routine medical care. The second group was randomly selected from individuals seen in a geriatric medicine clinic for diagnoses that included osteoarthritis and cardiopulmonary disorders. Altered surface marker expression and increased serum IL-2 receptor levels were seen only in the second group. On the other hand, lymphocyte proliferative responses to PHA, Leu 4 (anti-CD3) and a monoclonal antibody to the beta-chain of the T cell antigen receptor (WT31) were significantly decreased in both populations. Because we would expect primary aging to affect even extremely fit individuals of advanced age, we conclude that decrease in T cell proliferative response may represent a biomarker of primary aging in man. The alteration in surface marker expression and increased IL-2R levels in serum appear to be effects secondary to non-immunologic disease rather than aging.

Postmenopausal osteoporosis--intervention and prophylaxis. A review.

Postmenopausal osteoporosis is a common disorder associated with significant morbidity and mortality through fractures of the femoral neck, vertebrae and distal forearm. The national cost of this illness is measured in billions of dollars annually. Although the etiology of postmenopausal osteoporosis is unclear, specific effective therapies are available if initiated early in the course of the disease. A large body of information concerning this illness has been generated but many questions remain. The epidemiology, etiology, diagnosis and therapy of postmenopausal osteoporosis are discussed in this review with emphasis on prophylactic and interventional therapy as related to subpopulations of women at risk for osteoporosis.