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Biomedical subjects

W B Ershler

Publications and source records attributed to W B Ershler.

At least 19 recordsLinked to original sources
PubMed2001

Intrinsic and environmental influences on immune senescence in the aged monkey.

Several factors associated with the age-related decline in immunity were examined in three studies on aged rhesus monkeys. Natural killer (NK) cell activity was found to be low in many monkeys after 20 years of age, but exceptionally long-lived animals, older than 25 years, often had vigorous cytolytic responses. When NK activity was decreased in an aged monkey, it was predictive of fewer years of survival and a younger age at death. This prediction of mortality was associated with one nonimmune biomarker of aging in the monkey: nail growth rate. Monkeys with very slow nail growth and low NK activity were likely to die sooner. Although these findings might suggest an immutable course for the aging process, the housing conditions of old monkeys also had a pronounced effect on their NK activity. The highest NK responses were found in old monkeys housed with just one other old animal when compared to living alone or with just a young, juvenile monkey. It remains to be determined whether this type of psychosocial influence could have a sustained effect on immunity and ultimately change the pace of aging and time to mortality.

Aging↗
PubMed2000

Ovariectomy does not induce osteopenia through interleukin-6 in rhesus monkeys (Macaca mulatta).

To characterize the role of interleukin-6 (IL-6) in estrogen (E2)-depletion bone loss, we utilized a nonhuman primate model of human skeletal physiology. Adult female rhesus monkeys were sham-operated (S; n = 5), ovariectomized (ovx; n = 10), or ovx followed by E2 replacement (ovx + E2; n = 10) and evaluated for the indicated parameters at 0, 3, 6, and 9 months post-ovx. Lumbar spine bone mineral density (BMD) decreased by 3 months and continued to decline through 9 months in the ovx, but not in the ovx + E2 or S groups. Middle and distal radius BMD was decreased at 9 months in the ovx, but not in the ovx + E2 or S groups. The S group had marked fluctuations in bone remodeling parameters, and cytokine levels in S animals were consistent with menstrual cycling, and therefore only those values in the ovx and ovx + E2 groups are reported. Serum osteocalcin and skeletal-specific alkaline phosphatase were elevated in the ovx group compared with the ovx + E2 group. There was no difference in serum or bone marrow plasma IL-6 levels between the ovx and ovx + E2 groups. Similarly, there was no difference in basal or phorbol ester-stimulated IL-6 levels of peripheral blood mononuclear cell or bone marrow cell culture supernatants between groups. There was no difference in serum or bone marrow soluble IL-6 receptor between groups. However, the bone marrow plasma soluble IL-6 receptor levels were transiently increased from baseline at 3 months in the ovx but not in the ovx + E2 group. In summary, there was no bone loss in the ovx + E2 group, although the serum and bone marrow IL-6 levels were similar to those of the ovx group. These data suggest that modulation of IL-6 is not the key mechanism through which estrogen deprivation mediates bone loss in rhesus monkeys.

Animals↗
PubMed2000

Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty.

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

Age Factors↗
PubMed1999

Effects of estrogen replacement therapy on the circadian rhythms of serum cortisol and body temperature in postmenopausal women.

Estrogen replacement therapy (ERT) seems to enhance longevity in women. Both gender and aging have been shown to influence the regulation of circadian rhythms, yet little is known about the effect of ERT on circadian regulation. The aim of this study was to determine the effects of ERT (oral conjugated estrogen: Premarin, 0.625 mg) for 6-8 weeks on circadian serum cortisol by continuous blood sampling every 15 min for 24 h with simultaneous measurements of body temperature in six healthy postmenopausal women (range, 54-61 years). The results are presented as median values (range in quartiles). The circadian amplitude of cortisol increased during ERT from 20.20 (18.35, 23.61) to 25.97 (24.94, 27.74) microg/dL (p = 0.016), whereas the timing of nocturnal nadir and morning acrophase did not differ significantly. ERT lowered the 24-h body temperature from 37.03 degrees C (36.95 degrees C, 37.07 degrees C) to 36.90 degrees C (36.77 degrees C, 36.97 degrees C) (p = 0.038), but did not alter the peak and trough body temperatures significantly. These findings are noteworthy because the increased circadian amplitude of serum cortisol during ERT contrasts with the reduction in circadian amplitude seen with normal aging. The reduction in body temperature confirms the regulatory effect of ERT in thermoregulation and has implications regarding the correlation between basal metabolic rate and life span.

Body Temperature↗
PubMed1998

Estrogen inhibits phorbol ester-induced I kappa B alpha transcription and protein degradation.

Estrogen (E2) is known to prevent bone loss and the mechanism is, at least in part, mediated by inhibition of expression of cytokines such as interleukin-6 (IL-6). Expression of IL-6 is tightly regulated and the transcription factor NF kappa B can upregulate IL-6 gene expression by binding to its promoter region. NF kappa B is kept in an inactive state by associating with its cytoplasmic inhibitor I kappa B alpha. Upon mitogenic stimulation, I kappa B alpha becomes phosphorylated, followed by a rapid protein degradation. As a result, NF kappa B is released and translocate to the nucleus where DNA binding occurs. It has been shown that E2 treatment downregulates mitogen-induced IL-6 expression by inhibiting NF kappa B activity. Here, we sought to determine whether E2 regulates IL-6 gene expression by modulating the levels of I kappa B alpha. Our results show that E2 treatment almost completely inhibits phorbol ester-induced I kappa B alpha protein degradation. In addition, E2 inhibits phorbol ester-stimulated I kappa B alpha gene expression. Taken together, our results suggest that E2 maintains steady state levels of I kappa B alpha upon mitogen stimulation, resulting in inhibition of NF kappa B activation and IL-6 gene expression. This may explain the protective effect of E2 on bone loss.

DNA-Binding Proteins↗
PubMed1998

Orchiectomy increases bone marrow interleukin-6 levels in mice.

Interleukin-6 (IL-6) appears to be an important factor in disease states associated with bone resorption. There is both in vitro and in vivo evidence supporting the fact that androgens down-regulate interleukin-6 production. These observations, in combination with the fact that osteoblasts and bone marrow stromal cells produce IL-6, led us to hypothesize that orchiectomy-induced androgen loss will result in increased IL-6 expression in the bone microenvironment. To prove our hypothesis we assessed the effect of orchiectomy on IL-6 protein and mRNA expression in bone marrow and spleen. We found that orchiectomy was associated with increased serum IL-6 levels at 3 and 28 days postsurgery. Phorbol ester-stimulated IL-6 levels were also higher in supernatants from bone marrow and spleen cell cultures from orchiectomized mice compared with unoperated or sham-operated mice. Additionally, we found that steady state IL-6 mRNA levels were increased in bone marrow but not spleen cells. Finally, we found that orchiectomized mice had splenomegaly and increased bone marrow cellularity. Histopathology of the spleen revealed lymphoid hyperplasia accompanied by a marked mononuclear cell infiltration of the red pulp. We conclude that orchiectomy induces IL-6 expression in the bone marrow. These findings suggest that endocrine and cytokine interactions contribute to bone pathophysiology.

Animals↗
PubMed1997

Aging and cancer: issues of basic and clinical science.

The majority of patients with cancer in the United States are more than 70 years old. Despite the increased understanding of the molecular bases for both oncogenesis and aging, the overlap of cancer and aging at that level remains a wide-open research domain. Similarly, at the clinical level, there is also an increased awareness of the need for more information about the influence of host age on the development of tumors, on the growth and spread of the disease, and on treatment expectations. In this review, we have attempted to frame questions regarding cancer and aging from the perspective of biogerontology and geriatric medicine. An increased effort to address the issues of aging is of paramount importance at all levels of cancer investigation.

Adolescent↗
PubMed1997

The biology of aging: the current research agenda.

There has been and will continue to be a dramatic shift in the composition of our population with regard to age. Over the next several decades, the percentage of the population that is older than 65 years will nearly double. This has obvious and striking implications, particularly for health care. In anticipation of this change, there has been increased research activity in an attempt to understand the basic biology of aging and the mechanisms whereby older individuals become susceptible to disease. The authors reviewed MEDLINE data from the past 2 decades and key articles from the literature to develop a comprehensive overview of the background and current status of research in biomedical gerontology. They found that research in the mechanisms of aging has expanded strikingly during the past 20 years, and that there is now a more precise understanding of age-associated changes in cellular and molecular functions. Scientific overlap of these age-associated changes with the biology of cancer is now recognized. An appraisal of our current understanding of aging (or lack thereof) is made in this article. Selected key research questions are also presented, some of which are particularly germane to cancer biology and clinical oncology.

Aging↗
PubMed1997

Dietary restriction in rhesus monkeys: lymphopenia and reduced mitogen-induced proliferation in peripheral blood mononuclear cells.

Dietary restriction (DR) markedly extends mean and maximal life span, and retards the rate of biological aging in rodent models; however, it is unknown if these results occur in primate species. The purpose of the current study was to investigate selected immunologic outcomes in Rhesus monkeys subjected to DR for a period of seven years. Similar to observations in mice on DR, lymphopenia occurred in the restricted monkeys. Compared to normally fed controls, the mitogen-induced proliferative responses of peripheral blood mononuclear cells (PBMC) were reduced in monkeys subjected to DR very early in life (up to 1 year), but not in others restricted in young adulthood (3-5 years). These data indicate that lymphopenia is a shared occurrence in rodents and primates on DR. However, the mitogen-induced proliferative data accumulated in rodents and primates cannot now be compared because PBMC have not been studied long enough or in comparable detail in primates fed restricted diets.

Aging↗
PubMed1997

Ethanol activates the interleukin-6 promoter in a human bone marrow stromal cell line.

Chronic ethanol consumption is associated with the development of osteoporosis. The pro-inflammatory cytokine interleukin-6 (IL-6) plays a role in the development of osteoporosis through stimulation of osteoclastic activity. We hypothesized that ethanol promotes osteoporosis, in part, by increasing IL-6 production in the bone microenvironment. Accordingly, we evaluated ethanol's effect on IL-6 production in the Saka human bone marrow stromal cell line and in the HOBIT human osteoblast-like cell line. We found that ethanol increased IL-6 protein levels in the culture supernatants from Saka, but not HOBIT, cells. In addition, we observed that ethanol increased steady-state IL-6 mRNA levels and activated an IL-6 promoter-driven reporter vector in Saka cells. We conclude that ethanol stimulates IL-6 expression in the Saka bone marrow stromal cell line by enhancing transcriptional activity of the IL-6 gene. Our findings support the contention that ethanol may contribute to the pathogenesis of osteoporosis, in part, by increasing IL-6 expression in the bone microenvironment.

Bone Marrow Cells↗
PubMed1996

Molecular and cellular biology of interleukin-6 and its receptor.

Interleukin-6 (IL-6) is a member of the family of cytokines collectively termed "the interleukin-6 type cytokines." Among its many functions, IL-6 plays an active role in immunology, bone metabolism, reproduction, arthritis, neoplasia, and aging. IL-6 expression is regulated by a variety of factors, including steroidal hormones, at both the transcriptional and post-transcriptional levels. IL-6 achieves its effects through the ligand-specific IL-6 receptor (IL-6R). Unlike most other cytokine receptors, the IL-6R is active in both membrane bound and soluble forms. Defining mechanisms to control IL-6 or IL-6R expression may prove useful for therapy of the many clinical disorders in IL-6 plays a role.

Animals↗
PubMed1996

Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter.

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.

Cell Line↗