Dietary restriction from middle age attenuates age-associated lymphoma development and interleukin 6 dysregulation in C57BL/6 mice.

Dietary restriction (DR) started in middle age profoundly reduces the occurrence of lymphoma in C57BL/6 mice. Here, we report immunocellular and molecular changes associated with this mode of cancer prevention. Twelve-month-old male C57BL/6 mice were either fed a control diet or subjected to moderate DR (approximately 25% < control intake). DR significantly reduced lymphoma development (incidence at 25 months, 19% of 72 control mice versus 5% of 60 DR mice). Flow cytometry of splenocytes showed that DR increased the percentage of CD4+ and CD8+ cells. Lymphomatous spleens displayed varied labeling patterns and high percentages of cells in S phase. Splenocyte c-myc expression tended to increase with age in controls and was reduced by DR. Lymphopenia and markedly reduced nucleated cell yields from peripheral lymphoid tissues were induced by DR. Serum interleukin 6 levels increased with age and were quite high (> 2500 pg/ml) in several mice with lymphoma and other histopathological findings. DR attenuated this age-associated increase. Immunohistochemical studies of lymphomatous spleens showed the presence of interleukin 6 in monocytic appearing cells but not in lymphoma cells. These observations support the possibility that an age-associated interleukin 6 dysregulation is important in lymphomagenesis.

The influence of immunosenescence on tumor growth and spread: lessons from animal models.

There has been a long-standing clinical impression that tumor grow more slowly in elderly patients, but, because of confounding variables, this impression has been difficult to substantiate by epidemiologic data. Animal models offer a way to explore the relationship between host age and tumor growth under more controlled conditions. Our studies with murine B16 melanoma xenografts, discussed here, show that tumor growth and spread is in fact reduced in older animals and suggest that age-associated changes in immune function may be partially responsible.

Polyribosome Formation in Relation to Cytokinin-induced Cell Division in Suspension Cultures of Glycine max [L.] Merr.

We have investigated the relationship between cell proliferation and protein synthetic capacity in a cytokinin-requiring strain of cultured soybean cells (Glycine max [L.] Merr. cv. Sodifuri, of cotyledonary origin) in suspension culture. When transferred to a defined medium lacking cytokinin, very little cell division or cell enlargement took place over the course of a 6-day culture period. Cells transferred to medium of the same composition, but containing 0.5 mum zeatin, exhibited rapid initial growth, with maximum mitotic activity occurring after 24 hours in culture, and a doubling of the cell population within the first 36 hours of the culture period. The polyribosomal RNA content of the cells decreased over the course of the first 24 hours of the growth cycle while the polyribosome to monoribosome (P/M) ratio increased. The increase in the P/M ratio was greater in the cytokinin-treated cells. This apparent relationship between cytokinin-induced cell proliferation and polyribosome formation was examined further. Polyribosome formation was stimulated when zeatin was added directly to cell populations which had been cultured for 24 hours in medium lacking a cytokinin. Transfer to fresh medium alone also stimulated polyribosome formation, whether this medium contained a cytokinin or not. The magnitude of transfer-induced polyribosome formation depended upon the initial cell density (number of cells/ml of medium). Regardless of the initial cell density and independent of the P/M ratios attained, the cytokinin-treated cell populations divided while the cytokinin-deprived cell populations did not. In vivo labeling with [(35)S]methionine and slab gel electrophoretic separation of sodium dodecyl sulfate derivatives of the labeled polypeptides demonstrated qualitative changes in the spectrum of proteins synthesized by the cytokinin-treated cells. These qualitative changes were independent of the cell density (and hence, independent of the P/M ratio) but they preceded cytokinin-induced cell division.

Cardiac involvement in metastatic breast cancer.

Metastatic disease is the most common cause of death in breast cancer. Although cardiac involvement has been reported in 12% to 30% of cases, intra-atrial involvement is rare. In this report we describe a 41-year-old woman with metastatic breast cancer whose left atrium was invaded by a metastatic tumor that resulted in intermittent left ventricular in-flow obstruction. Such a presentation has not been described previously in metastatic breast cancer. The pertinent literature is reviewed.

Lymphocyte-induced angiogenesis factor is produced by L3T4+ murine T lymphocytes, and its production declines with age.

Lymphocyte-induced angiogenesis factor (LIA) is a product of T lymphocytes which has been shown to stimulate new vessel formation. Because immune senescence most profoundly affects T lymphocyte functions, we suspected that LIA production would decline with age. An assay for angiogenesis stimulated by allogeneic reaction was performed by injecting spleen cells from young or old donor mice into the skin of irradiated allogeneic recipient mice. The spleen cells from young mice induced a significantly greater number of vessels than did cells from older mice. In additional experiments, spleen cells from young and old animals were treated with a monoclonal antibody GK 1.5) directed at the L3T4 antigen on murine T helper lymphocytes. Such treatment significantly reduced the new vessel formation induced by young lymphocytes but had no effect on that induced by lymphocytes from old animals. Studies employing indirect immunofluorescence demonstrated that the proportion of L3T4+ cells in the mononuclear fraction of splenocytes was nearly identical in both young and old mice. From these investigations we can conclude that (1) L3T4+ lymphocytes are responsible for LIA production, and (2) production, like that of other T lymphokines, declines with age.

Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction.

Interleukin-6 (IL-6) is a multifunctional cytokine that is proving to be a major contributor to the acute phase inflammatory response. IL-6 expression is normally low and serum levels are usually nondetectable in the absence of inflammation. With advancing age, however, serum levels become detectable and it is proposed that this reflects an age-associated loss in the normal regulation of gene expression for this molecule. There is also speculation that IL-6 may contribute to the pathogenesis of several diseases that are common in late-life including lymphoma, osteoporosis, and Alzheimer's disease. In this report we demonstrate that plasma levels of IL-6 rise with advancing age in well-selected healthy elderly people and comparably in old rhesus monkeys. That this change reflects a primary aging process is suggested by our findings in C57BL/6 mice in which the age-associated increase in the in vitro synthesis of IL-6 is largely prevented by life span-extending dietary restriction.