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T-kininogen (T-KG) is a reliable biomarker of aging in male Sprague-Dawley rats. Here we confirm, in a longitudinal study, a similar behavior in Fisher 344 rats of both sexes. In males, the increase in serum levels of T-KG follows an exponential curve, whereas in females the increase is best fitted by a linear curve. In both genders, dietary restriction delays the increase in T-KG. We have previously shown that T-KG inhibits T lymphocyte proliferation. Here we show that serum T-KG levels correlate negatively with the ability of splenocytes (most likely B cells) to proliferate in response to lipopolysaccharide. A similar correlation was not observed with other markers of inflammation, including [alpha]1-acid glycoprotein (AGP), haptoglobin, or interleukin-10. We conclude that the increase in serum T-KG represents a useful biomarker of aging in Fisher 344, and it correlates with decreased lymphocyte proliferation with age, although a cause-effect relationship has not been established.

We have previously reported on a defect in both extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in splenocytes obtained from old rats. In order to investigate whether these effects are conserved across species, we have now used mouse splenocytes to measure the effect of aging on the activation of the same two MAPK families: ERK and JNK. Our results demonstrate that, as in rats, both MAPK signal transduction pathways are affected by aging in mice, indicating the existence of a further defect located downstream of the receptor-proximal events. Whereas ERK1 and [p46.sup.JNK] activation were not significantly modified, the kinetics of both ERK2 and [p54.sup.JNK] activation and inactivation were affected in splenocytes from old animals. Specifically, by analyzing the kinetics of activation and inactivation of these enzymes, we found a nearly 50% decrease in the fold of activation of both ERK2 and [p54.sup.JNK]. These defects result in an overall diminution of enzyme activities without changes in the steady-state levels of relevant proteins. The impaired activity of these two MAPK pathways is likely to play a role in the reduced expression of interleukin-2 and diminished lymphoproliferation observed in old animals.

The effects of aging on basal anti-tumor NK cytotoxicity in humans are investigated to elucidate the common differences typically encountered in various experimental methods. The results indicate that NK cytotoxicity remains constant and does not change as an individual ages. However, there is no conclusive proof that age-associated changes never take place in NK cells.