Aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide.

BACKGROUND: Age-related defects in the development of peripheral inflammatory responses have been observed in rodents and humans. OBJECTIVE: We examined the effects of age on a centrally injected endotoxin-induced cytokine production and cellular activation in mice. METHODS: Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injection of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter. ELISA for IL-1beta, IL-6, IL-12, and TNF-alpha were conducted on forebrain tissue homogenates as well as plasma samples, and lectin staining to detect activated microglia was prepared for selected brain slices. RESULTS: Intracerebroventricular injection of LPS in B6 mice produced an age-associated increase in mortality which was paralleled with a significant increase in brain and plasma levels of TNF-alpha. AntiTNF-alpha- and IL-6-immunoreactive cells possessed macrophagelike morphologies and were observed along the LPS injection tract and scattered throughout the hilus of the dorsal hippocampus and cerebral cortices. This LPS-mediated response was found to be specific in that the LPS-hyporesponsive mouse strain (C3H/HeJ) failed to demonstrate significant brain or plasma levels of TNF-alpha after LPS administration compared to C3H/HeN mice. CONCLUSION: These results suggest that the age-related increases in TNF-alpha production and mortality following the intracerebroventricular administration of LPS may be due to an increased endotoxin hypersensitivity of brain microglia/macrophages within aged animals.

Activity measures in rhesus monkeys on long-term calorie restriction.

Calorie restriction (CR), undernutrition without malnutrition, extends the mean and maximal lifespan of several ecologically diverse species. Rodents on CR demonstrate increased activity measured as spontaneous locomotion, wheel running, open field behavior or movement. Activity measures were recorded from 19 male rhesus monkeys (Macaca mulatta) as either controls (C) which were fed a nutritious diet to approximate ad libitum levels, or as experimentals (E) which were fed 30% less than age- and weight-matched controls. Within each diet group, some monkeys (n = 10) began CR at 2.3 years of age (range 2.2-2.4 yrs, J Group) while another group (n = 9) began CR at approximately 4.6 years of age (range 4-5.25, A group). Beginning about 6 years after initiation of the study, behavioral activity was measured via ultrasonic motion detectors and recorded on videotape. Diurnal and circadian activity was clearly discernible. Peaks in activity were associated with mealtime and colony husbandry. Compared to Group A, Group J monkeys exhibited higher overall activity as measured by sensors, and also significantly more circling. Compared to AC monkeys, group AE monkeys demonstrated higher rates of gross motor behavior, pacing, stereotypies and grooming. The increases in motor activity observed in one group of monkeys were consistent with results obtained from rodent studies of CR and aging. CR did not significantly inhibit or negatively influence the display of behavior of rhesus monkeys in the laboratory environment. We report here, for the first time, increases in activity due to CR in a model other than the rodent.