Effect of Age on Fever Response to Recombinant Tumor Necrosis Factor Alpha in a Murine Model

Abstract

Certain elderly humans show a blunted fever response to infection. A study was designed using a murine model to assess the influence of age on the febrile response to the endogenous pyrogen, tumor necrosis factor alpha (TNF alpha). Twenty (10 young: 4-6 months; 10 old: 24-28 months) BALB/c mice were injected with 50 ng of TNF alpha into the intraperitoneal space; the experiments were repeated one week later with 100 ng TNF alpha. Control animals received intraperitoneal injections of pyrogen-free phosphate buffered saline. Temperatures were measured rectally at baseline and at 10-minute intervals for 90 minutes post-injection using a thermistor probe and temperature gauge. In the majority of the time intervals following injection, the mean temperature changes of young mice were significantly higher than old mice for both 50 ng and 100 ng doses of TNF alpha. Similarly, peak temperature changes from baseline were consistently higher in young animals following injection of TNF alpha. Moreover, the peak temperature changes in young mice after 50 ng TNF alpha injection were significantly higher than those in old mice following a 100 ng injection of TNF alpha. These findings confirm that (a) TNF alpha has a role in the pathogenesis of fever; (b) aging alters significantly the febrile response; and (c) a mechanism of this age-related blunted febrile response may involve TNF alpha.

Characterization of the sickness response in young and aging rats following E. coli infection

“…The CBT data are consistent with what others have found (Buchanan et al, 2008; Foster et al, 1992; Miller et al, 1991; Scarpace et al, 1992). That is, aging rats exhibited a blunted and delayed rise in CBT within the first twelve hours following infection with E. coli .…”

“…These exaggerated sickness behaviors are concordant with the exaggerated proinflammatory response found in the brain of aging animals. In contrast, increases in CBT in response to a peripheral immune challenge, have been repeatedly shown to be blunted or absent in aging rodents (Buchanan et al, 2008; Foster et al, 1992; Miller et al, 1991; Scarpace et al, 1992). These findings are obviously inconsistent with the exaggerated proinflammatory profile and sickness behaviors of aging rodents.…”

Mechanisms behind Interindividual Variations in Diseases

“…Age-related differences in disease presentation: Atypical presentations of diseases are common in old age patients because of influences of several factors such as impaired immunological function, poor nutrition, multiple pathologies, sensory deficit, psychiatric disor-ders and intercurrent drug treatment, which both modify and mask the typical symptoms and signs of disease in many elderly patients. Elderly patients have a blunted or absent fever response to infection because aging alters the febrile response to tumour necrosis factor alpha [14]. Afebrile bacteraemia is more frequently found in elderly patients than in non-elderly patients and nonspecific abnormalities, such as an alteration in mental status or a general malaise, can constitute the exclusive manifestations of bacteraemia in elderly patients [15,16].…”

Avaliação dos efeitos do LPS sobre parâmetros comportamentais e imunológicos em camundongos idosos

“…Outros trabalham corroboram menor intensidade de febre em ratos (SCARPACE et al, 1992;WACHULEC, PELOSO, SATINOFF, 1997;PELOSO et al, 2003) e humanos (YOSHIKAWA, 1983;BERMAN, FOX, 1985). Em camundongos também foi relatado abrandamento da febre após estimulação com IL-1, (NORMAM, YAMAMURA, YOSHIKAWA, 1988) e TNF-α (MILLER et al, 1991). Estudos com IL-1 marcada demonstraram que a passagem dessa citocina pela barreira hemato-encefálica em camundongos idosos foi menor do que em camundongos jovens ou de meia idade, sugerindo um mecanismo adicional (e talvez complementar à menor produção de PGE2) pelo menor desenvolvimento de febre em idosos, já que a administração i.c.v.…”

“…A perda de peso dos animais idosos não deve estar relacionada a mecanismos termogênicos, como tremores musculares que requerem alto gasto metabólico, já que animais idosos apresentam dificuldades no desenvolvimento da febre, ou mesmo, ausência da mesma, após administração de LPS, TNF ou IL-1 (BIBBY, GRIMBLE, 1991;SCARPACE et al, 1992;WACHULEC, PELOSO, SATINOFF, 1997;PELOSO et al, 2003;NORMAM, YAMAMURA, YOSHIKAWA, 1988;MILLER et al, 1991). Dados opostos foram obtidos por Godbout et al (2005).…”