Mechanisms Underlying Low Grade Inflammation During Aging

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There are a number of potential mechanisms for the higher level of chronic inflammation and hence oxidant stress, observed in the elderly than in younger subjects. The first of these is that the elderly are experiencing a higher level of asymptomatic bacteriuria. This possibility was studied in 40 consecutive patients (age 70-91 years) admitted to hospital for functional disability. Patients were examined for the presence or absence of bacteria in urine. Twenty subjects had positive urine culture and 20 sex- and age-matched subjects had negative urine culture. Patients with asymptomatic bacteriuria had significantly increased levels of circulating tumor necrosis factor receptors (sTNFR-I) and a higher number of neu-trophils in the blood compared with the group without bacteriuria. Thus, the study provides some support for the hypothesis that asymptomatic urinary infections are associated with low-grade inflammatory activity in frail, elderly subjects (30).

A second potential mechanism resides in endocrine changes during aging. In aging, dysregulation of secretion of hormones that come under the regulation of the HPA axis may occur. This may have impact on the regulation of cortisol secretion. Cortisol is important as an anti-inflammatory agent. The effect of aging on glucocorticoid (GC) sensitivity of pro-inflammatory cytokine production was examined in elderly men, testosterone-treated elderly men, and young controls. Stress-induced increases in cortisol did not differ significantly between experimental groups, but GC sensitivity increased significantly in young controls and testosterone-treated elderly men, whereas a decrease was found in untreated elderly men. As the increase in GC sensitivity after stress serves to protect the individual from detrimental increases of pro-inflammatory cytokines, the disturbed mechanism in elderly men may result in enhancement of inflammation. The decrease in sensitivity is linked to decreased testosterone production during aging as impaired sensitivity was partly restored by testosterone treatment (31). Now, there is a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in pro-inflammatory cytokines. Studies in men and postmenopausal women indicate a remarkable individual constancy in the ability of PBMCs to produce TNF-a ex vivo. Genetic determinants underlie this constancy. However, in premenopausal women, production is highly variable at an individual level indicating how ovarian hormones are able to override the influence of genotype (32). The exact mechanisms by which estrogen interferes with cytokine activity are still incompletely known but may potentially include interactions of the estrogen receptor with other transcription factors, modulation of nitric oxide activity, anti-oxidative effects, plasma membrane actions, and changes in immune cell function. Experimental and clinical studies also strongly support a link between the increased state of pro-inflammatory cytokine activity and postmenopausal bone loss (33).

The third potential mechanism is the general increase in the incidence in inflammatory disease that occurs with aging. However, the link between inflammation and aging is of a two-way nature, as chronic inflammation may contribute to the pathogenesis of many diseases encountered with greater frequency in the elderly population.

A fourth mechanism for the increase in inflammatory and oxidant stress during aging may be the increased association with obesity in the middle-aged and the elderly populations. It is well known that the adipocyte is able to produce a wide range of pro-inflammatory cytokines. Furthermore, a body mass index of >25 is associated with increased signs of inflammation (raised plasma acute phase protein concentrations), which decline if a program of weight loss is initiated [for review see Ref. (34)].

A fifth potential mechanism involving changes in peroxisome proliferator-activated receptor-a (PPARalpha) activity has been revealed by recent studies on aged mice (see next section).

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