A Model of Premature Aging in Mice Based on Altered Stress-Related Behavioral Response and Immunosenescence

Abstract

The intensity of behavioral and neuroendocrine responses to stressful stimuli in rodent strains seems to be inversely related to their life span. We have previously shown that interindividual differences in members of outbred Swiss and inbred BALB/c mouse populations, both male and female, may be related to their behavior in a simple T-maze test. The animals that explore the maze slowly show impaired neuromuscular vigor and coordination, decreased locomotor activity, increased level of emotionality/anxiety, decreased levels of brain biogenic amines as well as immunosenescence and decreased life span, when compared to their control counterparts, which quickly explore the maze. These traits are similar to some of the alterations previously observed in aging animals and therefore we proposed that those ‘slow mice’ are biologically older than the fast animals and may be a model of prematurely aging mice (PAM). Although most of our work on this model has been performed on chronologically adult-mature animals, we have also shown that certain characteristics of PAM, such as increased anxiety and deficient immune response, are already present in chronologically young animals. Thus, it is tempting to hypothesize that chronic hyperreactivity to stress (trait anxiety) leading to immune dysfunction may have a causal relationship with impaired health and premature aging. In view of the link between oxidative stress and the aging process, the redox state of peritoneal leukocytes from PAM has been studied, showing an oxidative stress situation. In the present work we have determined the levels of a key antioxidant, reduced glutathione (GSH), and the oxidant malondialdehyde (MDA), a marker of lipid peroxidation, both in the spleen and brain of male and female PAM and non-PAM (NPAM). We found that GSH and MDA are decreased and increased, respectively, in PAM with respect to NPAM. Moreover, diet supplementation with antioxidants showed to be an effective strategy for protection against early immune and behavioral decline, altered redox state of leukocytes and premature mortality in PAM, which supports the validity of this model of premature aging as well as its link with oxidative stress.

Relationship between Oxidative Stress and Cardiomyopathic Changes in Ovariectomized Rats

“…LPO levels constitute a good marker of peroxidative damage to cell membranes [40,41]. Several studies have demonstrated that the amount of LPO increases with age [42,43,44]. It has also been described that the alteration in GSH concentration caused by ovariectomy is accompanied by increased LPO, with elevated production of malondialdehyde [42].…”

Psychological and metabolic stress: A recipe for accelerated cellular aging?

“…For example, in rats, freezing or slower maze performance predicts a premature aging syndrome, cognitive decline, lower antioxidants, and higher oxidative stress. 142,143 Further, greater behavioral reactivity or arousal is linked to shorter lifespan. 143 From an evolutionary perspective, anxiety prone individuals, those who tend to vigilantly monitor the environment, should do well in times of acute stress, but when exposed to chronic stress, the common condition in modern society, she or he will suffer from greater levels of allostatic load than other types of responders, such as those responding with anger rather than fear and anxiety.…”

Characterization of skeletal alterations in a model of prematurely aging mice

“…In addition, PAM was earlier characterized as a model of high oxidative stress in leukocytes (Alvarado et al 2006) and the neurological system (Viveros et al 2007). In the present study, we demonstrate that the gene expression levels of both FoxO1 and catalase, a FoxO1 target gene (Kops et al 2002), were increased in the femur of adult PAM.…”

“…A model of prematurely aging mice (PAM) in adult age has been proposed to study several molecular and physiological changes characteristic of premature senescence (Perez-Alvarez et al 2005;Viveros et al 2007). PAM are obtained from a regular colony of female ICR (CD-1) mice after submitting animals to a T-shaped maze.…”