Premature aging in behavior and immune functions in tyrosine hydroxylase haploinsufficient female mice. A longitudinal study

Abstract

Aging is accompanied by impairment in the nervous, immune, and endocrine systems as well as in neuroimmunoendocrine communication. In this context, there is an age-related alteration of the physiological response to acute stress, which is modulated by catecholamine (CA), final products of the sympathetic-adreno-medullary axis. The involvement of CA in essential functions of the nervous system is consistent with the neuropsychological deficits found in mice with haploinsufficiency (hemizygous; HZ) of tyrosine hydroxylase (TH) enzyme (TH-HZ). However, other possible alterations in regulatory systems have not been studied in these animals. The aim of the present work was to analyze whether adult TH-HZ female mice presented the impairment of behavioral traits and immunological responses that occurs with aging and whether they had affected their mean lifespan. ICR-CD1 female TH-HZ and wild type (WT) mice were used in a longitudinal study. Behavioral tests were performed on adult and old mice in order to evaluate their sensorimotor abilities and exploratory capacity, as well as anxiety-like behaviors. At the ages of 2 ± 1, 4 ± 1, 9 ± 1, 13 ± 1 and 20 ± 1 months, peritoneal leukocytes were extracted and several immune functions were assessed (phagocytic capacity, Natural Killer (NK) cytotoxicity, and lymphoproliferative response to lipopolysaccharide (LPS) and concanavalin A (ConA)). In addition, several oxidative stress parameters (catalase, glutathione reductase and glutathione peroxidase activities, and reduced glutathione (GSH) concentrations as antioxidant compounds as well as xanthine oxidase activity, oxidized glutathione (GSSG) concentrations, and GSSG/GSH ratio as oxidants) were analyzed. As inflammatory stress parameters TNF-alpha and IL-10 concentrations, and TNF-alpha/IL-10 ratios as inflammatory/anti-inflammatory markers, were measured. Animals were maintained in standard conditions until their natural death. The results indicate that adult TH-HZ mice presented worse sensorimotor abilities and exploratory capacity than their WT littermates as well as greater anxiety-like behaviors. With regards to the immune system, adult TH-HZ animals exhibited lower values of phagocytic capacity, NK cytotoxicity, and lymphoproliferative response to LPS and ConA than WT mice. Moreover, immune cells of TH-HZ mice showed higher oxidative and inflammatory stress than those of WT animals. Although these differences between TH-HZ and WT, in general, decreased with aging, this premature immunosenescence and impairment of behavior of TH-HZ mice was accompanied by a shorter mean lifespan in comparison to WT counterparts. In conclusion, haploinsufficiency of th gene in female mice appears to provoke premature aging of the regulatory systems affecting mean lifespan.