Age-associated alterations in sympathetic noradrenergic innervation of primary and secondary lymphoid organs in female Fischer 344 rats

Abstract

Normal aging processes, as well as, psychological stress affect the immune system; each can act alone, or interact with each other, to cause dysregulation of immune function substantially altering physical and mental health. The sympathetic nervous system (SNS), a major mediator of stress effects on immune function, is significantly affected by normal aging process, and stress can affect aging of the SNS. Previously, we have shown age-associated changes in sympathetic noradrenergic (NA) innervation of lymphoid organs in male rodents that affect immune regulation. The purpose of this study was to investigate sympathetic innervation of lymphoid organs and associated alterations in immune responses in young and aging female Fischer 344 (F344) rats. Histofluorescence and immunocytochemistry for NA innervation, and neurochemistry for norepinephrine (NE) levels were performed in the thymus, spleen, and mesenteric lymph nodes (MLN) isolated from 3-month-old young (normal estrous cycle), 8-to 9-month-old (onset of irregular estrous cycling), and 24-25 month, and 30-31 month female F344 rats (acyclic) at diestrus based on vaginal smears. Age-related alterations in natural killer (NK) cell activity, interleukin-2 (IL-2) and interferon-γ (IFN-γ) production, T and B lymphocyte proliferation were examined in splenocytes. Sympathetic NA innervation and NE levels increased with aging in the thymus, declined in spleen and MLN, and was accompanied by significant reductions in NK cell activity, IL-2 and IFN-γ production, and T and B cell proliferation in old female rats. In 8-9 mo rats, NE levels in the hilar region of the spleen and IFN-γ production were unaltered, while NE levels in the end region of the spleen and IL-2 production were reduced. Collectively, these results suggest that aging is characterized by significant alterations in sympathetic NA innervation in the thymus, spleen, and MLN associated with immunosuppression, and that there is a marked shift in NA activity and immune reactivity occurring during middle-aged female rats.

Age-Associated Remodeling of Neural and Nonneural Thymic Catecholaminergic Network Affects Thymopoietic Productivity

“…The age-related rise in the density of noradrenergic nervous fibers was also observed in thymi from other rat strains and several mouse strains [56,57,60,113] . In Fisher 344 rats, similar changes in the thymic density of noradrenergic nerve fibers were found in thymi from both genders [61] . Since noradrenergic nerve fibers are the main source of NA in the thymus [89] , and as significant changes in their NA content were not observed with age, the agerelated rise in the thymic NA level [55-57, 60, 61] was attributable to the increase in density of noradrenergic nerve fibers.…”

“…This age-associated rise in NA level was registered in rats of both sexes [61] . Irrespective of gender, peripubertal gonadectomy was shown to prevent the age-related changes in thymic NA concentration, so that the level of this hormone/transmitter was significantly lower in young adult gonadectomized animals than in age-matched controls [101] .…”

“…However, in spite of tremendous efforts, which have been made by many laboratories, the causes and cellular and molecular mechanisms standing behind the thymus involution and decline in the thymic output have not yet been fully elucidated . There is an accumulating body of evidence suggesting that there are three groups of factors driving or contributing to the development of age-related thymic changes: (a) a reduction in the number of and the intrinsic defects in aged progenitor cells seeding the thymus [reviewed in 49 ]; (b) changes in the thymic microenvironment mirrored by a disproportional loss of TEC subsets and alterations in their function [reviewed in 47,49,50 ], and (c) an altered thymic action of extrinsic circulating (hormones/cytokines) [49,[51][52][53][54] and neural factors [55][56][57][58][59][60][61] . However, there is also evidence that the adult thymus remains active late in life and contributes functional T cells to the peripheral lymphoid pool [62] .…”

Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by <smlcap>L</smlcap>-Deprenyl

“…This hypothesis is consistent with the deprenyl-mediated reversal of the age-associated suppression of cell-mediated immune responses that accompany the loss of splenic sympathetic innervation [9,10,24], and thus favors the development of cancer [4,6]. Our findings on the effects of age and deprenyl on splenic sympathetic innervation and immune responses and the tumor-associated loss of sympathetic NA innervation accompanied by reduced cellular immunity in this study are also consistent with this hypothesis.…”

“…A similar decline in sympathetic NA innervation and/or NE concentration in the spleen has been observed in aging [9,10,24], arthritis [25,26] and autoimmune diseases [27,28]. Loss of splenic sympathetic NA innervations may result from elevated estrogen and PRL in tumor-bearing rats known to damage hypothalamic dopaminergic neurons [29,30].…”