Aging is associated with reduced cellular immunity, which leads to increased rates of infectious disease, cancer and autoimmunity in the elderly. Previous findings from our laboratory revealed an age-related decline in sympathetic innervation of immune organs that affects immunity. These studies suggested potential sympathetic nervous system involvement in age-induced immune dysregulation. Objectives: The purpose of this study was to longitudinally characterize the effects of age on sympathetic neurotransmission in the spleen and net sympathetic activity/tone in male Fischer 344 rats. Methods: Splenic sympathetic neurotransmission was evaluated between 8 and 24 months of age by (1) splenic norepinephrine (NE) concentration and turnover, (2) β-adrenergic receptor (β-AR) expression and (3) β-AR-stimulated splenocyte cAMP production. Measures of sympathetic neurotransmission were correlated with age-related changes in Concanavalin A (Con A)-stimulated splenocyte proliferation. Results: Splenic NE turnover increased during middle age, then subsequently declined by 18 months of age compared with 8-month-old controls (young). Splenic NE concentration increased at 10 months and decreased at 18–24 months, compared with young rats; however, plasma NE levels were not affected by age. Plasma epinephrine levels were decreased at 24 months. NE synthesis blockade increased and decreased the rate of plasma catecholamine depletion in middle and old age, respectively. β-AR-stimulated cAMP production increased in splenocytes by 15 months. An age-related decrease in Con A-induced splenocyte proliferation was apparent by 10 months and persisted through 24 months. The decline in Con A-induced splenocyte proliferation correlated with the age-related increase in cAMP production. Conclusions: Aging alters sympathetic nervous system metabolism in the spleen to affect β-AR signaling to splenocytes, suggesting that altered sympathetic-immune modulation changes are evident by early middle age.

Aging leads to reduced cellular immunity with consequent increased rates of infectious disease, cancer and autoimmunity in the elderly. The sympathetic nervous system (SNS) modulates innate and adaptive immunity via innervation of lymphoid organs. In aged Fischer 344 (F344) rats, noradrenergic (NA) nerve density in secondary lymphoid organs declines, which may contribute to immunosenescence with aging. These studies suggest there is SNS involvement in age-induced immune dysregulation. Objectives The purpose of this study was to longitudinally characterize age-related change in sympathetic innervation of the spleen and sympathetic activity/tone in male Brown Norway (BN) rats, which live longer and have a strikingly different immune profile than the F344 rat, the traditional animal model for aging research. Methods Splenic sympathetic neurotransmission was evaluated between 8 and 32 months of age by (1) NA nerve fiber density; (2) splenic norepinephrine (NE) concentration; and (3) circulating catecholamines levels after decapitation. Results We report a decline in noradrenergic nerve density in splenic white pulp (45%) at 18 months of age compared with 8 month-old (M) rats, which is followed by a much slower rate of decline between 18 and 32 months. Lower splenic NE concentrations were consistent with morphometric findings. Circulating catecholamines levels generally dropped with increasing age. Conclusion These findings suggest there is a sympathetic-to-immune system dysregulation beginning at middle age. Given the unique T-helper-2 bias in Brown Norway rats, altered sympathetic-immune communication may be important for understanding the age-related rise in asthma and autoimmunity.

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Previous research in our laboratory demonstrated an age-related decline of noradrenergic (NA) sympathetic innervation in the spleens of male Fisher 344 (F344) rats, evident by 17 months of age that was not observed in 24-month-old male Brown Norway (BN) rats. Since, the growth and maintenance of mature sympathetic neurons is dependent on the synthesis of neurotrophic factors by a variety of cell types in target organs, we hypothesized that altered neurotrophic concentrations in spleens from aged F344 rats, but not in BN rats, may account for the strain-dependent differences. To test this hypothesis, total and free nerve growth factor (NGF) and neurotrophin-3 (NT-3) concentrations in spleens from young (3-month-old) and old male F344 (24-month-old) and BN (27-month-old) rats were determined by ELISA and correlated with splenic norepinephrine concentrations. Data were expressed as means + SEM, with subsequent Student's t-test performed to determine age-related difference (p≤0.05). In young adult F344 and BN rats the mean splenic concentrations of NT-3 and NGF were comparable to levels reported by other investigators. There was no effect of age on total splenic NGF concentrations (unbound + receptor bound) in either rat strain (p≥0.05). Unbound NGF concentrations in spleens from old F344 rats, and the ratio of free/bound NGF were significantly lower (p≤0.05) compared with young F344 controls. There was an age-related trend toward lower free NGF content in spleens from BN rats, but this was not statistically significant (p≥0.05). Conversely, the concentrations of free NT-3 in spleens from old F344 and BN rats were higher compared with young rats (p≤0.05). Age-associated changes in splenic neurotrophin content correlated with changes in splenic norepinephrine content. Collectively, these findings indicate altered neurotrophin expression in the aged spleen that may contribute to the previously reported strain-related differences in the density of sympathetic nerves in lymphoid compartments of the spleen with advancing age.