Aging is associated with cardiac autonomic nerve fiber depletion and reduced cardiac and circulating BDNF levels

Background Aging is a multifactorial process associated with an impairment of autonomic nervous system(ANS)function.Progressive ANS remodeling includes upregulation of expression of circulating catecholamines and depletion of cardiac autonomic nerve fibers,and it is responsible,in part,for the increased susceptibility to cardiac diseases observed in elderly subjects.Neurotrophic factors,such as brain-derived neurotrophic factor(BDNF)and nerve growth factor(NGF),are involved in synaptogenesis and neurite outgrowth processes,supporting neuronal cell differentiation and maturation.However,whether and how these factors and their downstream signaling are involved in cardiac aging remains unclear.Here,we tested whether,in the aged heart,the overall extent of autonomic fibers is reduced,owing to lower production of trophic factors such as BDNF and NGF.Methods In vivo,we used young(age:3 months;n=10)and old(age:24 months;n=11)male Fisher rats,whereas,we used human neuroblastoma(SH-SY5 Y)cells in vitro.Results Compared to the young rats,old rats displayed a marked reduction in the overall ANS fiber density,affecting both sympathetic and cholinergic compartments,as indicated by dopamineβ-hydroxylase(dβh)and vesicular acetylcholine transporter(Va Ch T)immunohistochemical staining.In addition,a marked downregulation of GAP-43 and BDNF protein was observed in the left ventricular lysates of old rats compared to those of young rats.Interestingly,we did not find any significant difference in cardiac NGF levels between the young and old groups.To further explore the impact of aging on ANS fibers,we treated SH-SY5 Y cells in vitro with serum obtained from young and old rats.Sera from both groups induced a remarkable increase in neuronal sprouting,as evidenced by a crystal violet assay.However,this effect was blunted in cells cultured with old rat serum and was accompanied by a marked reduction in GAP-43 and BDNF protein levels.Conclusions Our data indicate that physiological aging is associated with an impairment of ANS structure and function and that reduced BDNF levels are responsible,at least in part,for these phenomena.