The nitric oxide hypothesis of aging

Nitric oxide (NO), generated by endothelial (e) NO synthase (NOS) and neuro nal (n) NOS, plays a ubiquitous role in the body in controlling the functio n of almost every, if not every, organ system. Bacterial and viral products , such as bacterial lipopolysaccharide (LPS), induce inducible (i) NOS synt hesis that produces massive amounts of NO toxic to the invading viruses and bacteria, but also host cells by inactivation of enzymes leading to cell d eath. The actions of all forms of NOS are mediated not only by the free rad ical oxidant properties of this soluble gas, but also by its activation of guanylate cyclase (GC), leading to the production of cyclic guanosine monop hosphate (cGMP) that mediates many of its physiological actions. In additio n, NO activates cyclooxygenase and lipoxygenase, leading to the production of physiologically relevant quantities of prostaglandin E-2 (PGE(2)) and le ukotrienes. In the case of iNOS, the massive release of NO, PGE(2), and leu kotrienes produces toxic effects. Systemic injection of LPS causes inductio n of interleukin (IL)-1 beta mRNA followed by IL-beta synthesis that induce s iNOS mRNA with a latency of two and four hours, respectively, in the ante rior pituitary and pineal glands, meninges, and choroid plexus, regions out side the blood-brain barrier, and shortly thereafter, in hypothalamic regio ns, such as the temperature-regulating centers, paraventricular nucleus con taining releasing and inhibiting hormone neurons, and the arcuate nucleus, a region containing these neurons and axons bound for the median eminence. We are currently determining if LPS similarly activates cytokine and iNOS p roduction in the cardiovascular system and the gonads. Our hypothesis is th at recurrent infections over the life span play a significant role in produ cing aging changes in all systems outside the blood-brain barrier via relea se of toxic quantities of NO. NO may be a major factor in the development o f coronary heart disease (CHD). Considerable evidence has accrued indicatin g a role for infections in the induction of CHD and, indeed, patients treat ed with a tetracycline derivative had 10 times less complications of CHD th an their controls. Stress, inflammation, and infection have all been shown to cause induction of iNOS in rats, and it is likely that this triad of eve nts is very important in progression of coronary arteriosclerosis leading t o coronary occlusion. Aging of the anterior pituitary and pineal with resul tant decreased secretion of pituitary hormones and the pineal hormone, mela tonin, respectively, may be caused by NO. The induction of iNOS in the temp erature-regulating centers by infections may cause the decreased febrile re sponse in the aged by loss of thermosensitive neurons. iNOS induction in th e paraventricular nucleus may cause the decreased nocturnal secretion of gr owth hormone (GH) and prolactin that occurs with age, and its induction in the arcuate nucleus may destroy luteinizing hormone-releasing hormone (LHRH ) neurons, thereby leading to decreased release of gonadotropins. Recurrent infections may play a role in aging of other parts of the brain, because there are increased numbers of astrocytes expressing IL-1 beta thro ughout the brain in aged patients. IL-l and products of NO activity accumul ate around the plaques of Alzheimer's, and may play a role in the progressi on of the disease. Early onset Parkinsonism following flu encephalitis duri ng World War I was possibly due to induction of iNOS in cells adjacent to s ubstantia nigra dopaminergic neurons leading to death of these cells, which , coupled with ordinary aging fall out, led to Parkinsonism. The central ne rvous system (CNS) pathology in AIDS patients bears striking resemblance to aging changes, and may also be largely caused by the action of iNOS. Antio xidants, such as melatonin, vitamin C, and vitamin E, probably play an impo rtant acute and chronic role in reducing or eliminating the oxidant damage produced by NO. (C) 1998 Elsevier Science Inc.