The nitric oxide hypothesis of aging

Area of Science:

• Biochemistry
• Immunology
• Neuroscience

Background:

• Nitric oxide (NO) is a crucial signaling molecule produced by endothelial (e) and neuronal (n) NO synthases (NOS), regulating numerous physiological processes.
• Inducible (i) NOS is synthesized in response to bacterial and viral products like lipopolysaccharide (LPS), generating large amounts of NO that can be toxic to host cells.
• NO's actions involve both its radical oxidant properties and activation of guanylate cyclase (GC), leading to cyclic guanosine monophosphate (cGMP) production.

Purpose of the Study:

• To investigate the hypothesis that recurrent infections contribute to aging by inducing iNOS and releasing toxic levels of NO.
• To explore the role of NO in the pathogenesis of age-related conditions, including cardiovascular disease and neurodegenerative disorders.
• To examine the impact of LPS-induced iNOS production on various brain regions and endocrine glands.

Main Methods:

• Systemic LPS injection to induce iNOS synthesis in specific brain regions and endocrine glands.
• Measurement of interleukin (IL)-1 beta mRNA and protein levels following LPS administration.
• Assessment of iNOS mRNA induction and its latency in the anterior pituitary, pineal gland, meninges, choroid plexus, and hypothalamus.

Main Results:

• LPS induces IL-1 beta and iNOS mRNA in the anterior pituitary, pineal gland, meninges, and choroid plexus, with subsequent induction in hypothalamic regions.
• Hypothesis proposed that recurrent infections contribute to aging via toxic NO release, potentially impacting cardiovascular health and endocrine function.
• Potential mechanisms for age-related decline in hormone secretion (GH, prolactin, gonadotropins) and neurodegenerative diseases (Alzheimer's, Parkinson's) linked to iNOS activity.

Conclusions:

• Recurrent infections and the resulting iNOS induction may be a significant factor in the aging process and the development of age-related diseases.
• NO toxicity, particularly from iNOS, could underlie age-associated changes in the endocrine system and the central nervous system.
• Antioxidants like melatonin, vitamin C, and vitamin E may play a protective role against NO-induced oxidative damage.