Nitric oxide and geriatrics: Implications in diagnostics and treatment of the elderly

Abstract

The nation's aging population is growing rapidly. By 2030, the number of adults age 65 and older will nearly double to 70 million. Americans are living longer and older adults can now live for many years with multiple chronic illnesses but with a substantial cost to health care. Twenty percent of the Medicare population has at least five chronic conditions i.e., hypertension, diabetes, arthritis, etc. Studies in experimental models and even humans reveal that constitutive production of nitric oxide (NO) is reduced with aging and this circumstance may be relevant to a number of diseases that plague the aging population. NO is a multifunctional signaling molecule, intricately involved with maintaining a host of physiological processes including, but not limited to, host defense, neuronal communication and the regulation of vascular tone. NO is one of the most important signaling molecules in our body, and loss of NO function is one of the earliest indicators or markers of disease. Clinical studies provide evidence that insufficient NO production is associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension, smoking and severity of atherosclerosis, and also has a profound predictive value for disease progression including cardiovascular and Alzheimers disease. Thirty plus years after its discovery and over 13 years since a Nobel Prize was awarded for its discovery, there have been no hallmark therapeutic breakthroughs or even NO based diagnostics. We will review the current state of the science surrounding NO in the etiology of a number of different diseases in the geriatric patient. From these observations, it can be concluded that enzymatic production of NO declines steadily with increasing age in healthy human subjects. Implementing strategies to diagnose and treat NO insufficiency may provide enormous benefit to the geriatric patient.

Keywords: Alzheimer's disease; bloodflow; cardiovascular disease; circulation; nitrate; nitrite.

Figure 1.. An overview of nitric oxide (NO) in various physiological, biochemical and pathological systems.

Figure 2.. NO production and biochemistry. There are a number of critical steps for the NOS production of NO from L-arginine. Under healthy conditions (top), enzymatic function proceeds normally. Under disease conditions (bottom), there can be a number of problems with L-arginine availability, transport and conversion to NO due to enzyme uncoupling or insufficient co-factor availability. Once produced, NO can form nitrosothiols or become oxidized to nitrite and nitrate which now recognized can be recycled to regenerate NO. NO: nitric oxide; NOS: nitric oxide synthase; FAD: flavin adenine dinucleotide; FMN: flavin mononucleotide; GSH: glutathione; GSSG: oxidized glutathione; GSNO: nitrosoglutathione; NADPH: nicotinamide adenine dinucleotide phosphate; ADMA: asymmetric dimethyl L-arginine.

Figure 3.. Two pathways for endogenous nitric oxide (NO) production. The L-arginine NO pathway can be enhanced through regular exercise, which becomes dysfunctional with age. The dietary pathway through reduction of nitrate and nitrite is not affected by age but is dependent on specific foods and diets. Both systems work in concert to maintain NO homeostasis.

Figure 4.. Hypothetical representation of nitric oxide (NO) produc tion based on diet and lifestyle.