Considering Nitric Oxide Mechanisms as a Target

Nitric oxide is present in many areas of metabolism that change with aging or that influence the pace of aging. Calorie restriction results in increased nitric oxide levels, for example, though as always researchers are far from putting all the pieces of the calorie restriction response together in a neat arrangement of cause and effect. Nitric oxide levels are thought to influence mitochondrial activity and stem cell populations as well, and both of those are important in aging. There is interest in trying to manipulate nitric oxide mechanisms in efforts to slow the progression of aging:

Nutrition and medical advancements leading to increased lifespan are not adequately translating into improved healthspan. Present-day gerontology research suggests that, unlike traditional approaches that focus on specific diseases, deciphering, and targeting the aging process itself could be the most clever approach toward increased healthspan.

Multiple cell effectors work together to cause the senescent cell phenotype. Particularly, two cellular organelles - nucleus and mitochondrion - have been implicated in the "wear and tear" aspects of aging. Nitric oxide (NO) generated through the endothelial nitric oxide synthase (eNOS) acts to promote mitochondrial biogenesis and bioenergetics, with a favorable impact in diverse chronic diseases of the elderly. Obesity, diabetes and aging share common pathophysiological mechanisms, including mitochondrial impairment and dysfunctional eNOS. Here we review the evidences that eNOS-dependent mitochondrial biogenesis and quality control, and possibly the complex interplay among cellular organelles, may be affected by metabolic diseases and the aging processes, contributing to reduce healthspan and lifespan.

Though still in its infancy, research on the role of the eNOS-NO system in the control of cell organelle connections and quality control might reveal exciting avenues for disease treatment in the coming years. The development of novel therapies aiming to preserve eNOS-NO signaling will benefit from the identification of site-specific interaction with the eNOS structure. Drugs or nutrients able to sustain the eNOS-NO generating system might contribute to maintain organelle homeostasis and represent novel preventive and/or therapeutic approaches to chronic age-related diseases. Efforts to identify druggable eNOS sites are ongoing, although our knowledge about the therapeutic usability of the proposed eNOS-targeting molecules in the long-term is limited.

Link: http://journal.frontiersin.org/article/10.3389/fcell.2015.00006/full

Comments

That's interesting. We've seen that nNOS and iNOS are involved in the pathogenesis of Alzheimer's degree to some extent (http://www.ncbi.nlm.nih.gov/pubmed/25454121), and inhibitors of those 2 have fostered symptomatic improvement in the lab. The fact that eNOS serves a more protective role will need to be considered when trying to implement this knowledge clinically.

Agmatine is known to inhibit both nNOS and iNOS at reasonable concentrations, while its action on eNOS requires a vastly higher concentration (see http://examine.com/supplements/Agmatine/#summary5-1). On the other hand, it has also proven to be an oxidative inactivator of nNOS, the implications of which are not clear in terms of clinical effect. Further study of agmatine and its behavior might, however, lead to a drug that acts to curb nNOS and iNOS without interfering with eNOS.

Posted by: Andrew at March 3rd, 2015 1:05 PM

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