The nitric oxide hypothesis of aging

McCann, Samuel M.; Licinio, Júlio; Wong, Ma-Li; Yu, Wen H.; Karanth, Sharada; Rettorri, V

doi:10.1016/s0531-5565(98)00050-3

Cited by 136 publications

(65 citation statements)

References 34 publications

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“…Stimulation of this pathway during the life appears to play an important role in the induction of molecular changes that modify the cellular adaptive responses, leading to a decreased function of several systems (Sapolsky 1992;McCann et al 1998). This ongoing process is the fundamental basis for the establishment of the aging process, so it is always associated with processes involving prolonged exposure to agents that induce some kind of toxicity.…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Kawamoto

Vasconcelos

Degaspari

et al. 2012

AGE

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Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study agerelated disorders and new anti-aging therapies.

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Section: Discussionmentioning

confidence: 99%

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Kawamoto

Vasconcelos

Degaspari

et al. 2012

AGE

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“…McCann et al have proposed that repeated infections throughout life result in bouts of iNOS expression, high level of NO production, and cytotoxicity, whose cumulative effect across the life span contributes to the aging process. 73 During systemic inflammation, iNOS gene expression was accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). The spillover of NO metabolites, such as nitrites, into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis.…”

Section: Medical Relevance Of High Il-1␤/il-1ra Mrna Ratio In the Bramentioning

confidence: 99%

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection

1999

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Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation. Of those, inflammation is the most compatible with the waxing and waning course of depression, and could explain the biology of this disorder that has a fluctuating course with severe episodes that can be followed by partial or complete remission. Over the years a body of evidence has been accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Major depression commonly co-occurs with ischemic heart disease and decreased bone mineral density. Depressive symptoms are known to have a negative impact on cardiovascular prognosis, increasing the mortality rate of coronary artery disease. Several lines of evidence indicate that brain cytokines, principally interleukin-1␤ (IL-1␤) and IL-1 receptor antagonist may have a role in the biology of major depression, and that they might additionally be involved in the pathophysiology and somatic consequences of depression as well as in the effects of antidepressant treatment. A particularly unique and novel aspect of the studies and views discussed here is their potential to lead to interventions which may reduce the morbidity and mortality risks for osteoporosis, cardiovascular disease, and behavioral symptoms in patients with major depression. We also discuss the emerging concept of peripheral and central cytokine compartments: their integration and differential regulation is a key element for the optimal functioning of the immune and nervous systems.

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“…This suggests that neuroinflammatory cytokines may be one of the known toxicants including beta-amyloid (Cotman & Su, 1996;Square, 1997;Matsukawa et al ., 2002), presenilins (Cotman & Su, 1996;Furukawa et al ., 1998;Hashimoto et al ., 2002) and free radicals (Smith et al ., 1992(Smith et al ., , 1994Carney & Carney, 1994;Hensley et al ., 1996;Joseph et al ., 1998;McCann et al ., 1998;Butterfield et al ., 1999;Kaufmann et al ., 2001) involved in the neuronal impairments characterizing central nervous system (CNS) aging and the progression of associated diseases. TNF α acts through specific receptors (TNFR-I and TNFR-II) that can positively activate a dual signalling cascade that in different cell types may lead to apoptosis, proliferation, differentiation or survival (Gruss, 1996;Arch et al ., 1998;Orlinick & Chao, 1998;Macdonald et al ., 2000).…”

Section: Introductionmentioning

confidence: 99%

Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: distinct converging pathways

et al. 2003

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SummaryPerturbations of neuronal physiological homeostasis are likely to underscore neuronal demise/impairments that are reportedly associated with aging of the central nervous system and age-related neurodegenerative diseases such as Alzheimer's disease (AD). A number of ageand/or disease-associated neurotoxic events has been described. These include abnormally modified proteins such as beta amyloid and hyper-phosphorylated Tau, cytokines such as tumour necrosis factor-alpha (TNFα α α α ), high levels of free radicals conducive to oxidative stress, and impaired/decreased neuronal trophic support by neurotrophic factors. Overall, it could be argued that toxic events in the aged brain are either active, such as those due to a direct action of cytokines, or passive, such as those due to lack of growth factor support. It is therefore conceivable that cellular responses to such diverse toxic stimuli are different, suggesting that interventions should be targeted accordingly. In order to begin answering this question, we determined in PC12 cells the time course of activity, in response to TNFα α α α (active) or growth factor withdrawal (passive), of protein kinase c-zeta (PKCζ ζ ζ ζ ), nuclear factor kappa B (NFκ κ κ κ B), caspases 3 and 8, and poly (ADP-ribose) polymerase (PARP), key signal transduction elements associated with modulation of cell death/survival in PC12 cells. We found that the overall activity of PKCζ ζ ζ ζ , NFκ κ κ κ B and caspase 8 was significantly different depending on the apoptotic initiator. The pattern of caspase 3 and PARP activity, however, was not statistically different between serum-free-and TNFα α α α -induced cell death conditions. This suggests that two distinct cell responses are elicited that converge at caspase 3, which then induces downstream events involved in the execution of a common apoptotic programme. These results contribute to the aim of differentially targeting neuronal death in the aged brain (characterized by neurotrophic factor impairments) or in the diseased brain (e.g. AD, characterized by elevated levels of pro-inflammatory cytokines).

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The nitric oxide hypothesis of aging

Cited by 136 publications

References 34 publications

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection

Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: distinct converging pathways

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