Normalized Nitric oxide, Citrulline and a youthful endothelial function.
Nitric oxide (NO) is an important signaling molecule and the natural production of it decreases due to ageing. And this impacts or organism in a age related negative way. Citrulline is a substance that can be used to normalize NO.
-
Endothelial function and decreasing production of nitric oxide are signs of ageing and are correlated to multiple diseases. It is a well-known fact that targeting the levels nitric oxide can have an acute effect on the vascular system. Low levels of NO is a sign of dysfunction and/or ageing. For about 5 months I took 3-4 gr arginine alpha keto gluturate(AAKG) and 3-4 gr citrulline each evening. I used arginine AKG + citrulline in an experiment to rejuvenate my muscular and vascular system. This combination can improve declining levels of NO that comes with age. Right now I am questioning the risk reward profile when it comes to using large doses AAKG and Citrulline. I would like to share parts of what I have found regarding NO manipulation and citrulline related information.
Observations: The combination citrulline+ AAKG modestly increased my strength. But when I took large doses before exercise it blunted my exercise performance in endurance activities like running. Another anecdotal observation is that an 86 year old friend of the family, affected by sarcopenia and having difficulties walking up and down the stairs in her house and with several falls inside as well as outside in the garden, tried the same regimen and has had dramatically improvement in muscular strength and now she moves around much more easily in her house and has not had any falls for a few months. Her exercise program only helped her to a certain degree but the combination AAKG + citrulline + Exercise made the major improvement in her muscular function.
Nitric oxide in disease and aging
"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."
It has been shown that there is a gradual decline in endothelial function due to aging with greater than 50% loss in endothelial function in the oldest age group tested as measured by forearm blood flow assays. And there are also more dramatic findings in the coronary circulation of aging adults whereby there was a loss of 75% of endothelium-derived nitric oxide in 70-80 year old patients compared to young, healthy 20 year olds. This probably means that tjoe reach a youthful production of NO the ageing population need to rely on diet/supplementation/medications as the primary way to restore healthy NO levels and endothelial/vascular health.
Citrulline increase NO and acts as inhibitor of arginase (Arginase is an enzyme, which when it is overactive, is related to the dysfunction of many systems in the human body).
https://journals.physiology.org/doi/full/10.1152/physrev.00037.2016
"Arginase: A Multifaceted Enzyme Important in Health and Disease. In the last step in the urea cycle, arginase cleaves l-arginine to form urea and l-ornithine. In mammals, increases in arginase activity have been linked to dysfunction and pathologies of the cardiovascular system, kidney, and central nervous system and also to dysfunction of the immune system and cancer. overly active arginase can reduce the supply of l-arginine needed for the production of nitric oxide (NO) by NO synthase. Second, too much l-ornithine can lead to structural problems in the vasculature, neuronal toxicity, and abnormal growth of tumor cells.
The involvement of excessive activity of the arginase/ornithine pathway in cardiovascular and renal dysfunction and injury has been well documented by research in experimental models and human disease conditions. The involvement of these pathways in CNS disease and cancer has also been clearly demonstrated. Targeting specific elements in the arginase/ornithine pathways offers immense potential for the treatment of cardiovascular, renal, and CNS diseases as well as cancer. Studies in patients with cardiovascular disease have shown beneficial effects of local delivery of arginase inhibitors. However, extensive evidence substantiates a positive role for A1 activity in maintaining normal cell growth, collagen synthesis, and neuronal development as well as tissue repair from injury. Therefore, the global inhibition of arginase activity for extended periods could be detrimental."
A good thing is that supplementation with Citrulline Increases Plasma Nitric Oxide Levels as well as reduces Arginase Activity. Here the effects are reported from supplementation of Patients with Type 2 Diabetes. This indicate that citrulline might make it possible to adjust the level of NO upwards and at the same time adjust the level of Arginase downward.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783447/
"Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway."
l-Citrulline Supplementation: Impact on Cardiometabolic Health. This Is a good review of the effects of Citrulline on the cardiovascular system.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073798/
Citrulline supports vascular and muscle benefits from exercise in old persons. “vascular and muscular benefits associated with oral L-citrulline supplementation might be augmented by concomitant supplementation with exercise training in older adults”
https://www.citrage.com/wp-content/uploads/Revue-Figueroa-Moinard-2020.pdf
http://aups.org.au/Proceedings/44/13P/13P.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625972/
it is interesting that Citrulline might be able to reverse at least some of the agedependent decline of the muscular system and the preventive effect is (partly) achieved in an mTOR independent way.
“In conclusion, we demonstrate a novel direct protective effect of L-citrulline on skeletal muscle cell size independent of L-arginine that is mediated through induction of the inducible NOS (iNOS) isoform. This discovery of a nutritional modulator of iNOS mRNA expression in skeletal muscle cells could have substantial implications for the treatment of muscle wasting conditions.”
But what also is interesting with citrulline is that it might have a positive impact on brain health. (Could it be because improved endothelial function and reduced hypoperfusion?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934593/
Here, we show that citrulline (Cit) has powerful antioxidant properties that can limit ex vivo oxidative stress-induced LTP impairment in the hippocampus. We also illustrate that a three-month Cit supplementation has a protective effect on LTP in aged rats in vivo. The identification of a Cit oxidation byproduct in vitro suggests that the antioxidant properties of Cit could result from its own oxidation. Cit supplementation may be a promising preventive nutritional approach to limit age-related cognitive decline.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776113/
Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: Citrulline reduices APP (amyloid precursor protein) in hippocampus
But these findings regarding brainhealth are not undisputed. One hypothesis is that too much NO in the brain can act in a dysfunctional way and have a detrimental effect on our brains.
https://www.sciencedirect.com/science/article/pii/S0925443918304526?via%3Dihub
Functions and dysfunctions of nitric oxide in brain:
Nitric oxide (NO) works as a retrograde neurotransmitter in synapses, allows the brain blood flow and also has important roles in intracellular signaling in neurons from the regulation of the neuronal metabolic status to the dendritic spine growth. Moreover NO is able to perform post-translational modifications in proteins by the S-nitrosylation of the thiol amino acids, which is a physiological mechanism to regulate protein function. On the other hand, during aging and pathological processes the behavior of NO can turn harmful when reacts with superoxide anion to form peroxynitrite. This gaseous compound can diffuse easily throughout the neuronal membranes damaging lipid, proteins and nucleic acids. In the case of proteins, peroxynitrite reacts mostly with the phenolic ring of the tyrosines forming nitro-tyrosines that affects dramatically to the physiological functions of the proteins. Protein nitrotyrosination is an irreversible process that also yields to the accumulation of the modified proteins contributing to the onset and progression of neurodegenerative processes such as Alzheimer's disease or Parkinson's disease.
Where am I now?
When I came across the ideas that too much NO can do damage to the brain I decided to stop my experiment with 3-4 gr AAKG and 3-4 gr Citrulline. Citrulline may have positive effects on an ageing body but I am unsure of how to incorporate it into my regimen. At this point I can’t estimate what dose is optimal to reap the benefits from a normalized NO, a healthy endothelial function, improved bloodflow to the brain as well as to the muscles and other positive effects like normalizing an upregulated arginase.
I will be glad to receive general feedback and alternate ideas on what I have written as well as other ideas of how to optimize the endothelial function. Is what we already do enough to keep endothelial function in an optimal level?
-
Staffan Olsson
I would like to follow up on the importance of a rejuvenated vascular system with this paper. The paper does not provide us with a direct action to take, but it indicates that rejuvenation of the vascular system could be a fruitful way to stave of several of the effects of ageing.
"Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span | Science (sciencemag.org)"https://science.sciencemag.org/content/373/6554/eabc8479
They studied Vascular endothelial growth factor (VEGF) and found that insufficient VEGF signaling underlies vascular insufficiency in aged mice and that a slight compensatory increase in circulatory VEGF was sufficient to preserve a young-like vascular homeostasis, alleviate multiple adverse age-related processes, and ameliorate a host of age-associated pathologies in mice.“The study provides compelling evidence for the proposition that vascular aging is a hierarchically high driver of overall organismal aging. It places VEGF signaling insufficiency at center stage to multiorgan aging and suggests that its undoing might confer comprehensive geroprotection.”
“ Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice. Conversely, VEGF loss of function by conditional induction of transgenic sFlt1 in endothelial cells accelerated the development of these adverse age-related phenotypes. VEGF-treated mice lived longer and had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle loss (sarcopenia) associated with better preservation of muscle-generating force, reduced bone loss (osteoporosis), reduced kyphosis, and reduced burden of spontaneous tumors.”
-
Staffan Olsson
Another perspective on the importance ot a healthy vascular system and its role in antiaging. Hyperbaric oxygen therapy reduces brain hypoxia and improves cerebral functions.
"Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer’s disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. ..HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior....Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging."
-
-
HBOT has had some extremely promising new studies lately. If only it were more accessible!
