In youth, arteries effortlessly expand and contract with each heartbeat.

As we age, arteries lose functional elasticity, which contributes to cardiovascular disorders.

An underlying cause of arterial stiffening is the age-related decline in endothelial nitric oxide.

Endothelial dysfunction is associated with decreased nitric oxide that contributes to:^1-5

• Hypertension
• Atherosclerosis
• Inflammation
• Heart Attack/Stroke

Protecting against endothelial dysfunction is a critical objective for heart-healthy diets, drugs, nutrients, and lifestyles.

The challenge has been to increase nitric oxide to restore more flexibility to our aging vasculature.                     

Nitric oxide is synthesized in our bodies primarily from the amino acid arginine.⁶

Preclinical evidence suggests that an arginine-degrading enzyme called arginase may increase with age. This deprives the endothelium of nitric oxide needed for youthful functionality.⁷

A proposed solution is a long-acting arginine that resists enzymatic degradation.

In two clinical trials, a novel arginine compound increased flow-mediated dilation and salivary nitrite levels (a marker of nitric oxide production).^8,9

• The endothelium is a thin layer of cells that line blood vessel walls.
• Endothelial dysfunction refers to malfunction of the inner arterial lining.

Support for Aging Arteries

People who follow a healthy lifestyle often develop a false sense of security that they will not suffer the circulatory disorders that are the leading killers in the Western world.

One reason for this optimism is that heart disease death rates declined dramatically from 1969 to 2014.¹⁰ Much of this can be attributed to reduced tobacco use, improved diets and medical treatments, better control of hypertension, along with increased use of supplements, and drugs that lower heart attack risk.¹¹

Regrettably, today's obesity epidemic is reversing the trend of reduced heart disease prevalence.¹²

Atherosclerosis is most often associated with heart attack risk, but many age-related disorders, including kidney impairment and memory loss, are related to circulatory insufficiencies.^13,14

Sales of sex-enhancing drugs are popular mainly because so many men suffer from erectile dysfunction caused by endothelial dysfunction.¹⁵

Arginine: The Nitric Oxide Precursor

Nitric oxide is synthesized in the body primarily from the amino acid L-arginine.⁶

Since the mid-1980s, arginine has been a popular supplement for people wanting to protect against nitric oxide deficit.

In preclinical and clinical studies, L-arginine has demonstrated other benefits, such as accelerating wound healing, and helping to maintain kidney function.^17-19

The most important role of L-arginine is its ability to produce nitric oxide, and thus protect against endothelial dysfunction (and subsequent atherosclerosis risk).^1,20

The elderly often suffer from accelerated atherosclerosis.²¹ One reason, preclinical studies suggest, is that the arginine-degrading enzyme arginase may increase with age, thus causing disruption to the endothelial lining.⁷

It is encouraging that arginine can help reverse this type of atherogenic endothelial event.²⁰ The challenge has been how to achieve more sustained arginine blood levels.

Nitric Oxide Deficit

Nitric oxide bioavailability tends to decline with age, impairing the ability of blood vessels to dilate as needed.^22,23

A nitric oxide deficit results in disruption of healthy endothelial function and structure.²³

Arginase is an enzyme present in multiple tissues in the body.²⁴ In the intestinal tract, arginase degrades about 40% of ingested arginine before it can be absorbed into the bloodstream.²⁵

Once in the bloodstream, L-arginine is further degraded by other enzymes with only a small amount remaining that can synthesize endothelial nitric oxide.²⁶

Reversing Arterial Stiffness

In one animal study, when the arginase enzyme was blocked in rat arteries, arterial dilation was increased. In this study, arterial dilation of young animals increased only modestly in response to arginase-blockade. In old animals, however, arterial dilation was increased to levels observed in young animals when arginase was blocked!²⁷

This study found that the arteries of old rats (23 months old) regained the same vasodilation as young rats (3 months old) in response to blocking the arginine-degrading arginase.

This rat study provides evidence of the adverse effects that aging has on the endothelium. More important, it demonstrated that aged arteries may be improved by providing the vascular system with more L-arginine.

Studies show that 60- to 70-year-old humans lose up to 90% of their endothelial nitric oxide production compared to healthy 20-year-olds.²⁸ This helps explain why so many elderly people suffer vascular disorders, and how fast they sometimes worsen after initial diagnosis.

A decades-long challenge has been enabling older people to derive arginine's nitric oxide-boosting benefits. The main impediment is the rapid degradation of arginine in the intestines and blood.²⁶

Overcoming Arginine’s Limitations

The major drawback to L-arginine has been that to achieve sustained blood levels, people had to take high doses throughout the day.

It was difficult to comply with this rigorous dosing requirement and there may be gastrointestinal side effects with ingesting this much arginine on a daily basis.⁴³

A more troublesome shortcoming of L-arginine is preclinical evidence suggesting an age-related increase in the activity of enzymes that rapidly degrade arginine.^7,27 This means that little ingested arginine is available to promote nitric oxide synthesis.²⁵

For people with increased arginase activity, supplemental L-arginine may not support adequate nitric oxide synthesis to protect against endothelial dysfunction.

This month's issue also describes a stabilized L-arginine that was demonstrated in two clinical trials to increase a marker of nitric oxide production and improve flow-mediated arterial dilation.

For longer life,

William Faloon, Co-Founder, Life Extension®

References

1. Clinic C. Endothelial Dysfunction. Cleveland Clinic. Accessed June 12, 2024. https://my.clevelandclinic.org/health/diseases/23230-endothelial-dysfunction
2. Bryan NS. Nitric oxide deficiency is a primary driver of hypertension. Biochemical pharmacology. Dec 2022;206:115325. doi:10.1016/j.bcp.2022.115325
3. Chen JY, Ye ZX, Wang XF, et al. Nitric oxide bioavailability dysfunction involves in atherosclerosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Jan 2018;97:423-428. doi:10.1016/j.biopha.2017.10.122
4. Raddino R, Caretta G, Teli M, et al. Nitric oxide and cardiovascular risk factors. Heart Int. 2007;3(1):18. doi:10.4081/hi.2007.18
5. Sharma JN, Al-Omran A, Parvathy SS. Role of nitric oxide in inflammatory diseases. Inflammopharmacology. Dec 2007;15(6):252-9. doi:10.1007/s10787-007-0013-x.
6. Ghasemi A. Quantitative aspects of nitric oxide production from nitrate and nitrite. Excli j. 2022;21:470-486. doi:10.17179/excli2022-4727.
7. Moretto J, Girard C, Demougeot C. The role of arginase in aging: A systematic review. Experimental gerontology. Feb 2019;116:54-73. doi:10.1016/j.exger.2018.12.011
8. James Komorowski DG. Inositol-Stabilized Arginine Silicate Reduces Exercise Induced Muscle Damage and Increases Perceived Energy. Journal of Exercise and Nutrition. 2023;6(1)
9. Rogers JM, Gills J, Gray M. Acute effects of Nitrosigine(R) and citrulline malate on vasodilation in young adults. Journal of the International Society of Sports Nutrition. Feb 24 2020;17(1):12. doi:10.1186/s12970-020-00343-y
10. Weir HK, Anderson RN, Coleman King SM, et al. Heart Disease and Cancer Deaths - Trends and Projections in the United States, 1969-2020. Preventing chronic disease. Nov 17 2016;13:E157. doi:10.5888/pcd13.160211
11. Mensah GA, Wei GS, Sorlie PD, et al. Decline in Cardiovascular Mortality: Possible Causes and Implications. Circ Res. Jan 2017;120(2):366-380. doi:10.1161/CIRCRESAHA.116.309115
12. Alwadeai KS, Almeshari MA, Alghamdi AS, et al. Relationship Between Heart Disease and Obesity Indicators Among Adults: A Secondary Data Analysis. Cureus. Mar 2023;15(3):e36738. doi:10.7759/cureus.36738
13. Lee HS, Lim HI, Moon TJ, Lee SY, Lee JH. Trajectories of atherosclerotic cardiovascular disease risk scores as a predictor for incident chronic kidney disease. BMC nephrology. Apr 22 2024;25(1):141. doi:10.1186/s12882-024-03583-1
14. Sabayan B, Goudarzi R, Ji Y, et al. Intracranial Atherosclerosis Disease Associated With Cognitive Impairment and Dementia: Systematic Review and Meta-Analysis. Journal of the American Heart Association. Nov 20 2023;12(22):e032506. doi:10.1161/JAHA.123.032506
15. De Leonardis F, Colalillo G, Finazzi Agro E, Miano R, Fuschi A, Asimakopoulos AD. Endothelial Dysfunction, Erectile Deficit and Cardiovascular Disease: An Overview of the Pathogenetic Links. Biomedicines. Aug 1 2022;10(8)doi:10.3390/biomedicines10081848
16. Wu G, Meininger CJ, McNeal CJ, Bazer FW, Rhoads JM. Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans. Advances in experimental medicine and biology. 2021;1332:167-187. doi:10.1007/978-3-030-74180-8_10
17. Schneider KL, Yahia N. Effectiveness of Arginine Supplementation on Wound Healing in Older Adults in Acute and Chronic Settings: A Systematic Review. Advances in skin & wound care. Oct 2019;32(10):457-462. doi:10.1097/01.ASW.0000579700.20404.56
18. Tirani SA, Pezeshki Z, Nematbakhsh M, Nasri H, Talebi A. Effect of L-arginine and L-NAME on Kidney Tissue Damage in Rats after 24 h of Bilateral Ureteral Obstruction. International journal of preventive medicine. 2015;6:60. doi:10.4103/2008-7802.160339
19. Ghasemi M, Nematbakhsh M, Daneshmand F, Moeini M, Talebi A. Role of nitric oxide in kidney and liver (as distance organ) function in bilateral renal ischemia-reperfusion: Effect of L-Arginine and NG-nitro-L-Arginine methyl ester. Advanced biomedical research. 2015;4:233. doi:10.4103/2277-9175.167954
20. Strohle A, von Bibra H, Hahn A. L-Arginine and vascular health. Medizinische Monatsschrift fur Pharmazeuten. Dec 2016;39(12):515-20. Bedeutung von L-Arginin fur die Gefassgesundheit.
21. Wang JC, Bennett M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circulation research. Jul 06 2012;111(2):245-59. doi:10.1161/CIRCRESAHA.111.261388
22. Shannon OM, Clifford T, Seals DR, Craighead DH, Rossman MJ. Nitric oxide, aging and aerobic exercise: Sedentary individuals to Master's athletes. Nitric oxide : biology and chemistry. Aug 1 2022;125-126:31-39. doi:10.1016/j.niox.2022.06.002
23. Poeggeler B, Singh SK, Sambamurti K, Pappolla MA. Nitric Oxide as a Determinant of Human Longevity and Health Span. International journal of molecular sciences. Sep 26 2023;24(19)doi:10.3390/ijms241914533
24. Ming X-F, Yang Z. Functions and Mechanisms of Arginase in Age-Associated Cardiovascular Diseases. Current Translational Geriatrics and Experimental Gerontology Reports. 2013/12/01 2013;2(4):268-274. doi:10.1007/s13670-013-0060-7
25. Kurhaluk N. The Effectiveness of L-arginine in Clinical Conditions Associated with Hypoxia. International journal of molecular sciences. May 3 2023;24(9)doi:10.3390/ijms24098205
26. Wu G, Bazer FW, Davis TA, et al. Arginine metabolism and nutrition in growth, health and disease. Amino Acids. May 2009;37(1):153-68. doi:10.1007/s00726-008-0210-y
27. Berkowitz DE, White R, Li D, et al. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation. Oct 21 2003;108(16):2000-6. doi:10.1161/01.CIR.0000092948.04444.C7
28. Torregrossa AC, Aranke M, Bryan NS. Nitric oxide and geriatrics: Implications in diagnostics and treatment of the elderly. Journal of geriatric cardiology : JGC. Dec 2011;8(4):230-42. doi:10.3724/SP.J.1263.2011.00230
29. Hajizadeh-Sharafabad F, Sharifi Zahabi E. Role of alpha-lipoic acid in vascular function: A systematic review of human intervention studies. Crit Rev Food Sci Nutr. 2022;62(11):2928-2941. doi:10.1080/10408398.2020.1861425
30. Wang D, Ozen C, Abu-Reidah IM, et al. Vasculoprotective Effects of Pomegranate (Punica granatum L.). Frontiers in pharmacology. 2018;9:544. doi:10.3389/fphar.2018.00544
31. Zamani M, Rezaiian F, Saadati S, et al. The effects of folic acid supplementation on endothelial function in adults: a systematic review and dose-response meta-analysis of randomized controlled trials. Nutrition journal. Feb 24 2023;22(1):12. doi:10.1186/s12937-023-00843-y
32. Arabi SM, Bahari H, Chambari M, et al. Omega-3 fatty acids and endothelial function: A GRADE-assessed systematic review and meta-analysis. European journal of clinical investigation. Feb 2024;54(2):e14109. doi:10.1111/eci.14109
33. Ashor AW, Lara J, Mathers JC, Siervo M. Effect of vitamin C on endothelial function in health and disease: a systematic review and meta-analysis of randomised controlled trials. Atherosclerosis. Jul 2014;235(1):9-20. doi:10.1016/j.atherosclerosis.2014.04.004
34. Manolis AA, Manolis T, Melita H, Manolis AS. Role of Vitamins in Cardiovascular Health: Know Your Facts - Part 1. Current vascular pharmacology. 2023;21(6):378-398. doi:10.2174/1570161121666230912155548
35. Alalawi S, Albalawi F, Ramji DP. The Role of Punicalagin and Its Metabolites in Atherosclerosis and Risk Factors Associated with the Disease. International journal of molecular sciences. May 9 2023;24(10)doi:10.3390/ijms24108476
36. Miao Y, Guo Y, Chen Y, Lin Y, Lu Y, Guo Q. The effect of B-vitamins on the prevention and treatment of cardiovascular diseases: a systematic review and meta-analysis. Nutrition reviews. Oct 17 2023;doi:10.1093/nutrit/nuad127
37. Tutor A, O'Keefe EL, Lavie CJ, Elagizi A, Milani R, O'Keefe J. Omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases. Prog Cardiovasc Dis. May-Jun 2024;84:19-26. doi:10.1016/j.pcad.2024.03.009
38. Vajdi M, Noshadi N, Hassanizadeh S, Bonyadian A, Seyedhosseini-Ghaheh H, Askari G. The effects of alpha lipoic acid (ALA) supplementation on blood pressure in adults: a GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials. Frontiers in cardiovascular medicine. 2023;10:1272837. doi:10.3389/fcvm.2023.1272837
39. Khan SU, Lone AN, Khan MS, et al. Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis. EClinicalMedicine. Aug 2021;38:100997. doi:10.1016/j.eclinm.2021.100997
40. Guo J, Li K, Lin Y, Liu Y. Protective effects and molecular mechanisms of tea polyphenols on cardiovascular diseases. Front Nutr. 2023;10:1202378. doi:10.3389/fnut.2023.1202378
41. Margaritis M, Channon KM, Antoniades C. Statins as regulators of redox state in the vascular endothelium: beyond lipid lowering. Antioxidants & redox signaling. Mar 10 2014;20(8):1198-215. doi:10.1089/ars.2013.5430
42. Santos-Parker JR, Strahler TR, Bassett CJ, Bispham NZ, Chonchol MB, Seals DR. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging (Albany NY). Jan 3 2017;9(1):187-208. doi:10.18632/aging.101149
43. Grimble GK. Adverse gastrointestinal effects of arginine and related amino acids. The Journal of nutrition. Jun 2007;137(6 Suppl 2):1693S-1701S. doi:10.1093/jn/137.6.1693S