Asymmetric Dimethylarginine: A Never-Aging Story

Abstract

Human aging is intrinsically associated with the onset and the progression of several disease states causing significant disability and poor quality of life. Although such association was traditionally considered immutable, recent advances have led to a better understanding of several critical biochemical pathways involved in the aging process. This, in turn, has stimulated a significant body of research to investigate whether reprogramming these pathways could delay the progression of human ageing and/or prevent relevant disease states, ultimately favoring healthier aging process. Cellular senescence is regarded as the principal causative factor implicated in biological and pathophysiological processes involved in aging. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and an independent risk factor for several age-associated diseases. The selective extracorporeal removal of ADMA is emerging as a promising strategy to reduce the burden of age-associated disease states. This article discusses the current knowledge regarding the critical pathways involved in human aging and associated diseases and the possible role of ADMA as a target for therapies leading to healthier aging processes.

Keywords

asymmetric dimethylarginine - anti-aging therapy - therapeutic apheresis

Publication History

Received: 02 July 2024

Accepted after revision: 30 December 2024

Article published online:
26 May 2025

• References

• 1 Behr LC, Simm A, Kluttig A. et al. 60 years of healthy aging: on definitions, biomarkers, scores and challenges. Ageing Res Rev 2023; 88: 101934
• 2 Cosco TD, Howse K, Brayne C. Healthy ageing, resilience and wellbeing. Epidemiol Psychiatr Sci 2017; 26: 579-583
• 3 Olshansky SJ. From lifespan to healthspan. JAMA 2018; 320: 1323-1324
• 4 Malden DE, Mangoni AA, Woodman RJ. et al. Circulating asymmetric dimethylarginine and cognitive decline: a 4-year follow-up study of the 1936 Aberdeen Birth Cohort. Int J Geriatr Psychiatry 2020; 35: 1181-1188
• 5 Boger RH, Cooke JP, Vallance P. ADMA: an emerging cardiovascular risk factor. Vasc Med 2005; 10: S1-S2
• 6 Abbasi F, Asagmi T, Cooke JP. et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001; 88: 1201-1203
• 7 Boger RH, Bode-Boger SM, Thiele W. et al. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; 95: 2068-2074
• 8 North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res 2012; 110: 1097-1108
• 9 Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010; 362: 329-344
• 10 Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med 1988; 318: 818-828
• 11 Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol 2011; 23: 492-496
• 12 Gunasekaran U, Gannon M. Type 2 diabetes and the aging pancreatic beta cell. Aging (Albany NY) 2011; 3: 565-575
• 13 Nalysnyk L, Cid-Ruzafa J, Rotella P. et al. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 2012; 21: 355-361
• 14 Kwon YH, Fingert JH, Kuehn MH. et al. Primary open-angle glaucoma. N Engl J Med 2009; 360: 1113-1124
• 15 Cortes-Canteli M, Iadecola C. Alzheimer’s disease and vascular aging: JACC Focus Seminar. J Am Coll Cardiol 2020; 75: 942-951
• 16 Yuan Q, Wang H, Gao P. et al. Prevalence and risk factors of metabolic-associated fatty liver disease among 73,566 individuals in Beijing, China. Int J Environ Res Public Health 2022; 19: 2096
• 17 Bettonte S, Berton M, Marzolini C. Magnitude of drug-drug interactions in special populations. Pharmaceutics 2022; 14: 789
• 18 Campisi J, Kapahi P, Lithgow GJ. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 2019; 571: 183-192
• 19 Lopez-Otin C, Blasco MA, Partridge L. et al. The hallmarks of aging. Cell 2013; 153: 1194-1217
• 20 Aman Y, Schmauck-Medina T, Hansen M. et al. Autophagy in healthy aging and disease. Nat Aging 2021; 1: 634-650
• 21 Minami S, Nakamura S, Yoshimori T. Rubicon in metabolic diseases and ageing. Front Cell Dev Biol 2021; 9: 816829
• 22 Northrop JH. The influence of the intensity of light on the rate of growth and duration of life of Drosophila. J Gen Physiol 1925; 9: 81-86
• 23 Zhang ZD, Milman S, Lin JR. et al. Genetics of extreme human longevity to guide drug discovery for healthy ageing. Nat Metab 2020; 2: 663-672
• 24 McCay CM, Maynard LA, Sperling G. et al. The Journal of Nutrition. Volume 18 July-December, 1939. Pages 1–13. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. Nutr Rev 1975; 33: 241-243
• 25 Burkle A, Moreno-Villanueva M, Bernhard J. et al. MARK-AGE biomarkers of ageing. Mech Ageing Dev 2015; 151: 2-12
• 26 Guo J, Huang X, Dou L. et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 2022; 7: 391
• 27 Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell 2016; 61: 654-666
• 28 Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25: 585-621
• 29 Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37: 614-636
• 30 Baker DJ, Jeganathan KB, Cameron JD. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet 2004; 36: 744-749
• 31 Baker DJ, Jin F, van Deursen JM. The yin and yang of the Cdkn2a locus in senescence and aging. Cell Cycle 2008; 7: 2795-2802
• 32 Chinta SJ, Woods G, Demaria M. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson's disease. Cell Rep 2018; 22: 930-940
• 33 Bussian TJ, Aziz A, Meyer CF. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 2018; 562: 578-582
• 34 Childs BG, Baker DJ, Wijshake T. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 2016; 354: 472-477
• 35 Jeon OH, Kim C, Laberge RM. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 2017; 23: 775-781
• 36 Yosef R, Pilpel N, Tokarsky-Amiel R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 2016; 7: 11190
• 37 Childs BG, Baker DJ, Kirkland JL. et al. Senescence and apoptosis: dueling or complementary cell fates?. EMBO Rep 2014; 15: 1139-1153
• 38 Ovadya Y, Landsberger T, Leins H. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun 2018; 9: 5435
• 39 Fumagalli M, Rossiello F, Mondello C. et al. Stable cellular senescence is associated with persistent DDR activation. PLoS One 2014; 9: e110969
• 40 d'Adda di Fagagna F, Reaper FM, Clay-Farrace L. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426: 194-198
• 41 Mallette FA, Ferbeyre G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle 2007; 6: 1831-1836
• 42 Beausejour CM, Krtolica A, Galimi F. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 2003; 22: 4212-4222
• 43 Dulic V, Beney GE, Frebourg G. et al. Uncoupling between phenotypic senescence and cell cycle arrest in aging p21-deficient fibroblasts. Mol Cell Biol 2000; 20: 6741-6754
• 44 Herbig U, Jobling WA, Chen BP. et al. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 2004; 14: 501-513
• 45 D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43: 582-592
• 46 Islam MA, Sooro MA, Zhang P. Autophagic regulation of p62 is critical for cancer therapy. Int J Mol Sci 2018; 19: 1405
• 47 Barbosa MC, Grosso RA, Fader CM. Hallmarks of aging: an autophagic perspective. Front Endocrinol (Lausanne) 2018; 9: 790
• 48 Simonsen A, Cumming RC, Brech A. et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 2008; 4: 176-184
• 49 Ulgherait M, Rana A, Rera M. et al. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep 2014; 8: 1767-1780
• 50 Juhasz G, Erdi B, Sass M. et al. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 2007; 21: 3061-3066
• 51 Hars ES, Qi H, Ryazanov AG. et al. Autophagy regulates ageing in C. elegans. Autophagy 2007; 3: 93-95
• 52 Pyo JO, Yoo SM, Ahn HH. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 2013; 4: 2300
• 53 Fernandez AF, Sebti S, Wei Y. et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 2018; 558: 136-140
• 54 Cassidy LD, Young ARJ, Young CNJ. et al. Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk. Nat Commun 2020; 11: 307
• 55 Tabibzadeh S. Role of autophagy in aging: the good, the bad, and the ugly. Aging Cell 2023; 22: e13753
• 56 Ortega MA, Fraile-Martinez O, de Leon-Oliva D. et al. Autophagy in its (proper) context: molecular basis, biological relevance, pharmacological modulation, and lifestyle medicine. Int J Biol Sci 2024; 20: 2532-2554
• 57 Wiley CD, Velarde MC, Lecot P. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 2016; 23: 303-314
• 58 Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest 2013; 123: 951-957
• 59 Indo HP, Yen HC, Nakanishi I. et al. A mitochondrial superoxide theory for oxidative stress diseases and aging. J Clin Biochem Nutr 2015; 56: 1-7
• 60 Genova ML, Lenaz G. The interplay between respiratory supercomplexes and ROS in aging. Antioxid Redox Signal 2015; 23: 208-238
• 61 Zhang Y, Ikeno Y, Qi W. et al. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J Gerontol A Biol Sci Med Sci 2009; 64: 1212-1220
• 62 Kwon MJ, Lee KY, Lee HW. et al. SOD3 Variant, R213G, altered SOD3 function, leading to ROS-mediated inflammation and damage in multiple organs of premature aging mice. Antioxid Redox Signal 2015; 23: 985-999
• 63 Mossad O, Batut B, Yilmaz B. et al. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N(6)-carboxymethyllysine. Nat Neurosci 2022; 25: 295-305
• 64 Yeung SSY, Kwan M, Woo J. Healthy diet for healthy aging. Nutrients 2021; 13: 4310
• 65 Kiefte-de Jong JC, Mathers JC, Franco OH. Nutrition and healthy ageing: the key ingredients. Proc Nutr Soc 2014; 73: 249-259
• 66 Le Couteur DG, Simpson SJ. 90th Anniversary commentary: caloric restriction effects on aging. J Nutr 2018; 148: 1656-1659
• 67 Dominguez LJ, Veronese N, Baiamonte E. et al. Healthy aging and dietary patterns. Nutrients 2022; 14: 889
• 68 Shanley DP, Kirkwood TB. Caloric restriction does not enhance longevity in all species and is unlikely to do so in humans. Biogerontology 2006; 7: 165-168
• 69 Nowosad K, Sujka M. Effect of various types of intermittent fasting (IF) on weight loss and improvement of diabetic parameters in human. Curr Nutr Rep 2021; 10: 146-154
• 70 Vasim I, Majeed CN, DeBoer MD. Intermittent fasting and metabolic health. Nutrients 2022; 14: 631
• 71 Johnson JB, Summer W, Cutler RG. et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med 2007; 42: 665-674
• 72 Shen Y, Shi Q, Nong K. et al. Exercise for sarcopenia in older people: a systematic review and network meta-analysis. J Cachexia Sarcopenia Muscle 2023; 14: 1199-1211
• 73 Landi F, Liperoti R, Fusco D. et al. Prevalence and risk factors of sarcopenia among nursing home older residents. J Gerontol A Biol Sci Med Sci 2012; 67: 48-55
• 74 Furrer R, Handschin C. Lifestyle vs. pharmacological interventions for healthy aging. Aging (Albany NY) 2020; 12: 5-7
• 75 Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl 2003; 4: 33-40
• 76 Vallance P, Leone A, Calver A. et al. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol 1992; 20: S60-S62
• 77 Meinitzer A, Seelhorst U, Wellnitz B. et al. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study). Clin Chem 2007; 53: 273-283
• 78 Schlesinger S, Sonntag SR, Lieb W. et al. Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. PLoS One 2016; 11: e0165811
• 79 Zoccali C, Bode-Boger S, Mallamaci F. et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001; 358: 2113-2117
• 80 Jacobi J, Maas R, Cardounel AJ. et al. Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine. Am J Pathol 2010; 176: 2559-2570
• 81 Sydow K, Mondon CE, Schrader J. et al. Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler Thromb Vasc Biol 2008; 28: 692-697
• 82 Nakayama Y, Ueda S, Yamagishi S. et al. Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury. Kidney Int 2014; 85: 570-578
• 83 Stuhlinger MC, Conci E, Haubner BJ. et al. Asymmetric dimethyl l-arginine (ADMA) is a critical regulator of myocardial reperfusion injury. Cardiovasc Res 2007; 75: 417-425
• 84 Konishi H, Sydow K, Cooke JP. Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury. J Am Coll Cardiol 2007; 49: 1099-1105
• 85 Boger RH, Sullivan LM, Schwedhelm E. et al. Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation 2009; 119: 1592-1600
• 86 Schulze F, Maas R, Freese R. et al. Determination of a reference value for N(G), N(G)-dimethyl-l-arginine in 500 subjects. Eur J Clin Invest 2005; 35: 622-626
• 87 Sverdlov AL, Ngo DT, Chan WP. et al. Aging of the nitric oxide system: are we as old as our NO?. J Am Heart Assoc 2014; 3: e000973
• 88 El Assar M, Angulo J, Santos-Ruiz M. et al. Asymmetric dimethylarginine (ADMA) elevation and arginase up-regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans. J Physiol 2016; 594: 3045-3060
• 89 Perticone F, Sciacqua A, Maio R. et al. Endothelial dysfunction, ADMA and insulin resistance in essential hypertension. Int J Cardiol 2010; 142: 236-241
• 90 Juonala M, Viikari JS, Alfthan G. et al. Brachial artery flow-mediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study. Circulation 2007; 116: 1367-1373
• 91 Bode-Boger SM, Scalera F, Martens-Lobenhoffer J. Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc Med 2005; 10: S65-S71
• 92 Xiong Y, He YL, Li XM. et al. Endogenous asymmetric dimethylarginine accumulation precipitates the cardiac and mitochondrial dysfunctions in type 1 diabetic rats. Eur J Pharmacol 2021; 902: 174081
• 93 Xiong Y, Hai CX, Fang WJ. et al. Endogenous asymmetric dimethylarginine accumulation contributes to the suppression of myocardial mitochondrial biogenesis in type 2 diabetic rats. Nutr Metab (Lond) 2020; 17: 72
• 94 Scalera F, Borlak J, Beckmann B. et al. Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl l-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol 2004; 24: 1816-1822
• 95 Adelibieke Y, Shimizu H, Muteliefu G. et al. Indoxyl sulfate induces endothelial cell senescence by increasing reactive oxygen species production and p53 activity. J Ren Nutr 2012; 22: 86-89
• 96 Antoniades C, Shirodaria C, Leeson P. et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J 2009; 30: 1142-1150
• 97 Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 2006; 113: 1708-1714
• 98 Bode-Boger SM, Muke J, Surdacki A. et al. Oral l-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med 2003; 8: 77-81
• 99 Nisoli E, Clementi E, Paolucci C. et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 2003; 299: 896-899
• 100 Lourenco CF, Ledo A, Barbosa RM. et al. Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration. Free Radic Biol Med 2017; 108: 668-682
• 101 Chirkov YY, Horowitz JD. Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier?. Pharmacol Ther 2007; 116: 287-305
• 102 Wu Y, Shen S, Chen J. et al. Metabolite asymmetric dimethylarginine (ADMA) functions as a destabilization enhancer of SOX9 mediated by DDAH1 in osteoarthritis. Sci Adv 2023; 9: eade5584
• 103 Xie Z, Hou L, Shen S. et al. Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation. Nat Commun 2022; 13: 50
• 104 Alonso-Bouzon C, Carcaillon L, Garcia-Garcia FJ. et al. Association between endothelial dysfunction and frailty: the Toledo study for healthy aging. Age (Dordr) 2014; 36: 495-505