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Ageing Research Reviews 49 (2019) 144–164 Ageing Research Reviews 49 (2019) 144–164 Contents lists available at ScienceDirect Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr Homocysteine and age-associated disorders T ⁎ E.A. Ostrakhovitch , S. Tabibzadeh Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, CA, USA ARTICLE INFO ABSTRACT Keywords: There are numerous theories of aging, a process which still seems inevitable. Aging leads to cancer and multi- Homocysteine systemic disorders as well as chronic diseases. Decline in age- associated cellular functions leads to neurode- Hyperhomocysteinemia generation and cognitive decline that affect the quality of life. Accumulation of damage, mutations, metabolic Metabolism changes, failure in cellular energy production and clearance of altered proteins over the lifetime, and hy- Aging perhomocysteinemia, ultimately result in tissue degeneration. The decline in renal functions, nutritional defi- Age associated diseases ciencies, deregulation of methionine cycle and deficiencies of homocysteine remethylation and transsulfuration cofactors cause elevation of homocysteine with advancing age. Abnormal accumulation of homocysteine is a risk factor of cardiovascular, neurodegenerative and chronic kidney disease. Moreover, approximately 50% of people, aged 65 years and older develop hypertension and are at a high risk of developing cardiovascular in- sufficiency and incurable neurodegenerative disorders. Increasing evidence suggests inverse relation between cognitive impairment, cerebrovascular and cardiovascular events and renal function. Oxidative stress, in- activation of nitric oxide synthase pathway and mitochondria dysfunction associated with impaired homo- cysteine metabolism lead to aging tissue degeneration. In this review, we examine impact of high homocysteine levels on changes observed with aging that contribute to development and progression of age associated dis- eases. 1. Introduction (9.3+4.5 μmol/l) (Dankner et al., 2004). However, differences are at- tenuated after menopause (Fonseca et al., 1999). Development of hyperhomocysteinemia is a characteristic feature of Elevations in the plasma Hcy concentration in elderly can occur due aging. A marked increase in the incidence and prevalence of the disease to impairment of enzymes involved in homocysteine and B vitamins with advancing age associate with elevated homocysteine levels (Henry metabolism, impaired metabolism, nutritional deficiencies in vitamin et al., 2012). Up-regulation of homocysteine (Hcy) contributes to the cofactors, lifestyle conditions or other factors including use of drugs development of age-associated disorders, notably bone fractures, poor (Fig. 1). Decline in renal function due to structural and functional wound healing, loss of regenerative ability, cardiovascular dysfunction, changes that occur in the kidney with aging affects removal of Hcy and and decline in renal and cognitive functions. Increased levels of Hcy are causes elevation of Hcy (Glassock and Rule, 2012; Levi et al., 2014; seen in 5–7% of the general population (Clarke et al., 1991). The serum O’Sullivan et al., 2017). Physical inactivity in older age may also play a level of Hcy increases with age and reaches 16.5+0.5 μmol/l in elderly role in modulating the plasma level of Hcy (Kulkarni and Richard, people of 65 years of age with highest concentrations being found in 2003; Nygard et al., 1995). Numerous drugs can interfere with vitamin people 75 years of age or older (Adachi et al., 2002; Rodriguez et al., cofactors in homocysteine metabolism. Fibrates and nicotinic acid 2006). The most extreme values are associated with health issues. Some drugs used in the treatment of hypercholesterolemia can raise homo- studies have shown the probable association of various endogenous sex cysteine levels of Hcy by approximately 30 percent (Desouza et al., hormones and homocysteine levels. It has been shown that the serum 2002; Rosenson, 2003). Methotrexate and anticonvulsant, such as car- level of Hcy is higher in man (11.4+6.1 μmol/l) than in women bamazepine and valproic acid, impair folate metabolism causing the Abbreviations: Hcy, homocysteine; HHcy, hyperhomocysteinemia; AD, Alzheimer’s disease; CKD, chronic kidney disease; CBS, cystathionine β-synthase; MTR, methionine synthase; MTRR, MTR reductase; MTHFR, methylenetetrahydrofolate reductase; MTRR, 5-methyltetrahydrofolate-homocysteine methyltransferase re- ductase; BHMT, betaine-homocysteine S-methyltransferase; SAM, S-adenosyl methionine; SAH, S-adenosyl-homocysteine; THF, tetrahydrofolate; NLRP3, nucleotide- binding oligomerization domain-like receptor family pyrin domain-containing 3; HO-1, heme oxygenase; GFR, glomerular filtration rate; SOD, superoxide dismutase; ROS, reactive oxygen species; NO, nitric oxide; NOS, nitric oxide synthase ⁎ Corresponding author. E-mail addresses: [email protected] (E.A. Ostrakhovitch), [email protected] (S. Tabibzadeh). https://doi.org/10.1016/j.arr.2018.10.010 Received 9 March 2018; Received in revised form 30 September 2018; Accepted 25 October 2018 Available online 02 November 2018 1568-1637/ © 2018 Elsevier B.V. All rights reserved. E.A. Ostrakhovitch, S. Tabibzadeh Ageing Research Reviews 49 (2019) 144–164 Fig. 1. A schematic diagram relating aging and homocysteine upregulation. Various factors like hypertension, obesity, diabetes, diet and life style cause deregulation of homocysteine level. rise of Hcy level (Refsum and Ueland, 1990; Schwaninger et al., 1999). which lies at the cross-roads of several metabolic pathways. Hcy is the Smoking, alcohol consumption and nutritional deficiencies of B vita- product of the de novo pathway of the methionine metabolic reactions mins and folate are associated with elevated Hcy in older age (Jacques catalyzed by S-adenosyl methionine (SAM) and S-adenosylhomocys- et al., 2001; Nygard et al., 1998). Most vegetarians develop hyperho- teine (Dziegelewska et al., 2016). Hcy can be remethylated to methio- mocysteinemia and vitamin B12 deficiency since the major food source nine via the cobalamin (B12)-dependent and independent pathways or of vitamin B12 is meat (Obersby et al., 2013). High Hcy with low vi- can be metabolized to cysteine and other metabolites via transsulfura- tamin B12 and folate status was found in all centenarians tion pathway (Finkelstein, 2000). Hcy can also be converted into (Malaguarnera et al., 2004; Ravaglia et al., 2000). It has been suggested homocysteine thiolactone by methionyl-tRNA synthetase (MetRS). that centenarians may have some protective mechanisms that allow for Metabolism of Hcy depends on function of metabolic enzymes such as their longevity despite elevated levels of Hcy. methionine synthase (MTR), methylenetetrahydrofolate reductase DNA methylation has become a hallmark of aging. The age-specific (MTHFR), cystathionine β-synthase (CBS), 5-methylenetetrahy- drift in DNA methylation was linked to increased levels of homo- drofolate-homocysteine methyltransferase reductase (MTRR), betaine- cysteine and S-adenosylhomocysteine (Kamat et al., 2016; Tapp et al., homocysteine S-methyltransferase (BHMT) and availability of cofactors 2013; Wang et al., 2008). It was reported that regular intake of vitamins including vitamin B6 and B12 and folate (Fig. 2). involved in the methionine metabolism such as folic acid or vitamin B12 can slow down DNA methylation changes observed during the 2.1. CBS aging process. Supplementation of vitamins B and D associated with lower homocysteine were shown to slow down the epigenetic drift Cystathionine β-synthase (CBS) catalyzes pyridoxal phosphate-de- (Obeid et al., 2018). pendent conversion of Hcy to cystathionine. In animal models, it was The serum level of Hcy associates with increased all-cause mortality shown that during aging the expression of CBS was not changed fi risk in a linear fashion. Hyperhomocysteinemia (HHcy) is de ned when whereas its activity was significantly decreased (Wang et al., 2017a). μ plasma level exceeds 15 mol/L (Ravaglia et al., 2006). The level of Hcy The N-nitration of Trp208, Trp43 and Tyr223 and loss of thiolate co- μ reaches the level of 17.8+0.7 mol/l in patients with heart failure and ordination inhibits the CBS activity and contribute to age-related hy- μ the level as high as 20.2+1.5 mol/l in patients with cognitive im- perhomocysteinemia. One of the cause of high level of Hcy is a diet μ pairment. The risk of mortality increases for each 5 mol/L Hcy by enriched in methionine as confirmed in homozygous and heterozygous 33.6% (Fan et al., 2017). The development of neurodegenerative dis- CBS knockout mice placed on a high methionine diet (Dayal et al., ’ eases including Alzheimer s disease (AD) can be directly attributed to 2001). Both low dietary folate and cobalamin intake also lead to ele- ff neurotoxic e ect of Hcy (Eto et al., 2002; Sachdev, 2004; Seshadri vated Hcy since they required for reactions of methionine regeneration. et al., 2002; Van Dam and Van Gool, 2009). High Hcy concentrations, MTR and BHMT catalyze the regeneration of methionine from homo- μ over 30 M, are associated with cognitive impairment (Bonetti et al., cysteine. CBS expression decreases gradually with cellular aging 2016; Jin and Brennan, 2008). The prevalence of hyperhomocystei- leading to endothelial dysfunction (Albertini et al., 2012). nemia is significantly higher in patients with hypertension and ischemic heart disease (Asfar and Safar, 2007). Chronic hyperhomocysteinemia causes vascular remodeling by instigating vein phenotype in artery thus
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