Recent research shows that energy metabolism can strongly influence proteostasis and thereby affect onset of aging and related disease such as Parkinson’s disease (PD). Changes in glycolytic and proteolytic activities (influenced by diet and development) are suggested to synergistically create a self-reinforcing deleterious cycle via enhanced formation of triose phosphates (dihydroxyacetone-phosphate and glyceraldehyde-3-phosphate) and their decomposition product methylglyoxal (MG). It is proposed that triose phosphates and/or MG contribute to the development of PD and its attendant pathophysiological symptoms. MG can induce many of the macromolecular modifications (e.g. protein glycation) which characterise the aged-phenotype. MG can also react with dopamine to generate a salsolinol-like product, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinaline (ADTIQ), which accumulates in the Parkinson’s disease (PD) brain and whose effects on mitochondria, analogous to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), closely resemble changes associated with PD. MG can directly damage the intracellular proteolytic apparatus and modify proteins into non-degradable (cross-linked) forms. It is suggested that increased endogenous MG formation may result from either, or both, enhanced glycolytic activity and decreased proteolytic activity and contribute to the macromolecular changes associated with PD. Carnosine, a naturally-occurring dipeptide, may ameliorate MG-induced effects due, in part, to its carbonyl-scavenging activity. The possibility that ingestion of highly glycated proteins could also contribute to age-related brain dysfunction is briefly discussed.
Hipkiss Alan R.. On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine[J]. Aging and disease,
2017, 8(3): 334-345.
Possible common causal factors or processes to Parkinson’s disease and aging
Endogenous synthesis of methylglyoxal (MG): possible causes
High glycemic index diet
Inactivation of triose-phosphate isomerase
Decline of MG-scavenging or MG-eliminating processes
Effects of MG include
Formation of ADTIQ (neurotoxin)
Increased intake and possible effects of dietary protein-AGEs
Reaction with RAGEs in gut wall
Cell to cell transmission to CNS (??)
Induction of cognitive dysfunction (??)
Possible ameliorative strategies towards aging and PD
Increased mitochondrial function
Low glycemic index diet
Increased intake or synthesis of carnosine (an anti-glycating/MG-scavenging agent).
Increased intake of leafy plant tissues containing anti-glycating/MG scavenging agents.
Raised glyoxalase activity.
Table 1 Summary of factors which may either provoke or ameliorate age-related changes which contribute to Parkinson’s disease onset
Ingram DK, Roth GS (2011). Glycolytic inhibition as a strategy for developing calorie restriction mimetics. Expt Gerontol, 46: 148-154.
Hipkiss AR (2006). On the mechanisms of ageing suppression by dietary restriction - is persistent glycolysis the problem? Mech Ageing Dev, 127: 8-15.
Fontana L, Partridge L, Longo VD (2010). Extending human life span - from yeast to humans. Science, 328: 321-326.
Anderson RM, Weindruch R (2010). Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Meta, 21: 134-141.
Mattson MP, Wan R (2005). Beneficial effects of intermittent feeding and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem, 18: 129-137.
Martin B, Mattson MP, Maudsley S (2006). Caloric restriction and intermittent feeding: two potential diets for successful brain aging. Ageing Res Rev, 5: 332-353.
Partidge L (2010). The new biology of aging. Phil Trans R Soc B, 365: 147-154.
Ralser M, Warnelink MM, Struys EA, et al (2008). A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth. Proc Natl Acad Sci USA, 105, 17807-11.
Dai DF, Karunadharma PP, Chiao YA, et al (2014). Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell, 13: 529-39.
Kapahi P, Chen D, Rogers AN, et al (2010). With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab, 11:453-465.
Evans DS, Kapahi P, Hsueh W-C, Kockel L (2010). TOR signalling never gets old: aging, longevity and TORC1 activity. Aging Res Revs, 10: 225-237
Hipkiss AR (2010). NAD+ and metabolic regulation of age-related proteotoxicity: a possible role for methylglyoxal. Exp Gerontol, 45: 395-3099.
Desai KM, Wu L (2008). Free radical generation by methylglyoxal in tissues. Drug Metab Drug Interact 23, 151-173.
Desai KM, Chang T, Wang H, et al (2010). Oxidative stress and aging: is methylglyoxal the hidden enemy? Can J Physiol Pharmacol, 88: 273-284.
Semba RD, Nicklett EJ, Feerrucci L (2010). Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol (Med Sci), 65A: 963-75.
Adolphe JL, Drew MD, Huang Q, Silver TI, Weber LP (2012). Postprandial impairment of flow-mediated dilation and elevated methylglyoxal after simple but not complex carbohydrate consumption. Nutrit Res, 32: 278-284.
Uchiki T, Weikel KA, Jiao W, Shang F, et al (2012). Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease(in nondiabetics). Aging Cell, 11: 1-13.
Ahmed N, Thornalley PJ (2007). Advanced glycation endproducts: what is their relevance to diabetic complications? Diabetes Obes Metab, 9: 233-245.
Dhar I, Dhar A, Wu L, Desa KM (2013). Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose-fed Sprague- Dawley rats. PLoS One, 8(9) e74212
Fleming T, Cuny T, Nawroth G, Djuric Z et al. (2012). Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates? Diabetologia, 55: 1151-1155.
Beisswenger PJ, Howell SK, Smith K, Szwergold BS (2003). Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methyglyoxal levels in diabetes. Biochim Biophys Acta, 1637: 98-106.
Gracy RW, Talent JM, Zvaigze AL (1998). Molecular wear and tear leads to a terminal marking and the unstable isoforms of aging. Expt J Zool, 282: 18-27.
Hipkiss AR (2011). Energy metabolism and ageing regulation: metabolically driven deamidation of triosephosphate isomerase may contribute to proteostatic dysfunction. Ageing Res Revs, 10: 498-502.
Kalapos MP (2013). Where does plasma methylglyoxal originate from? Diabetes Res Clin Pract, 99: 260-71.
Newsholme EA, Start C. In Regulation in Metabolism, pp99, John Wiley and Sons, London 1973.
Ambrosi G, Ghezzi C, Sepe S, Milanese C, et al. (2014). Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson’s disease. Biochim Biophys Acta, 1842: 1385-1394.
Kalapos MP (1999). Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications. Toxicol Letts, 110: 145-175.
Rabbini N, Thornalley PJ (2012). Methylglyoxal, glyoxalase-1 and the dicarbonyl proteome. Amino Acids, 42:1133-42.
Untereiner AA, Dhar A, Liu J, Wu L (2011). Increased renal methylglyoxal formation with down-regulation of PGC-1α-FBPase pathway in cystathione-γ-lyase knockout mice. PLoS ONE, 6, e29592
Auburger G, Kurz A (2011). The role of glyoxalases for sugar stress and aging, with relevance for dyskinesia, anxiety and Parkinson’s disease. Aging 3: 5-9.
Munch G, Westcott B, Menini T, Gugliucci A (2012). Advanced glycation endproducts and their pathogenic roles in neurological disorders. Amino Acids, 42: 1221-1226.
Chondrogianni N, Petropoulos I, Grimm S, Georgila K, Catalgol B, Friguet B, Grune T, Gonos ES (2014). Protein damage, repair and proteolysis. Mol Aspects Med, 35:1-71
Rabbani N, Shaheen F, Anwar A, Masania J, Thornalley PJ (2014). Assay of methylglyoxal-derived protein and nucleotide AGEs. Biochem Soc Trans, 42: 511-517.
Queisser MA, Yao D, Geisler S, et al. (2009). Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes, 59: 670-678
Moheimani F, Morgan PE, van Reyk DM, Davies MJ (2010). Deleterious effects of reactive aldehydes and glycated proteins on macrophage proteasomal function: possible links between diabetes and atherosclerosis. Biochim Biophys Acta, 1802: 561-571.
Bento CF, Marques F, Fernandez R, Pereira P (2010). Methylglyoxal alters the function and stability of critical components of the protein quality control. PLoS One, 5, e13007.
SinhaRoy S, Banerjee S, Ray M, Ray S (2005). Possible involvement of glutamic and/or aspartic residue(s) and requirement of mitochondrial integrity for the protective effect of creatine against inhibition of cardiac mitochondrial respiration by methyglyoxal. Mol Cell Biochem, 271: 167-176.
Wang H, Liu J, Wu L (2009). Methylglyoxal-induced mitochondrial dysfunction in vascular smooth muscle cells. Biochem Pharmacol, 77: 1709-1715.
Campello L, Esteve-Rudd J, Bru-Martinez R, et al. (2013). Alterations in energy metabolism, neuroprotection and visual signal transduction in the retina of Parkinsonian MPTP-treated monkeys. PLoS One, 8(9) e74439.
Gomez A, Ferrer I (2009). Increased oxidation of certain glycolysis and energy metabolism enzymes in the frontal cortex in Lewy body disease. J Neurosci Res, 87: 1002-1013.
Dunn L, Allen Gfg, Mamais A, et al. (2014). Dysregulation of glucose metabolism is an early event in sporadic Parkinson disease. Neurobiol Aging, 35, 1111-1115.
Murakami K, Miyake Y, Sasaki S, Tanaka K. et al. (2010). Dietary glycemic index is inversely associated with the risk of Parkinson’s disease: a case-control study in Japan. Nutrition, 26: 515-521.
Okubo H, Miyake Y, Sasaki S, Murakami K. et al. (2012). Dietary patterns and risk of Parkinson's disease: a case-control study in Japan. Eur J Neurol, 19: 681-688.
Yang X, Cheng B (2010). Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced neurotoxicity. J Mol Neurosci, 42:145-153.
Cheng B, Yang X, An L, et al. (2009). Ketogenic diet protects dopaminergic neurones against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson’s disease. Brain Res, 1286: 25-31.
Stafstrom CE, Rho JM (2012). The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol, 3: 59
Zhang C, Lin M, Wu R, Wang X. et al. (2011). Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci USA, 108:16259-64.
Ferrer I, Martinez A, Bianco R, Dalto E, Carmona M (2011). Neuropathology of sporadic Parkinson’s disease before the appearance of parkinsonianism: preclinical Parkinson’s disease. J Neural Transm, 118: 821-839.
Vincent A, Briggs L, Chatwin GFJ, Emery E. et al. (2012). Parkin-induced defects in neurophysiology and locomotion are generated by metabolic dysfunction and not oxidative stress. Human Mol Gen, 21: 1760-1769.
Davison EJ, Pennington K, Hung CC, et al. (2009). Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function. Proteomics, 9: 4284-4297.
Requejo-Aguilar R, Lopez-Fabuel I, Fernandez E, et al. (2014). PINK-1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1. Nat Commun, 24:5:4514.
Gao J, Teng J, Liu H, Han X, Chen B, Xie A. (2014). Association of RAGE gene polymorphisms with sporadic Parkinson's disease in Chinese Han population. Neurosci Lett, 559:158-62.
Vincente Miranda H, El-Agnaf OM, Outeiro TF (2016). Glycation in Parkinson’s disease and Alzheimer’s disease. Mov Disord, 31: 782-90.
Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G (2012). Clinical features of Parkinson disease when onset of diabetes came first: A case-control study. Neurology, 78: 1507-1511
Kurz A, Rabbani N, Walter M, Thornalley P. et al. (2011). α-Synuclein deficiency leads to increased glyoxalase 1 expression and glycation stress. Cell Mol Life Sci, 68: 721-733.
Shi SY, Lu SY, Sivasubramaniyam T, et al. (2015). DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice. Nat Commun, 16;6:7415.
Requejo-Aguilar R, Lopez-Fabuel I, Jimenez-Blasco D, Fernandez E, Almeida A, Bolaños JP (2015). DJ1 represses glycolysis and cell proliferation by transcriptionally up-regulating Pink1. Biochem J, 467: 303-10.
Mihoub M, Abdallah J, Gontero B, Dairou J, Richarme G (2015). The DJ-1 superfamily member Hsp31 repairs proteins from glycation by methylglyoxal and glyoxal. Biochem Biophys Res Commun, 463: 1305-10.
Im JY, Lee KW, Woo JM, Junn E, Mouradian MM (2012). DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum Mol Gen, 21: 3013-3024.
Xue M, Rabbani N, Momiji H, et al. (2012). Transcriptional control of glyoxalase-1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation. Biochem J, 443: 213-222
Piec I, Listrat A, Alliot J, Chambon C, Taylor RG, Bechet D (2005). Differential proteome analysis of aging in rat skeletal muscle. FASEB J, 19:1143-5.
Ahmed EK, Rogowska-Wrzesinska A, Roepstorf P, Bulteau AM, Friguet B (2010). Protein modification and replicative senescence of WI-38 human embryonic fibroblasts. Aging Cell, 9: 252-2725.
Kuhla B, Boeck K, Luth HJ, Schmidt A, et al. (2006). Age-dependent changes of glyoxalase expression in human brain. Neurobiol Aging, 27: 815-822
Morcos M, Du X, Pfisterer F, et al. (2008). Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in C. elegans. Aging Cell, 7: 260-269.
Pun PB, Murphy MP (2012). Pathological Significance of Mitochondrial Glycation. Int J Cell Biol, 2012: 843505.
Tatone C, Heizenrieder T, Di Emidio G, et al. (2011). Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum Reprod, 26:1843-1859.
Beeri MS, Moshier E, Schmeidler J, Godbold J, et al. (2011). Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals. Mech Ageing Dev, 132: 583-587.
Szent-Gyorgyi A, McLaughlin JA (1975). Interaction of glyoxal and methylglyoxal and biogenic amines. Proc Natl Acad Sci USA, 72:1610-1611.
Deng Y, Zhang Y, Li Y, et al. (2012). Occurrence and distribution of a salsolinol-like compound, 1-acetyl-6.7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ) in Parkinsonian brains. J Neural Transm, 119: 435-441.
Song DW, Xin N, Xie BJ, et al. (2014). Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes. Int J Mol Med, 33: 736-742.
Bonnet R, Pavlovic S, Lehmann J, Rommelspacher H (2004). The strong inhibition of triose-phosphate isomerase by the natural beta-carbolines may explain their neurotoxic actions. Neurosci, 127: 443-453.
Tajes M, Eraso-Pichot A, Rubio-Moscardo F, et al. (2014). Methylglyoxal reduces mitochondrial potential and activates Bax and caspase-3 in neurons: implications for Alzheimer’s disease. Neurosci Lett, 580:78-82
Tajes M, Eraso-Pichot A, Rubio-Moscardo F, et al. (2014). Methylglyoxal produced by amyloid-B peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in Alzheimer’s disease. J Alzheimer’s Dis, 41: 273-288.
Degen J, Vogel M, Richter D, Hellwig M, Henle T (2013). Metabolic transit of dietary methylglyoxal. J Agric Food Chem, 61: 10253-10260.
Watanabe K, Okada K, Fukabori R, Hayashi Y, Asahi K (2014). Methylglyoxal (MG) and cerebro-renal interaction: does long-term orally administered MG cause cognitive impairment in normal Sprague-Dawley rats? Toxins (Basel), 6: 254-269.
Cai W, He JC, Zhu L, et al.2008. Oral glycotoxins determine the effects of calorie restriction on oxidant stress, age-related disease and lifespan. Am J Pathol, 173: 327-336.
Cai W, Uribarri J, Zhu L, et al. (2014). Oral glycotoxins are a modifiable cause of dementia and the metaboilic syndrome in mice and humans. Proc Natl Acad Sci USA, 111(13):4940-5.
West R, Mosher E, Lubitz I, et al. (2014). Dietary advanced glycation end products are associated with decline in memory in young elderly. Mech. Ageing Dev, 140:10-2
Sathe K, Maetzler W, Laang JD, Mounsey RB et al. (2012). S100 is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through RAGE and TNF-alpha pathway. Brain, 135:3336-3347.
Teismann P, Sathe K, Bierhaus A, et al. (2012). Receptor for advanced glycation endproducts (RAGE0 deficiency protects against MPTP toxicity. Neurobiol Aging, 33: 2478-2490.
Wang YH, Yu HT, Pu XP, Du GH (2014). Myricitrin alleviates methylglyoxal-induced mitochondrial dysfunction and AGEs/RAGE/NF-KB pathway activation in SH-SY5Y cells. J Mol Neurosci, 53: 562-570.
Natale G, Pasquali L, Paparelli A, Fornai F (2011). Parallel manifestations of neuropathologies in the enteric and central nervous systems. Neurogastroenterol Motil 23: 1056-1065.
Natale G, Pompili E, Biagioni F, Paparelli S et al. (2013). Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases. Eur J Histochem, 57: e5.
Olanow CW, Brundin P (2013). Parkinson’s disease and alpha-synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord, 28: 31-40.
Kovacs GG, Breydo L, Green R, Kis V, Puska G et al. (2014). Intracellular processing of disease-associated alpha-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis, 69: 76-92.
Reeve A, Meagher M, Lax N et al. (2013). The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons. J Neurosci, 33: 10790-801.
Reeve A, Simcox E, Turnbull D (2014). Ageing and Parkinson’s disease: Why is advancing age the biggest risk factor? Ageing Res Rev, 14:15-30.
Cook C, Stetler C, Petrucelli L (2012). Disruption of protein quality control in Parkinson’s disease. Cold Spring Harb Perspect Med, 2: a009423.
Zhang H, Duan C, Yang H (2015). Defective autophagy in Parkinson’s disease: lessons from genetics. Mol. Neurobiol, 1:89-104
Nifouro K, Chelmonidou C, Trougakos IP (2014). Molecular chaperones and proteostasis regulation during redox imbalance. Redox Biology, 2: 323-332.
Gleixner AM, Pulugulla SH, Pant DB, Posimo JM, Crum TS, Leak RK (2014). Impact of aging on heat shock protein expression in the substantia nigra and striatum of the female rat. Cell Tissue Res, 357(1):43-54
Kirstein-Miles J, Scior A, Deuerling E, Morimoto RI (2013). The nascent polypeptide-associated complex is a key regulator of proteostasis. EMBO J, 32:1451-1468.
Takino J, Kobayashi Y, Takeuchi KJ (2010). The formation of intracellular glyceraldehyde-derived advanced glycation end-products and cytotoxicity. Gastroenterol, 45, 646-655
Gawlowski T, Stratmann B, Stork I, et al. (2009). Heat shock protein 27 modification is increased in the human diabetic failing heart. Horm Metab Res, 41: 594-599.
Taylor A (2012). Mechanistically linking age-related disease and dietary carbohydrate via autophagy and the ubiquitin proteolytic systems. Autophagy, 8: 1404-6.
Zhao S, Lin L, Kan G, et al. (2014). High autophagy in the naked mole rat play a significant role in maintaining good health. Cell Physiol Biochem, 33: 321-332.
Herrero-Mendez A, Almeida A, Fernández E, Maestre C, Moncada S, Bolaños JP (2009). The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol, 11: 747-752.
Rodriguez-Rodriguez P, Fernandez E, Bolaños JP (2013). Underestimation of the pentose-phosphate pathway in intact primary neurons as revealed by metabolic flux analysis. J Cereb Blood Flow Metab, 33:1843-1845.
Almeida F, Santos-Silva D, Rodrigues T, et al. (2013). Pyridoxamine reverts methylglyoxal-induced impairment of survival pathways during heart ischemia. Cardiovasc Ther, 31: e79-85.
Xie B, Lin F, Ullah K, et al. (2015). A newly discovered neurotoxin ADTIQ associated with hyperglycemia and Parkinson’s disease. Biochem Biophys Res Commun, 459: 361-6.
Luce K, Weil AC, Osiewacz HD (2010). Mitochondrial protein quality control systems in aging and disease. Adv Exp Med Biol, 694: 108-125.
Ngo JK, Pomatto LC, Bota DE, Koop AL, Davies KJ (2011). Impairment of lon-induced protection against the accumulation of oxidized proteins in senescent wi-38 fibroblasts. J Gerontol A Bio Sci MedSci, 66: 1178-1185.
Ngo JK, Pomatto LC, Davies KJ (2013). Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging. Redox Biol, 1: 258-264.
Erjavec N, Bayot A, Gareil M, Camougrand N, et al. (2013). Deletion of the mitochondrial Pim1/Lon protease in yeast results in accelerated aging and impairment of the proteasome. Free Rad Biol Med, 56: 9-16.
Zhu J, Vereshchagina N, Sreekumar V, Burbulla LF et al. (2013). Knockdown of Hsc70-5/mortalin induces loss of synaptic mitochondria in Drosophila Parkinson’s disease model. PLoS One, 8: e83714.
Lee C, Yen K, Cohen P (2013). Humanin: a harbinger of mitochondrial-derived peptides. Trends Endocrinol Metab, 24: 222-228.
Rosenberger RF, Carr AJ, Hipkiss AR (1990). Regulation of breakdown of canavanyl proteins in Escherichia coli by growth conditions in lon+ and lon- cells. FEMS Microbiol Lett, 56: 19-25.
Inagi R (2014). Glycative stress and glyoxalase in kidney disease and aging. Biochem Soc Trans, 42: 457-60.
Hipkiss AR, Chana H (1998). Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun, 248:28-32.
Brownson C, Hipkiss AR (2000). Carnosine reacts with a glycated protein. Free Radic Biol Med, 28:1564-70
McFarland GA, Holliday R (1994). Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res, 212:167-75
Holliday R, McFarland GA (1996). Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine. Br J Cancer, 73: 966-71
Renner C, Asperger A, Seyffarth A, Meixensberger J, Gebhardt R, Gaunitz F (2010). Carnosine inhibits ATP production in cells from malignant glioma. Neurol Res, 32:101-5.
Kohen R, Yamamoto Y, Cundy KC, Ames BN (1998). Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci USA, 85: 3175-9.
Aruoma OI, Laughton MJ, Halliwell B (1989). Carnosine, homocarnosine and anserine: could they act as antioxidants in vivo? Biochem J, 264: 863-9.
Quinn PJ, Boldyrev AA, Formazuyk V (1992). Carnosine: its properties, functions and potential therapeutic applications. Mol Aspects Med, 13 :379-444
Horning MS, Blakemore LJ, Trombley PQ (2000). Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Brain Res, 852:56-61
Hipkiss AR, Michaelis J, Syrris P (1995). Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. FEBS Lett, 371: 81-5.
Hipkiss AR, Preston JE, Himsworth DT, et al. (1998). Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann N Y Acad Sci, 854:37-53.
Aldini G, Orioli M, Rossoni G, et al. (2011). The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J Cell Mol Med, 15:1339-54.
Seidler NW (2000). Carnosine prevents the glycation-induced changes in electrophoretic mobility of aspartate aminotransferase. J Biochem Mol Toxicol, 14: 215-20.
Liu Y, Xu G, Sayre LM (2003). Carnosine inhibits (E)-4-hydroxy-2-nonenal-induced protein cross-linking: structural characterization of carnosine-HNE adducts. Chem Res Toxicol, 16:1589-97.
Hipkiss AR (2014). Aging risk factors and Parkinson's disease: contrasting roles of common dietary constituents. Neurobiol Aging, 35:1469-72
Bellia F, Vecchio G, Rizzarelli E. (2014). Carnosinases, their substrates and diseases. Molecules. 19: 2299-329.
Boldyrev AA, Aldini G, Derave W (2013). Physiology and pathophysiology of carnosine. Physiol Rev, 93:1803-45.
Peters V, Lanthaler B, Amberger A, et al. (2015). Carnosine metabolism in diabetes is altered by reactive metabolites. Amino Acids, 47: 2367-76
Peters V, Schmitt CP, Zschocke J, Gross ML, Brismar K, Forsberg E. (2012). Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice. Amino Acids, 42: 2411-6.
Bellia F, Calabrese V, Guarino F, et al. (2009). Carnosinase levels in aging brain: redox state induction and cellular stress response. Antioxid Redox Signal, 11: 2759-75.
Licker V, Côte M, Lobrinus JA, et al. (2012). Proteomic profiling of the substantia nigra demonstrates CNDP2 overexpression in Parkinson's disease. J Proteomics, 75: 4656-67.
Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev AA (2003). Protective effect of carnosine on Cu, Zn-superoxide dismutase during impaired oxidative metabolism in the brain in vivo. Bull Exp Biol Med, 135:130-2.
Cararo JH, Streck EL, Schuck PF, Ferreira GC (2015). Carnosine and related peptides: therapeutic potential in age-related disorders. Aging Dis, 6 :369-79.
Liu Y, Su D, Zhang L, Wei S, Liu K, Peng M, Li H, Song Y (2016). Endogenous L-Carnosine Level in Diabetes Rat Cardiac Muscle. Evid Based Complement Alternat Med, 2016:6230825.
Menini S, Iacobini C, Ricci C, Blasetti Fantauzzi C, Pugliese G (2015). Protection from diabetes-induced atherosclerosis and renal disease by D-carnosine-octylester: effects of early vs late inhibition of advanced glycation end-products in Apoe-null mice. Diabetologia, 58: 845-53.
Riedl E, Pfister F, Braunagel M, et al. (2011). Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats. Cell Physiol Biochem, 28: 279-88
Janssen B, Hohenadel D, Brinkkoetter P, et al. (2005). Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes, 54: 2320-7.
Baye E, Ukropcova B, Ukropec J, Hipkiss A, Aldini G, de Courten B (2016). Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. Amino Acids, 48:1131-49
Brown BE, Kim CH, Torpy FR, et al. (2014). Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. Atherosclerosis, 232 :403-9
Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, Bhatnagar A, Srivastava S. (2013). Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol, 33: 1162-70.
Abdelkader H, Swinden J, Pierscionek BK, Alany RG. (2015). Analytical and physicochemical characterisation of the senile cataract drug dipeptide β-alanyl-L-histidine (carnosine). J Pharm Biomed Anal, 114:241-6
Villari V, Attanasio F, Micali N (2014). Control of the structural stability of α-crystallin under thermal and chemical stress: the role of carnosine. J Phys Chem B, 118: 13770-6.
Babizhayev MA, Yegorov YE (2014). Biomarkers of oxidative stress and cataract. Novel drug delivery therapeutic strategies targeting telomere reduction and the expression of telomerase activity in the lens epithelial cells with N-acetylcarnosine lubricant eye drops: anti-cataract which helps to prevent and treat cataracts in the eyes of dogs and other animals. Curr Drug Deliv, 11: 24-61.
Dizhevskaya AK, Muranov KO, Boldyrev AA, Ostrovsky MA (2012). Natural dipeptides as mini-chaperones: molecular mechanism of inhibition of lens βL-crystallin aggregation. Curr Aging Sci, 5:236-41
Babizhayev MA (2006). Biological activities of the natural imidazole-containing peptidomimetics n-acetylcarnosine, carcinine and L-carnosine in ophthalmic and skin care products. Life Sci, 78: 2343-57
Baek SH, Noh AR, Kim KA, et al. (2014). Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke, 45: 2438-43
Park HS, Han KH, Shin JA, Park JH, Song KY, Kim DH (2014). The neuroprotective effects of carnosine in early stage of focal ischemia rodent model. J Korean Neurosurg Soc, 55:125-30
Bae ON, Majid A. (2013). Role of histidine/histamine in carnosine-induced neuroprotection during ischemic brain damage. Brain Res, 1527: 246-54.
Rajanikant GK, Zemke D, Senut MC, Frenkel MB, Chen AF, Gupta R, Majid A. (2007). Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke, 38: 3023-31
Aloisi A, Barca A, Romano A, Guerrieri S, Storelli C, Rinaldi R, Verri T (2013). The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. PLoS One, 8: e68159.
Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli M, Canzoniero LM, Ciavardelli D, Rizzarelli E, Sensi SL (2011). Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One, 6(3): e17971.
Attanasio F, Convertino M, Magno A, et al. (2013). Carnosine inhibits Aβ(42) aggregation by perturbing the H-bond network in and around the central hydrophobic cluster. Chem Biochem, 14: 583-92.
Afshin-Majd S, Khalili M, Roghani M, Mehranmehr N, Baluchnejadmojarad T (2015). Carnosine exerts neuroprotective effect against 6-hydroxydopamine toxicity in hemiparkinsonian rat. Mol Neurobiol, 51:1064-70.
Tsai SJ, Kuo WW, Liu WH, Yin MC (2010). Antioxidative and anti-inflammatory protection from carnosine in the striatum of MPTP-treated mice. J Agric Food Chem, 58: 11510-6.
Boldyrev A, Fedorova T, Stepanova M, Dobrotvorskaya I, Kozlova E, Boldanova N, Bagyeva G, Ivanova-Smolenskaya I, Illarioshkin S (2008). Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson's disease: a pilot study. Rejuvenation Res, 11: 821-7.
Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J. (2002). Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol, 17: 833-7.
Chengappa KN, Turkin SR, DeSanti S, et al. (2012). A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia. Schizophr Res, 142:145-52.
Lombardi C, Carubelli V, Lazzarini V, et al. (2015). Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition, 31:72-8.
Baraniuk JN, El-Amin S, Corey R, Rayhan R, Timbol C (2013). Carnosine treatment for gulf war illness: a randomized controlled trial. Glob J Health Sci, 5: 69-81.
Szcześniak D, Budzeń S, Kopeć W, Rymaszewska J (2014). Anserine and carnosine supplementation in the elderly: Effects on cognitive functioning and physical capacity. Arch Gerontol Geriatr, 59:485-90.
Hayflick L (1987). Origins of longevity. In: Warner HR, Butler RN, Sprott RL, Schneider EL, editors. Modern biological theories of aging., New York: Raven Press, 21-34.