Journal of Aging Science

Vulnerability of Human Erythrocytes to Persistent High Glycemic Index Diets: Implications for Ageing and Neurodegeneration: Possible Amelioration by Carnosine

Alan R Hipkiss^* Aston Research Centre for Healthy Ageing (ARCHA), Aston University, Birmingham B4 7ET, UK
^*Correspondence: Alan R Hipkiss, Aston Research Centre for Healthy Ageing (ARCHA), Aston University, Birmingham B4 7ET, UK, Email:

Received: 05-Nov-2019 Published: 05-Dec-2019

Introduction

It is clear that changes in cellular energy metabolism play important and even causal roles in onset and progression of aging; excessive glycolysis appears to accelerate aging onset, whereas upregulation of mitochondrial ATP generation appears to be somewhat protective towards age-related dysfunction [1-3]. The fact that human erythrocytes are solely glycolytic raises questions concerning their possible causal role towards aging generally and neurodegeneration in particular. A typical characteristic of cellular aging and associated dysfunction is the accumulation of altered protein, obvious pathological examples being amyloid peptide plaques and Lewy bodies in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. Indeed, this suggestion is reinforced by the recent finding that erythrocytes obtained from Alzheimer’s disease patients appear to possess lower levels of certain protective activities (20S proteasome and glyoxalase-1), functions that are usually regarded as exerting anti-aging roles [4]. That erythrocytes may influence aging onset or development is supported by two more recent papers which discuss (i) the causal effects of glycemic index (GI) and load with respect to type-2 diabetes in humans [5], and (ii) age-related changes in mouse erythrocyte metabolism following parabiosis [6]. Two other papers have recently explored the potential efficacy of the endogenous dipeptide carnosine (betaalanyl- L-histidine) towards brain disorders [7] and the effects of carnosine supplementation on cognitive impairment in human subjects [8].

The objectives of the present communication are threefold. First, to suggest that high GI diets in humans induce erythrocytes to perform almost continuous glycolysis, a likely consequence of which is enhanced production of the reactive bicarbonyl methylglyoxal (MG); MG has been suggested to play a causal role in much age-related dysfunction including type-2 diabetes and cognitive dysfunction [9,10] via glycation of proteins, aminolipids and nucleic acid [11,12]. Secondly, to suggest that high GI diets may convert erythrocytes into systemic sources of MG and macromolecular modification throughout the body. Thirdly, to propose that carnosine’s pluripotent properties towards energy metabolism and proteostasis [13] can exert ameliorative activity with respect to MG generation and/or its reactivity, and, under certain circumstances, may help to suppress age-related dysfunction.

Glycolysis And Age-Related Macromolecular Modification

Much age-related modifications of proteins, lipids and nucleic acids mostly occur following generation of highly-reactive products and intermediates of normal metabolism. While the productions of reactive oxygen species (ROS) has been regarded as a consequence of mitochondrial metabolism and have long been regarded as causal to much age-related dysfunction, it is important to note that glycolysis can directly generate dihydroxyacetone-phosphate (DHAP) and glyceraldehyde-3- phosphate (G3P), highly reactive intermediates that can directly modify (glycate) proteins. Furthermore, both these compounds can spontaneously decompose into methylglyoxal (MG) which is even more reactive [10]. Indeed glycolytically–generated MG is regarded as a major source of protein glycation associated with not only aging but much of the protein modifications (secondary complications) which accompany type-2 diabetes [11]. It is also important to note that many of the processes or agents which delay aging onset have a common characteristic, namely partial suppression of carbohydrate catabolism which decreases glycolytic flux [1-3,12,13].

In contrast, two recent studies have shown that the age-related neurodegenerative disease, AD, is associated with lowered glycolytic function [14,15], a conclusion which appears to contradict the notion that age-related dysfunction is a consequence of glycolytic excess. It is, however, possible to reconcile this apparent dilemma by suggesting that dietaryinduced excessive glycolysis decreases the activity of the glycolytic enzyme triosephosphate isomerase (TPI) in either or both erythrocytes and astrocytes. Because TPI catalyses the conversion of DHAP into G3P, loss or decline in its activity will cause DHAP to accumulate and enhance MG formation and consequential protein glycation [16]; indeed much evidence shows a strong associated between protein glycation and AD pathology [17,18].

Glycolysis in erythrocytes: Triose-phosphate isomerase inactivation

The process of glycolysis involves the release of energy, as ATP, mediated by the step-wise conversion of glucose to lactic acid. One of the steps is carried out by the enzyme triose-phosphate isomerase (TPI). TPI catalyses the conversion of DHAP into G3P, both of which are generated by the action of aldolase on fructose-1.6-diphosphate. However TPI is not a true catalyst because its structure can become altered as result of its catalytic activity via a process which has been termed “molecular wear and tear” [19]. Some 30 years ago it was found by Gracy et al. [20] that, as a consequence of its catalytic action, certain asparagine residues (15 and 71) in TPI spontaneously deamidate into aspartic acid residues. It was concluded that “ the probability of deamidation of an individual TPI molecule is a function of the number of times that it is used as a catalyst” [21]. A consequence of such deamidation is the disassociated of the dimeric enzyme into monomers and their subsequent proteolytic destruction. As erythrocytes are unable to synthesize proteins, due to lack of nuclei and ribosomes, it is obvious that should TPI activity become rate-limiting, then MG generation from the accumulated DHAP would accelerate [22]. However, TPI activity in erythrocytes is reported to be more than 3-times that of any other glycolytic enzyme [23], which suggests an evolutionary adaptation to prevent TPI becoming rate-limiting during the normal (limited) lifespan of the human erythrocyte.

It is reasonable to suggest that the human diet has radically changed from that of the “hunter-gatherer” during which much of humankind’s evolution occurred. The modern “Western” diet contains a much higher amount of carbohydrate than that of preceding generations, and almost certainly is very different indeed from that of the hunter-gatherer in terms of carbohydrate intake. Consequently, it is suggested that the high GI and load of the current “ Western ” diet can induce a decline in erythrocytic TPI (as outlined above) which in turn provokes an increase in MG formation. Thus it is suggested that erythrocyte TPI maybe a metabolic “Achilles Heel” when presented with the current high carbohydrate “ Western ” diet. Although the presence of erythrocyte glyoxalase activity would be expected to facilitate MG detoxification, this enzyme can become inactivated by excess MG and furthermore has been found to decline in aged erythrocytes [24].

Erythrocytes and methylglyoxal

As outlined above, it is likely that diets of high GI and almost continuous carbohydrate load can provoke MG accumulation within erythrocytes in the modern human consuming an overabundance of carbohydrate. One possible consequence could be erythrocyte-mediated MG distribution throughout the body; indeed as the erythrocyte membrane is permeable to MG then it likely that the highly glycolytic erythrocyte is a “Trojan Horse” supplying the deleterious glycating agent to many tissues including the brain [16]. Furthermore, MG can glycate proteins within the erythrocyte and thus contribute to the glycotoxin burden, in addition to the glycated proteins in the diet [25] and those generated within the gut [26]. Erythrocytes contain the protein alpha-synuclein (Asyn) which is very readily glycated by MG. Aggregated forms of Asyn (called Lewy bodies) are found in the PD brain [27]. As MG can induce eryptosis (red cell lysis) [28], one wonders whether erythrocyte Asyn could contribute to Lewy body formation, especially as there is a strong association between type-2 diabetes and neurodegenerative conditions e.g. AD and PD [29,30]. It is also interesting to note that the neurotoxin ADTIQ (1-acetyl-6,7-dihydroxyl-1,2,3,4- tetrahydroisoquinoline) has been detected in the brains of type-2 diabetics and PD patients [31]: ADTIQ is the spontaneous product of the reaction between dopamine and MG [32], an observation which reinforces the notion that increased levels of MG contribute to both these pathologies.

During construction of this review, new evidence emerged which supports the proposal that changes in erythrocytic metabolism accompany neurodegenerative condition; Lv et al. reported that erythrocytes from AD patients possessed decreased glyoxalase activity, whilst papers by Graham et al. and Tian et al. showed that erythrocytes from dementia subjects contained increased levels of aggregated alpha-synuclein, observations also possibly related to the deceased proteasome activity also reported by Lv et al. [4,33,34]. Furthermore, MG has been recently reported to be causal towards brain senescence in an aging mouse model [35].

Triose-phosphate isomerase, aging and the brain

As noted above, studies have shown that AD is accompanied by glycolytic dysfunction [14,15] coupled with increased MG generation [35-39]. Furthermore it has recently been reported that brain senescence in a mouse aging model is caused by elevated levels of MG [40]. Theoretically, both these observations may derive from either erythrocytic MG [4,33,34,39] or/and, the inactivation of astrocyte TPI and glyceraldehyde-3-phosphate dehydrogenase activities, perhaps driven by not only astrocytic excessive glycolysis but also due to the effects of MG released from erythrocytes.

It is very likely that TPI is present in all cells which undertake either glycolysis or gluconeogenesis. Neurons are not particularly glycolytic as they receive their energy via input of lactate supplied by astrocytes in which glycolysis readily occurs; altered forms of TPI have been detected in aged cells and tissues [40-42], including the brain. There is evidence for the occurrence of asparagine deamidation in human brains [43] and dysfunctional TPI has been detected in the brains of AD patients [44]. Although there are no reports on whether TPI deamidation occurs in the aged human brain, there is evidence suggesting that upregulation of TPI enhances longevity in mice [45]; TPI activity in a senescence-accelerate mouse strain (SAMP3) brain and liver was found to be substantially lower than in the “normal” SAMR mice, while acupuncture improved organism longevity and enhanced tissue TPI activity [45]. Furthermore, treatment of senescent human fibroblasts with gammatocotrienol not only increased in vitro proliferation but also increased TPI expression [46]. While explanation of the beneficial effects resulting from enhanced TPI expression may reside in the possibility outlined above (i.e. decreased MG generation), it has been pointed out that TPI may perform undefined non-metabolic “ moonlighting ” activities [47]. For example, it is possible that TPI could be involved in cell cycle regulation [48], thereby enhancing organism longevity and stress responses, least in Drosphila [49]. As cell cycle dysregulation has been described in Alzheimer ’ s disease [50], it cannot be necessarily assumed that the consequences of TPI decline in the brain can all be explained in terms of MG accumulation and glycation-related phenomena [51]. Nevertheless there is substantial evidence from animal and human studies showing that TPI dysfunction provokes neurological dysfunction, possibly related in part to enhanced MG-induced protein glycation [52,53]. It has, however, also been suggested that the phenotypic effects of lowered TPI might involve a response to protein miss-folding and its consequences [47]. Additionally it should also be noted that enhancement of MG formation has been shown to promote a hormetic response, thereby improving cellular ability to deal with toxic dicarbonyls. [54,55].

Enhanced protein glycation is frequently associated with agerelated neurodegeneration such as AD and PD [9-12,17,18], and the two major proteins which accumulate in the AD brain, betaamyloid and aggregated Tau, can profoundly affect TPI function. Beta-amyloid induces nitration of TPI and decreases the enzyme’s activity and thereby provokes MG accumulation [56]. In contrast, the Tau protein is normally protective towards TPI, but this activity is lost following Tau hyperphosphorylation and aggregation [57]. Both observations seem to point to a pivotal role for TPI in neurodegenerative conditions.

It has recently been reported that a phenylpyrrole fungicide, frequently used on crops worldwide, induces MG production via the agent’s inhibitory effects on TPI [58]. Such a finding may help to explain the apparent association between pesticide exposure and the increased occurrence of neurodegenerative conditions such as PD, and obviously has serious implications for the food industry.

It is likely that enhanced protein glycation plays a major role in PD. The protein Asyn is present in most cells including erythrocytes, and in aggregated form it is a major component of Lewy bodies in the PD brain, and it has recently been shown that glycation of Asyn provokes its binding to and inhibition of glyceraldehyde-3-phosphate dehydrogenase, thereby provoking G3P accumulation and increasing the potential for enhanced MG formation [59].

Carnosine, aging and age-related dysfunction

Carnosine (beta-alanyl-L-histidine) is synthesized by many animals (mammals, birds and fish) and is mainly located in muscle tissue and the brain, especially in the olfactory lobe of mammals [7,60-62]. It is likely that carnosine is present in most carnivorous diets; there is only one report of carnosine occurring in plant tissue (gourd skin) [63]. Originally discovered over 100 years ago, many properties have been ascribed to the dipeptide. These included wound healing agent [64,65], immune-stimulant [66,67] and anti-aging agent [68,69], while at the biochemical level, pH buffering [70,71], anti-oxidant [72,73] and anti-glycating [74-77] activities have been detected. More recently, beneficial effects of the dipeptide on lung disease [78,79], various brain disorders [80-82] and a variety of conditions related to diabetes such as diabetic kidney disease [83-85], cardiovascular disease [86,87] and stroke [88,89] have been observed. Anti-viral activity towards Denge and Zika viruses has also been detected. [90]. Toxicity towards tumour cell growth was first observed some decades ago [91,92] and whilst it appears that the dipeptide’s effect is associated with decreased glycolytic ATP generation [93,94], there is no agreement on the precise mechanisms responsible [95-97]. Another recent finding is that carnosine induces intestinal cells to release exosomes that activate neuronal cells [98].

As outlined above, it is likely that MG formation and detoxification can strongly influence age-related macromolecular modification. Although model systems have demonstrated that carnosine can react with MG [99], there is little in vivo evidence for occurrence of the putative reaction products i.e. carnosine- MG adducts. In fact, the major carnosine-adduct found in human urine is that formed between the dipeptide and acrolein [100-102]. However, acrolein is usually thought to be a product of lipid oxidative damage [103]. Given that carnosine seems to protect against the consequence of excessive carbohydrate catabolism, the lipid origin of acrolein in the carnosine-acrolein adduct may therefore be questionable. As the structures of acrolein and MG are quite similar, the theoretical conversion of MG into acrolein could occur in two steps, first a reduction generating lactaldehyde followed by a dehydration to generate acrolein. Hence one has to consider whether MG is a source of acrolein in vivo. In support of this proposition, a recent study using glyoxalase-knockout mouse cells has demonstrated the presence of an additional/alternative route by which MG is detoxified to lactaldehyde using uncharacterized aldehyde/keto reductases [104]. The conversion of lactaldehyde to acrolein has yet to be demonstrated, however. Nevertheless should this route of MG detoxification be established, it would have the advantage of ensuring the elimination of two molecules of MG per carnosine, as the carnosine-acrolein adduct is a cyclic structure formed by two acrolein molecules per carnosine [102].

It has been shown that there is a strong association between schizophrenia and elevated levels of plasma protein glycation (i.e. carbonyl stress) mediated by triose-phosphates [105]. There are reports showing that dietary supplementation with carnosine can exert beneficial effects towards human schizophrenics [106,107]. Thus, one is tempted to speculate that carnosine’s apparent beneficial effects towards schizophrenia may reside at least in part from the dipeptide’s anti-glycating activity, especially as it has recently been reported that schizophrenia is associated with glial cell glycolytic dysfunction, which produces an advanced aging phenotype and accelerated aging [108].

Carnosine and energy metabolism

The many beneficial effects of carnosine (some of which outlined above) suggest that the dipeptide is pluripotent in its actions. It not only can protect cells against deleterious agents such MG, acrolein and malondialdehyde, but it may directly interfere with glycolysis. However, the dipeptide’s effects can vary depending on cell metabolism. For example, carnosine’s effect on yeast cells varied according to the growth conditions; the dipeptide was somewhat inhibitory to cells growing on glucose as sole carbon source i.e. where glycolysis was the major ATP generating pathway, whereas in cells growing aerobically on glycerol, i.e. where mitochondria provided ATP generation, the dipeptide stimulated growth and exerted no inhibitory effects on cell proliferation [109]. Thus it appears from these yeast studies that carnosine can exert suppressive activity towards glycolysis.

Studies using transformed cells also show that carnosine exerts inhibitory effects upon glycolytic ATP synthesis [93,96]. However, the mechanism(s) by which these effects are mediated remains uncertain: there are at least three possibilities. First, it is possibility that carnosine stimulates the enzyme fructose-1,6- bisphosphatase (FBP). FBP is regarded as a gluconeogenic as it converts fructose-1,6-bisphosphate into fructose-6-phosphate (F6P), but does not generate ATP. Many years ago, it was shown that carnosine and histidine could activate FBP by binding to zinc ions which otherwise inhibit FBP activity [110]. Thus upon FBP activation in yeast or tumor cells, the presence of the dipeptide would provoke a futile ATP-consuming cycle in which fructose-6-phosphate is phosphorylated using ATP, yielding fructose-1,6-diphosphate which then dephosphorylated by FBP back to F6P and inorganic phosphate. A second possibility is that carnosine exerts effects upon the regulatory complex mTOR. mTOR activity is suppressed by the immune-suppressor rapamycin which results in decreased glycolytic activity and upregulation of mitochondrial ATP generation [111]. Rapamycin [112] and carnosine [113] have both been shown to induce similar anti-aging effects such as delaying senescence in cultured human fibroblasts and stimulating proteolysis of long-lived proteins in replicative senescent cells, observations suggesting that carnosine may possess rapamycin-like properties [111]. However, carnosine’s putative rapamycin-like activity has been questioned in studies using various glioblastoma cells which are unresponsive to rapamycin but whose growth is still inhibited by carnosine [114]. The third possible mechanistic route of carnosine’s inhibitory effects of glycolysis involves upregulation of the enzyme pyruvate dehydrogenase kinase-4 (PDK4) [115], whose activity decreases glycolysis. It is interesting to note that aging in cultured mouse oocytes is delayed by the polyamine putrecine which also upregulates PDK4 expression [116]; carnosine has been shown to delay aging in cultured human fibroblasts [117], although whether this is also accompanied by increased PDK4 has yet to be explored. Thus one may conclude that carnosine’s anti-aging activity might explained by its antiglycolytic effects mediated by upregulation of PDK4. However, the various effects on glycolysis induced by the presence of carnosine may not be necessarily mutually exclusive; hence it is suggested that, as carnosine appears to be pluripotent in terms of its effects on glycolysis, any one or more of the possible mechanisms outlined above could be responsible for its suppressive effects on glycolysis.

Carnosine and erythrocytes

There has only been one report of the occurrence of carnosine in human erythrocytes [118]; interestingly, carnosine was shown to be enriched (up to ten-fold) within erythrocytes compared to serum, whereas acetyl-carnosine (unsusceptible to carnosinase attack) was found predominantly in serum. Although these findings have yet to be confirmed, it was also found that when erythrocytes and sera from young (29 years old ± 4) and elderly (81 years ± 7) human subjects were compared, both carnosine and acetyl-carnosine levels were substantially lower in the elderly individuals. The origin of red cell carnosine has yet to be studied; presumably erythrocytic carnosine is synthesized during red cell development in the bone marrow. Hence it is conceivable that raised levels of erythrocyte carnosine could be achieved by dietary supplementation with beta-alanine (or carnosine as a source of beta-alanine), although full benefit might be not be achievable until complete red cell replacement is achieved (i.e. around 120 days, the maximum lifespan of human erythrocytes.). It would also be interesting to determine if high GI diets affect erythrocyte carnosine levels. Whether carnosine-loaded erythrocytes supply the dipeptide to the tissues, including the brain, has yet to be investigated.

Carnosine and neurodegeneration

Theoretically carnosine could exert beneficial effects in brain tissue by (i) decreasing glycolytic flux in astrocytes and glia, (ii) directly facilitating elimination of glycating agents such as MG, or (iii) indirectly, by decreasing erythrocyte-generated MG and/or glycated proteins such as Asyn. Carnosine has been previously proposed as potentially therapeutic towards both AD and PD [119,120], especially if administered nasally to avoid serum carnosinase activity [79]. Recent findings support these suggestions [121,122], including the potential efficacy of the nasal route [123]. It is also interesting to note that the olfactory lobe is enriched in carnosine and loss of a sense of smell is a frequent early symptom of neurodegeneration [124], which, at least superficially, supports the notion that carnosine might play a role in controlling aspects of neurological function[125-127].

Discussion and Conclusion

It is clear that aging onset can be delayed if excessive glycolytic activity is suppressed to a minimum. Biochemically, under such a circumstance, generation of deleterious agents such as MG and its reaction products (AGEs) would be reduced to a minimum. It is likely that the current “Western” diet (almost permanent high GI carbohydrate input) may turn erythrocytes into a major source of systemic of MG and protein-AGEs, thereby accelerating aging onset and age-related dysfunction, partly as a result of the activity-induced change in the primary structure of red cell TPI. Indeed recent studies support the notion that enhanced erythrocytic MG generation plays a role in certain age-related neurodegenerative conditions.

Carnosine’s ability to suppress glycolysis may help to explain its apparent beneficial effects towards cellular aging and tumor cell growth. It is possible that carnosine also exerts anti-glycating activity by scavenging reactive carbonyls such as MG. Indeed carnosine-acrolein adducts can be detected in human urine, which suggest that the dipeptide could be beneficial towards human aging where AGE formation occurs, especially as carnosine is far less toxic than other anti-glycating agents such as aminoguanidine. Thus, increasing synthesis or dietary input of carnosine could be beneficial by suppressing glycation-related, age-related, phenomena.

Green vegetables are, of course, another source of naturallyoccurring anti-glycating agents, due to the synthesis of MG precursors during photosynthesis, against which plants must protect themselves. Indeed there are multiple claims in the literature suggesting that plant preparations possess antiglycating activity. It would be interesting to determine whether increased intake of vegetable-derived anti-glycating agents affects erythrocyte carnosine levels and the excretion of carnosineacrolein adducts.

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