The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease

doi:10.1016/j.mehy.2008.01.017

Medical Hypotheses

Volume 71, Issue 1, 2008, Pages 22-31

https://doi.org/10.1016/j.mehy.2008.01.017 Get rights and content

Summary

Humans have relatively low plasma ascorbate levels and high serum uric acid levels compared to most mammals due to the presence of genetic mutations in l-gulonolactone oxidase and uricase, respectively. We review the major hypotheses for why these mutations may have occurred. In particular, we suggest that both mutations may have provided a survival advantage to early primates by helping maintain blood pressure during periods of dietary change and environmental stress. We further propose that these mutations have the inadvertent disadvantage of increasing our risk for hypertension and cardiovascular disease in today’s society characterized by Western diet and increasing physical inactivity. Finally, we suggest that a “planetary biology” approach in which genetic changes are analyzed in relation to their biological action and historical context may provide the ideal approach towards understanding the biology of the past, present and future.

Section snippets

Ascorbate synthesis and its role as an antioxidant

Ascorbate (vitamin C) is synthesized in most mammals by an active five-enzyme process that begins with an activated form of glucose, UDP-glucose. UDP-glucose is present primarily in the liver or kidney, depending on species (Fig. 1). As such, its concentration is highly dependent on intracellular glucose reserves and glycogenolysis. Further, factors that reduce glucose reserves (starvation, low carbohydrate diets) or inhibit glycogenolysis (such as fructose) inhibit ascorbate synthesis [6].

Uric acid and the mutation of uricase

Uric acid is a metabolic product of purine metabolism generated from the breakdown of DNA, RNA and ATP (Fig. 2). The immediate precursor enzyme is xanthine oxidoreductase which converts xanthine to uric acid with the generation of oxidants (superoxide anion or hydrogen peroxide) or NADH. In some species uric acid is then metabolized to allantoin by the enzyme uricase (urate oxidase). Depending on the species, allantoin may be further degraded by allantoinase and allantoincase to generate

Why did early primates lose their ability to synthesize ascorbate?

Several hypotheses have been proposed to account for the loss of ascorbate synthesis by early primates. Pauling suggested that the loss of ascorbate synthesis resulted as a consequence of the lack of need, as early primates may have had ample access to dietary ascorbate from root tips, seed sprouts, fruits and green leaves [45]. However, Darwinian theory suggests that there was likely a positive selection mechanism that made it advantageous to lack ascorbate synthesis; otherwise, both

What was the advantage to having uricase mutated?

The observation that parallel mutations involving uricase occurred in early hominoid evolution strongly suggests that there must have also been a selection advantage during the Miocene to having higher serum uric acid levels.

The most quoted hypothesis is that originally proposed by Proctor [49] and later Ames [25] who suggested that the uricase mutation may have occurred as a means to replace serum antioxidant activity after the loss of ascorbate synthesis. Indeed, uric acid can help maintain

Ascorbate and blood pressure

The inability to synthesize ascorbate would have forced early primates to ingest a vitamin C-rich diet to maintain their ascorbate stores. The gorilla, who lacks the ability to synthesize Vitamin C, eats about 4.5 g of ascorbate per day [53]. Pauling has calculated, based on synthetic rates in other mammals, that the average 70 kg human would have to ingest 1.8–4.1 g/d ascorbate to achieve similar blood levels [45].

What would happen if suddenly a change in climate occurred that resulted in less

Planetary biology and the approach to the uricase/ascorbate hypotheses

How can planetary biology help determine which hypothesis is correct? By pinpointing the date of the mutations and cross checking with the paleoecological and anthropological record, we can evaluate the effects of environment with the genetic changes.

Emerging tools in paleogenetics provide an experimental tool to test hypotheses that emerge from this correlative science [93]. In a paleogenetics experiment, the structures of ancestral genes are inferred from the sequences of their descendents;

Disclaimers

Dr. Johnson is listed as an inventor on several patent applications related to lowering of uric acid in cardiovascular disease and also is author on a book on fructose that will be published in 2008 by Rodale press. Dr. Benner and Dr. Gaucher are listed as inventors on several patent applications to apply evolutionary analysis to understand protein evolution.

Acknowledgment

SAB is indebted to the National Science Foundation for its support of this work via an OPUS grant (DEB 0717335). Supported by NIH Grantss HL-68607, DK-52121, and research funds from Gatorade.

References (96)

G. Banhegyi et al.
Ascorbate metabolism and its regulation in animals
Free Radical Biol Med
(1997)
R.W. Welch et al.
Accumulation of vitamin C (ascorbate) and its oxidized metabolite dehydroascorbic acid occurs by separate mechanisms
J Biol Chem
(1995)
P.W. Washko et al.
Ascorbic acid recycling in human neutrophils
J Biol Chem
(1993)
N.J. Chinoy
Ascorbic acid levels in mammalian tissues and its metabolic significance
Comp Biochem Physiol A
(1972)
M. Nishikimi et al.
Cloning and chromosomal mapping of the human nonfunctional gene for l-gulono-gamma-lactone oxidase, the enzyme for l-ascorbic acid biosynthesis missing in man
J Biol Chem
(1994)
Y. Ohta et al.
Random nucleotide substitutions in primate nonfunctional gene for l-gulono-gamma-lactone oxidase, the missing enzyme in l-ascorbic acid biosynthesis
Biochim Biophys Acta
(1999)
M. Nishikimi et al.
Guinea pigs possess a highly mutated gene for l-gulono-gamma-lactone oxidase, the key enzyme for l-ascorbic acid biosynthesis missing in this species
J Biol Chem
(1992)
W.A. Waugh et al.
The isolation and identification of vitamin C
J Biol Chem
(1932)
C.X. Santos et al.
Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation
Arch Biochem Biophys
(1999)
C.M. Barrera et al.
Uric acid: a participating factor in the symptoms of hyperactivity
Biol Psychiatry
(1988)

R.E. Hunter et al.

Effects of uric acid and caffeine on A1 adenosine receptor binding in developing rat brain

Pharmacol Biochem Behav

(1990)

D.C. Logan et al.

Uric acid catabolism in the woolly monkey

Metabolism

(1976)

T.B. Friedman et al.

On the loss of uricolytic activity during primate evolution--I. Silencing of urate oxidase in a hominoid ancestor

Comp Biochem Physiol B

(1985)

J.J. Challem

Did the loss of endogenous ascorbate propel the evolution of anthropoidea and Homo sapiens?

Med Hypotheses

(1997)

J.J. Challem et al.

Retroviruses, ascorbate, and mutations, in the evolution of Homo sapiens

Free Radical Biol Med

(1998)

I.F. Benzie

Evolution of dietary antioxidants

Comp Biochem Physiol A Mol Integr Physiol

(2003)

A. Sevanian et al.

Conservation of vitamin C by uric acid in blood

J Free Radical Biol Med

(1985)

A. Nandi et al.

Evolutionary significance of vitamin C biosynthesis in terrestrial vertebrates

Free Radical Biol Med

(1997)

M. Lopez-Torres et al.

Maximum life span in vertebrates: relationship with liver antioxidant enzymes, glutathione system, ascorbate, urate, sensitivity to peroxidation, true malondialdehyde, in vivo H₂O₂, and basal and maximum aerobic capacity

Mech Ageing Dev

(1993)

C.A. Hubel et al.

Increased ascorbate radical formation and ascorbate depletion in plasma from women with preeclampsia: implications for oxidative stress

Free Radical Biol Med

(1997)

S.J. Duffy et al.

Treatment of hypertension with ascorbic acid

Lancet

(1999)

U.M. Khosla et al.

Hyperuricemia induces endothelial dysfunction

Kidney Int

(2005)

G.N. Rao et al.

Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression

J Biol Chem

(1991)

D.I. Feig et al.

Hypothesis: uric acid, nephron number, and the pathogenesis of essential hypertension

Kidney Int

(2004)

R.J. Johnson et al.

Uric acid, evolution and primitive cultures

Semin Nephrol

(2005)

S. Abadeh et al.

Purification and partial characterization of xanthine oxidase from human milk

Biochim Biophys Acta

(1992)

P. Xu et al.

Repressed expression of the human xanthine oxidoreductase gene. E-box and TATA-like elements restrict ground state transcriptional activity

J Biol Chem

(2000)

F.S. Collins et al.

Implications of the human genome project for medical science

JAMA

(2001)

C.R. Woese

A new biology for a new century

Microbiol Mol Biol Rev

(2004)

S.A. Benner et al.

Planetary biology--paleontological, geological, and molecular histories of life

Science

(2002)

D.A. Liberles

Experimental paleogenetics

(2007)

S.A. Benner et al.

Molecular paleoscience: systems biology from the past

Adv Enzymol Relat Areas Mol Biol

(2007)

B. Halliwell

The role of oxygen radicals in human disease with particular reference to the vascular system

Haemostasis

(1993)

V. Darley-Usmar et al.

Blood radicals: reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system

Pharm Res

(1996)

C.L. Linster et al.

Vitamin C. Biosynthesis, recycling and degradation in mammals

FEBS J

(2007)

H. Tsukaguchi et al.

A family of mammalian Na⁺ dependent l-ascorbic acid transporters

Nature

(1999)

J.I. Pollock et al.

Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius

Am J Phys Anthropol

(1987)

C.G. King

The biological synthesis of ascorbic acid

World Rev Nutr Diet

(1973)

J. Lind

A treatise of the scurvy, originally published in 1753

S. Qiu et al.

Ascorbate transport by primary cultured neurons and its role in neuronal function and protection against excitotoxicity

J Neurosci Res

(2007)

M.R. Luck et al.

Ascorbic acid and fertility

Biol Reprod

(1995)

Y.H. Wang et al.

Ascorbic acid bioavailability in humans. Ascorbic acid in plasma, serum, and urine

Ann NY Acad Sci

(1992)

C.M. Siman et al.

Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats

Diabetologia

(1997)

B.N. Ames et al.

Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis

Proc Natl Acad Sci USA

(1981)

Gersch C, Palii S, Angerhofer A, Imaram W, Johnson RJ, Henderson GN. Inactivation of nitric oxide by uric acid,...

Gersch C, Palii S, Angerhofer A, Imaram W, Johnson RJ, Henderson GN. Uric acid’s reaction with Peroxynitrite: formation...

W.S. Waring et al.

Uric acid reduces exercise-induced oxidative stress in healthy adults

Clin Sci (Lond)

(2003)

E. Orowan

The origin of man

Nature

(1955)

Cited by (66)

Peroxiredoxin AhpC1 protects Pseudomonas aeruginosa against the inflammatory oxidative burst and confers virulence
2021, Redox Biology
Citation Excerpt :
We had previously demonstrated that incubation of neutrophils with uric acid decreased their microbicide activity against PA14 [28]. Uric acid is the end product of purine metabolism in humans, accumulates in plasma at 50–400 μM range, reaching millimolar concentration in hyperuricemia [29]. Uric acid is also abundant in other extracellular fluids and acts as a substrate for the neutrophil enzyme myeloperoxidase to produce the oxidants urate free radical and urate hydroperoxide.
Pseudomonas aeruginosa is an opportunistic bacterium in patients with cystic fibrosis and hospital acquired infections. It presents a plethora of virulence factors and antioxidant enzymes that help to subvert the immune system. In this study, we identified the 2-Cys peroxiredoxin, alkyl-hydroperoxide reductase C1 (AhpC1), as a relevant scavenger of oxidants generated during inflammatory oxidative burst and a mechanism of P. aeruginosa (PA14) escaping from killing. Deletion of AhpC1 led to a higher sensitivity to hypochlorous acid (HOCl, IC₅₀ 3.2 ± 0.3 versus 19.1 ± 0.2 μM), hydrogen peroxide (IC₅₀ 91.2 ± 0.3 versus 496.5 ± 6.4 μM) and the organic peroxide urate hydroperoxide. ΔahpC1 strain was more sensitive to the killing by isolated neutrophils and less virulent in a mice model of infection. All mice intranasally instilled with ΔahpC1 survived as long as they were monitored (15 days), whereas 100% wild-type and ΔahpC1 complemented with ahpC1 gene (ΔahpC1 attB:ahpC1) died within 3 days. A significantly lower number of colonies was detected in the lung and spleen of ΔahpC1-infected mice. Total leucocytes, neutrophils, myeloperoxidase activity, pro-inflammatory cytokines, nitrite production and lipid peroxidation were much lower in lungs or bronchoalveolar liquid of mice infected with ΔahpC1. Purified AhpC neutralized the inflammatory organic peroxide, urate hydroperoxide, at a rate constant of 2.3 ± 0.1 × 10⁶ M⁻¹s⁻¹, and only the ΔahpC1 strain was sensitive to this oxidant. Incubation of neutrophils with uric acid, the urate hydroperoxide precursor, impaired neutrophil killing of wild-type but improved the killing of ΔahpC1. Hyperuricemic mice presented higher levels of serum cytokines and succumbed much faster to PA14 infection when compared to normouricemic mice. In summary, ΔahpC1 PA14 presented a lower virulence, which was attributed to a poorer ability to neutralize the oxidants generated by inflammatory oxidative burst, leading to a more efficient killing by the host. The enzyme is particularly relevant in detoxifying the newly reported inflammatory organic peroxide, urate hydroperoxide.
CRISPR-Cas9-mediated reactivation of the uricase pseudogene in human cells prevents acute hyperuricemia
2021, Molecular Therapy Nucleic Acids
Citation Excerpt :
We have also extended the biomedical utility of ancient proteins to treat/prevent diseases.32–35 We further anticipate that future studies will provide more insights into the advantages and/or disadvantages of uric acid’s role as a critical antioxidant and its connection to the loss of vitamin C synthesis in the Haplorhini clade of mammals (tarsiers, monkeys, and apes).5,6,8,36,37 Human embryonic kidney cells (HEK293) were purchased from ATCC.
The utility of CRISPR-Cas9 to repair or reverse diseased states that arise from recent genetic mutations in the human genome is now widely appreciated. The use of CRISPR to “design” the outcomes of biology is challenged by both specialized ethicists and the general public. Less of a focus, however, is the ability of CRISPR to provide metabolic supplements or prophylactic molecules that improve long-term human health by overwriting ancient evolutionary events. Here, we use CRISPR to genomically integrate a functional uricase gene that encodes an enzymatically active protein into the human genome. These uricase-producing cells are able to reduce or even eliminate high concentrations of exogenous uric acid despite the enzyme being localized to peroxisomes. Our evolutionary engineered cells represent the first instance of the primate ape lineage expressing a functional uricase encoded in the genome within the last 20 million years. We anticipate that human cells expressing uricase will help prevent hyperuricemia (including gout) as well as hypertension and will help protect against fatty liver disease in the future.
The Impact of Uric Acid and Hyperuricemia on Cardiovascular and Renal Systems
2021, Cardiology Clinics
An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism
2021, Cell Reports
The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase 1 (IDH1) plays a central role in this process. IDH1 downregulation augments mitochondrial oxidation of αKG and inhibits reticulocyte generation. Furthermore, IDH1 knockdown results in the generation of multinucleated erythroblasts, a morphological abnormality characteristic of myelodysplastic syndrome and congenital dyserythropoietic anemia. We identify vitamin C homeostasis as a critical regulator of ineffective erythropoiesis; oxidized ascorbate increases mitochondrial superoxide and significantly exacerbates the abnormal erythroblast phenotype of IDH1-downregulated progenitors, whereas vitamin C, scavenging reactive oxygen species (ROS) and reprogramming mitochondrial metabolism, rescues erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.
Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors
2020, Journal of Cardiac Failure
Citation Excerpt :
Aside from the prevention of gout and renal stones, there is little evidence that the therapeutic reduction of uric acid exerts favorable benefits on heart or on heart failure events.19 In fact, at a physiologic pH, uric acid exists primarily as urate, accounts for a large proportion of the antioxidant capacity of blood, and suppresses oxidative stress in the myocardium.20,21 A major site of urate production in cardiac tissue is the endothelium, where it acts as a scavenger of a reactive oxygen species, thus interfering with oxidant-induced cardiomyocyte and vascular dysfunction.20,22
Hyperuricemia increases the risk of heart failure, and higher levels of serum uric acid are seen in patients who have worse ventricular function, functional capacity, and prognosis. Heart failure is also accompanied by an upregulation of xanthine oxidase, the enzyme that catalyzes the formation of uric acid and a purported source of reactive oxygen species. However, the available evidence does not support the premise that either uric acid or the activation of xanthine oxidase has direct injurious effects on the heart in the clinical setting. Xanthine oxidase inhibitors (allopurinol and oxypurinol) have had little benefit and may exert detrimental effects in patients with chronic heart failure in randomized controlled trials, and the more selective and potent inhibitor febuxostat increases the risk of cardiovascular death more than allopurinol. Instead, the available evidence indicates that changes in xanthine oxidase and uric acid are biomarkers of oxidative stress (particularly in heart failure) and that xanthine oxidase may provide an important source of nitric oxide that quenches the injurious effects of reactive oxygen species. A primary determinant of the cellular redox state is nicotinamide adenine dinucleotide, whose levels drive an inverse relationship between xanthine oxidase and sirtuin-1, a nutrient deprivation sensor that exerts important antioxidant and cardioprotective effects. Interestingly, sodium-glucose cotransporter 2 inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase, and lowering of serum uric acid. The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of sodium-glucose cotransporter 2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to decrease serious heart failure events.
Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease
2018, EBioMedicine
Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD).
Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP.
Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions.
Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP.
U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.

View all citing articles on Scopus

View full text

The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease

Summary

Section snippets

Ascorbate synthesis and its role as an antioxidant

Uric acid and the mutation of uricase

Why did early primates lose their ability to synthesize ascorbate?

What was the advantage to having uricase mutated?

Ascorbate and blood pressure

Planetary biology and the approach to the uricase/ascorbate hypotheses

Disclaimers

Acknowledgment

Free Radical Biol Med

J Biol Chem

J Biol Chem

Comp Biochem Physiol A

J Biol Chem

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Arch Biochem Biophys

Biol Psychiatry

Pharmacol Biochem Behav

Metabolism

Comp Biochem Physiol B

Med Hypotheses

Free Radical Biol Med

Comp Biochem Physiol A Mol Integr Physiol

J Free Radical Biol Med

Free Radical Biol Med

Mech Ageing Dev

Free Radical Biol Med

Lancet

Kidney Int

J Biol Chem

Kidney Int

Semin Nephrol

Biochim Biophys Acta

J Biol Chem

Implications of the human genome project for medical science

JAMA

A new biology for a new century

Microbiol Mol Biol Rev

Planetary biology--paleontological, geological, and molecular histories of life

Science

Experimental paleogenetics

Molecular paleoscience: systems biology from the past

Adv Enzymol Relat Areas Mol Biol

The role of oxygen radicals in human disease with particular reference to the vascular system

Haemostasis

Blood radicals: reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system

Pharm Res

Vitamin C. Biosynthesis, recycling and degradation in mammals

FEBS J

A family of mammalian Na+ dependent l-ascorbic acid transporters

Nature

Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius

Am J Phys Anthropol

The biological synthesis of ascorbic acid

World Rev Nutr Diet

A treatise of the scurvy, originally published in 1753

Ascorbate transport by primary cultured neurons and its role in neuronal function and protection against excitotoxicity

J Neurosci Res

Ascorbic acid and fertility

Biol Reprod

Ascorbic acid bioavailability in humans. Ascorbic acid in plasma, serum, and urine

Ann NY Acad Sci

Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats

Diabetologia

Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis

Proc Natl Acad Sci USA

Uric acid reduces exercise-induced oxidative stress in healthy adults

Clin Sci (Lond)

The origin of man

Nature

A family of mammalian Na⁺ dependent l-ascorbic acid transporters