Ketogenic Diets, Vitamin C, and Metabolic Syndrome

This is an excerpt from today's guest post on breaknutrition.com:

The Recommended Daily Allowances (RDA) for different nutrients were developed on Western diets, and therefore, high-carb diets. Given that a ketogenic metabolism uses different metabolic pathways and induces cascades of drastically different metabolic and physiological effects, it would be astonishing if any of the RDAs are entirely applicable as is.

One micronutrient that seems to be particularly warranting reassessment is vitamin C, because vitamin C is biochemically closely related to glucose. Most animals synthesize it themselves out of glucose. It shares cellular uptake receptors with glucose. Some argue that because we don’t make vitamin C, we need to ensure a large exogenous supply. I will argue the opposite: so long as we are eating a low-carb diet, we actually need less. On our way, we’ll briefly re-examine the relationship between vitamin C deficiency and insulin resistance.

End-to-End Citations:

Evidence type: review
Louis Rosenfeld
Clinical Chemistry Vol. 43, Issue 4 April 1997
"In 1911, Casimir Funk isolated a concentrate from rice polishings that cured polyneuritis in pigeons. He named the concentrate “vitamine” because it appeared to be vital to life and because it was probably an amine. Although the concentrate and other “accessory food substances” were not amines, the name stuck, but the final “e” was dropped. "
Evidence type: review
Drouin, Guy, Jean-Rémi Godin, and Benoît Pagé.
Current Genomics 12.5 (2011): 371–378. PMC. Web. 19 Dec. 2016.
"Vitamin C (ascorbic acid) plays important roles as an anti-oxidant and in collagen synthesis. These important roles, and the relatively large amounts of vitamin C required daily, likely explain why most vertebrate species are able to synthesize this compound. Surprisingly, many species, such as teleost fishes, anthropoid primates, guinea pigs, as well as some bat and Passeriformes bird species, have lost the capacity to synthesize it. Here, we review the genetic bases behind the repeated losses in the ability to synthesize vitamin C as well as their implications. In all cases so far studied, the inability to synthesize vitamin C is due to mutations in the L-gulono-γ-lactone oxidase (GLO) gene which codes for the enzyme responsible for catalyzing the last step of vitamin C biosynthesis. The bias for mutations in this particular gene is likely due to the fact that losing it only affects vitamin C production. Whereas the GLO gene mutations in fish, anthropoid primates and guinea pigs are irreversible, some of the GLO pseudogenes found in bat species have been shown to be reactivated during evolution. The same phenomenon is thought to have occurred in some Passeriformes bird species. Interestingly, these GLO gene losses and reactivations are unrelated to the diet of the species involved. This suggests that losing the ability to make vitamin C is a neutral trait."
Evidence type: observation
Bánhegyi Gábor,Csala Miklós,Braun László,Garzó Tamás and Mandl József
FEBS Letters, 381, doi: 10.1016/0014-5793(96)00077-4 (1996)
"Ascorbic acid and glutathione are involved in the antioxidant defense of the cell. Their connections and interactions have been described from several aspects: they can substitute each other [1], dehydroascorbate can be reduced at the expense of GSH [2] and glutathione depletion results in the stimulation of ascorbate synthesis [3]. In ascorbate-synthesising animals, the formation of ascorbate from gulonolactone catalysed by microsomal gulonolactone oxidase is accompanied by the stoichiometric consumption of 02 and production of the oxidant hydrogen peroxide [4]. Metabolism of hydrogen peroxide by glutathione peroxidase requires reduced glutathione. Therefore, we supposed that synthesis of ascorbate should decrease the intracellular glutathione level. To prove our hypothesis, experiments were undertaken to investigate the effect of ascorbate synthesis stimulated by the addition of gulonolactone on the oxidation of GSH in isolated mouse hepatocytes and liver microsomal membranes."
"In this paper, a new connection between ascorbate and GSH metabolism is described. Our data show that the synthesis of ascorbate leads to consumption of GSH, the other main intracellular antioxidant (Fig. 1). We suppose that the formation of hydrogen peroxide is underlying the increased GSH consumption. First, oxidation of GSH caused by increased ascorbate synthesis was prevented by the addition of catalase in microsomal membranes (Table 1). Second, inhibition of glutathione peroxidase by mercaptosuccinate moderated the gulonolactone-dependent glutathione consumption in microsomes (Table 2). Third, the inhibition of catalase by aminotriazole deepened the ascorbate synthesis-dependent GSH depletion in isolated hepatocytes (Table 3). This interaction may be one of the causes why primates and some other species have lost their ascorbate-synthesising ability. This event occurred in the ancestors of primates about 70 million years ago, owing to mutation(s) in the gulonolactone oxidase gene [14]. Despite the well-known benefits [15] of ascorbate, the mutation(s) had to be advantageous, as this metabolic error did not remain an enzymopathy affecting only a minority of the population, but spread widely amongst the species (and individuals) of primates and became exclusive [16]. There is no explanation for this unexpected outcome. Based on these analytical data, the following conceptual evolutionary hypothesis can be outlined: in the tropical jungle of the Cretaceous Period, when exogenous ascorbate was abundant [17,18], the loss of gulonolactone oxidase activity could have proved to be advantageous. It saved the reduced GSH, the main defence system against oxidants, while the access to ascorbate was not hindered. Later, the evolutionary gains of these periods allowed the conservation of the genetic disorder manifested in the loss of ascorbate synthesis."
Evidence type: experiment
Reactive oxygen species (ROS)-induced mitochondrial abnormalities may have important consequences in the pathogenesis of degenerative diseases and cancer. Vitamin C is an important antioxidant known to quench ROS, but its mitochondrial transport and functions are poorly understood. We found that the oxidized form of vitamin C, dehydroascorbic acid (DHA), enters mitochondria via facilitative glucose transporter 1 (Glut1) and accumulates mitochondrially as ascorbic acid (mtAA). The stereo-selective mitochondrial uptake of D-glucose, with its ability to inhibit mitochondrial DHA uptake, indicated the presence of mitochondrial Glut. Computational analysis of N-termini of human Glut isoforms indicated that Glut1 had the highest probability of mitochondrial localization, which was experimentally verified via mitochondrial expression of Glut1-EGFP. In vitro mitochondrial import of Glut1, immunoblot analysis of mitochondrial proteins, and cellular immunolocalization studies indicated that Glut1 localizes to mitochondria. Loading mitochondria with AA quenched mitochondrial ROS and inhibited oxidative mitochondrial DNA damage. mtAA inhibited oxidative stress resulting from rotenone-induced disruption of the mitochondrial respiratory chain and prevented mitochondrial membrane depolarization in response to a protonophore, CCCP. Our results show that analogous to the cellular uptake, vitamin C enters mitochondria in its oxidized form via Glut1 and protects mitochondria from oxidative injury. Since mitochondria contribute significantly to intracellular ROS, protection of the mitochondrial genome and membrane may have pharmacological implications against a variety of ROS-mediated disorders.
Evidence type: non-human animal experiment
"Effect of starvation and subsequent feeding. The effect of starvation was then investigated, and it appeared that a 24 hr. period of starvation was enough to decrease the synthesis of ascorbic acid (Table 2). Since Caputto et al. (1958) had shown that the maximum effect of vitamin-E deficiency on the synthesis of ascorbic acid was reached as shortly as 3-4 days after deprivation, the possibility was considered that the effect of starvation was actually due to lack of vitamin E. This was discounted by giving starved animals enough vitamin E to prevent formation of peroxides; there was no effect on the synthesis of ascorbic acid. The effect ofstarving was quickly reversed by feeding the rats again for 24 hr."
"Effect of omission of carbohydrates from the diet and of administration of precursors: The effect of starvation could be attributed either to the stress or to the lack of some dietary components. A strong impairment of the synthesis of ascorbic acid was observed in rats given a carbohydrate-free diet for 24 hr., whereas values significantly higher but still below normal ones were obtained by giving this same diet for 6 days (Table 3). Rats on this ration had a lower content of ascorbic acid in the liver, but showed an enhanced excretion of ascorbic acid in the urine. Since carbohydrates are precursors of ascorbic acid in the rat, this observation led to the hypothesis of an adaptive response of the enzyme system to lack of substrates, and evidence was sought by giving glucuronolactone to rats. Administration of glucuronolactone did not affect the rate of synthesis in normal rats, but caused a moderate but significant enhancement in starved animals. However, a similar enhancement followed the administration of an equal amount of glucose. All rats receiving glucuronolactone had a higher liver content and an enhanced urinary excretion of ascorbic acid."
Evidence type: non-human animal experiment
Braun L1, Garzó T, Mandl J, Bánhegyi G.
FEBS Lett. 1994 Sep 19;352(1):4-6.
"The role of the hepatic glycogen content in ascorbic acid synthesis was investigated in isolated mouse hepatocytes. The cells were prepared from fed or 48 h-starved mice and the ascorbic acid content was measured in the suspension (cells+medium). After 48 h starvation hepatocytes did not contain measurable amounts of glycogen. The initial concentration of ascorbic acid was lower in the suspension of glycogen-depleted hepatocytes compared to the fed controls (Fig. 1) and only a moderate synthesis could be observed under both nutritional conditions. The effects of dibutyryl CAMP and glucagon on ascorbate synthesis were examined. Glucagon or dibutyryl cyclic AMP caused a stimulation of ascorbic acid synthesis in hepatocytes from fed mice, while in hepatocytes from 48 hstarved animals ascorbic acid production was not increased significantly by the two agents (Fig. 1). The addition of glucose and gluconeogenic precursors to the incubation medium did not result in a significant increase in ascorbic acid production (Fig. 1). In another series of experiments glucose and ascorbic acid production of the cells was measured simultaneously. The rate of glucose production (in the absence of gluconeogenic precursors mainly via glucogenolysis) and ascorbic acid synthesis showed a close correlation (r = 0.9091) (Fig. 2). As ascorbic acid synthesis and glycogenolysis seemed to be connected, we examined the effect on ascorbic acid synthesis of various agents known to increase glycogenolysis. The al agonist phenylephrine, the protein phosphatase inhibitor okadaic acid and vasopressin all increased the rate of ascorbic acid production in isolated hepatocytes prepared from fed mice similarly to glucagon (Table 1).
"Glycogenolysis was stimulated by the in vivo addition of glucagon. Glucagon elevated the blood glucose level of mice by 50%; at the same time a more than fifteenfold increase of plasma ascorbic acid concentration could be observed (Table 2). The concentration of ascorbic acid in the liver was also increased, indicating a stimulated hepatic synthesis (Table 2).
Glycogen content is considered to be a sensitive marker showing the actual metabolic state of the liver. Observations described in this paper suggest that ascorbic acid synthesis in murine liver is tightly connected with the glycogen pool; the source of ascorbic acid is glycogen. The following results gained in isolated hepatocytes support this assumption: first, in hepatocytes isolated from glycogen-depleted animals the ascorbic acid level as well as the rate of synthesis is lower than that in hepatocytes from control fed mice (Fig. 1); second, different glycogen-mobilizing agents acting via different mechanisms enhance ascorbic acid production in hepatocytes from fed but not from fasted animals (Fig. 1, Table 1); third, addition of glucose to hepatocytes prepared from glycogen-depleted mice failed to increase the formation of ascorbic acid (Fig. 1). The results gained under in vitro conditions in isolated hepatocytes were confirmed by in vivo experiments: a single i.p. injection of glucagon elevated both the plasma and liver ascorbic acid levels within 15 min (Table 2). "
"The finding that the source of ascorbate production is glycogenolysis is in according with the fact that liver and kidney -the main sites of glycogen storage - are responsible for the ascorbic acid supply in most animal species [2]. The increased hepatic ascorbic acid production after glucagon administration can be explained as a compensatory mechanism of the missing intake of ascorbate, i.e. adaptation of ascorbic acid supply from external to internal sources. Considering the fifteenfold elevation of plasma ascorbate levels, in the light of recent findings concerning the effect of ascorbate on insulin secretion [18] and on the calcium channels in pancreatic beta cells [19] it might be also regarded as a possible intercellular messenger. "
Evidence type: experiment
Drew KL, Tøien Ø, Rivera PM, Smith MA, Perry G, Rice ME.
Comp Biochem Physiol C Toxicol Pharmacol. 2002 Dec;133(4):483-92.
"During hibernation plasma ascorbate concentrations w(Asc)px were found to increase 3–5 fold in two species of ground squirrels, AGS and 13-lined ground squirrels (TLS); S. tridecemlineatus and cerebral spinal fluid (CSF) ascorbate concentration w(Asc)CSFx doubled in AGS (CSF was not sampled in TLS) (Drew et al., 1999). During arousal, however, when oxygen consumption peaks and the generation of reactive oxygen species is thought to be maximal, plasma ascorbate concentrations progressively decrease to levels typical for euthermic animals (Fig. 3)."
Evidence type: observation
George Mann and Pamela Newton
Ann N Y Acad Sci. 1975 Sep 30;258:243-52.
"We have formulated two hypotheses. The first proposes that the transport of ascorbate across cell membranes may be impaired by glucose. The second proposes that the transport of ascorbate in certain tissues is facilitated by insulin. If either hypothesis is valid, those species requiring exogenous ascorbate would be in double jeopardy if they were also hyperglycemic. Carbohydrate intolerance resulting from eithcr a lack of or a resistance to insulin is common in Western man. Gore et al. have shown with electron microscopy that the vascular lesion of scurvy involves collagenous structures in the basement membranes, and this is also the site of the lesion in diabetic microangiopathy. These hypotheses, which propose that the intracellular availability of dehydroascorbate (DHA), the transportable form of vitamin C, would be impaired in certain tissues by either hypcrglycemia or lack of insulin, suggest that diabetic microangiopathy, the main complication of human diabetes, may be a consequence of local ascorbate deficiency. The laboratory investigations described here deal with the first and somewhat simpler of these hypotheses: Glucose will impair the transport of dehydroascorbate into cells. The data collected show that D-glUCOSe does inhibit the transport of dehydroascorbate into human red blood cells, a noninsulin-dependent tissue. Trials wiih other sugars show a hierarchy of sugars that inhibit transport, suggesting that DHA and D-glucose share a carrier mechanism."
Evidence type: review
"Hyperglycemia-induced ascorbic acid deficiency
Vitamin C is a derivative of glucose and Mann [138] proposed that the structural similarity between these two molecules may account for many of the complications of diabetes. Glucose has been shown to inhibit vitamin C transport in several mesenchymal cell types, including endothelial cells [139], mononuclear leukocytes [140], neutrophils [141,142], fibroblasts [143,144], and erythrocytes [145]. Facilitative glucose transporters (GLUTs) bind dehydroascorbic acid and are thought to be the primary transporters of vitamin C in mammalian cells [146]. After transport, dehydroascorbic acid is quickly reduced to ascorbic acid. Glucose competitively inhibits the uptake of dehydroascorbic acid but does not affect ascorbic acid transport. Ascorbic acid is transported by a family of membrane-bound proteins that are Na+-dependent and whose function is not directly inhibited by elevated extracellular concentrations of glucose [146,147]. This latter system is prevalent in bulk-transporting epithelia (e.g. kidney and small intestine) and have been recently isolated in both human [148] and rat [149] biological systems. Many cell types, of course, [150,151] express both transport systems.
High blood glucose concentrations mimic the conditions of vitamin C deficiency. Acute hyperglycemia, for example, impairs endothelium-dependent vasodilation in healthy humans [152], an effect which can be reversed by acute administration of vitamin C [153]. Ascorbic acid plays an important role in extracellular matrix regulation and has a stimulatory effect on sulfate incorporation in mesangial cell and matrix proteoglycans; high glucose concentrations have been shown to impair this effect [154]. Endothelial surface proteoglycans help prevent thrombus formation and also inhibit smooth-muscle growth [1]. High glucose concentrations also have been shown to inhibit the stimulatory effect of ascorbic acid on collagen and proteoglycan synthesis in cultured fibroblasts [114]. Moreover, a high concentration of glucose can induce the expression of intercellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells [155]. Endothelial cells express these and other membrane-bound proteins to enable leukocyte adhesion and transmigration across the endothelium during an inflammatory response. Atherosclerosis is one such inflammatory response.
Experimental and clinical studies suggest that latent scurvy is characterized by IGT [16,24] and diabetes mellitus is a disease complex characterized by impaired glucose and vitamin C metabolism [27,28]. Diabetic patients are prone to hyperglycemia, prolonged wound healing, infection, increased synthesis of cholesterol, decreased liver glycogen, and notably, diffuse vascular disease. All of these findings are consistent with latent scurvy [16]. Diabetic platelets have been shown to have low intracellular ascorbic acid concentrations and display hypercoagulability [156]. Long-term vitamin C administration has beneficial effects on glucose and lipid metabolism in aged NIDDM patients [157]. It has also been suggested that vitamin C consumption above the RDA may provide important health benefits for individuals with IDDM [158]. This latter recommendation is supported by recent evidence. For example, mesenchymal cells from patients with IDDM have an impaired uptake of dehydroascorbic acid that persists in culture [159] and ascorbic acid has been shown to prevent the inhibition of DNA synthesis induced by high glucose concentrations in cultured endothelial cells [160]. Diabetic patients have been observed to have a lowered ascorbic acid/dehydroascorbic acid plasma ratio, indicating a decreased vitamin C status [161]. Therefore, diabetic patients may benefit from vitamin C supplementation to alleviate multiple physiologic and metabolic impairments in a variety of cell types."
Evidence type: review
Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M.
J Am Coll Nutr. 2003 Feb;22(1):18-35.
"Problems in Demonstrating Antioxidant Benefit of Vitamin C in Clinical
"Studies Despite epidemiological and some experimental studies, it has not been possible to show conclusively that higher than anti-scorbutic intake of vitamin C has antioxidant clinical benefit. This is despite the fact that vitamin C is a powerful antioxidant in vitro. It is of course possible that the lack of antioxidant effect of vitamin C in clinical studies is real. It seems more likely that vitamin C has antioxidant or other benefits. Detection of these benefits has remained elusive due to the vicissitudes of experimental design. Vitamin C may be a weak antioxidant in vivo, or its antioxidant actions may have no physiological role, or its role may be small. The oxidative hypothesis is unproven, and oxidative damage may have a smaller role than anticipated in some diseases. Further, antioxidant actions of vitamin C may occur at relatively low plasma vitamin C concentrations. Thus additional clinical benefits that occur at higher vitamin C concentrations may be difficult to demonstrate. Although all these are possible explanations, it seems unlikely that these are the real reasons for the lack of detectable effects of vitamin C in clinical studies. Many factors may contribute to the failure so far to demonstrate clear antioxidant benefits of vitamin C in clinical studies. The antioxidant actions of vitamin C may be specific to certain reactions or occur only at specific locations. In either case, beneficial effects can be shown only in disorders where such reactions or sites are the focus of disease process. There may be many different antioxidants that are active at the same time. In the face of such redundancy, only multiple antioxidant deficiencies will have detectable clinical effects. Antioxidant deficiency may have to be of long duration for accumulated damage to be noticeable. Antioxidant effects may be of importance only in those with oxidant stress. Thus, normal subjects or those with mild disease may have no need for high antioxidant concentrations. In a way analogous to the effect of acetaminophen on fever, antioxidants may have no effect in the absence of marked oxidant stress. A further problem is presented by the sigmoidal dose concentration curve for vitamin C. Small changes in oral intake of vitamin C produce large changes in plasma vitamin C concentrations. This makes it difficult to conduct controlled studies such that the plasma vitamin C concentrations of the control and study groups differ sufficiently to have physiological meaning."
Evidence type: review
Padayatty SJ, Levine M
Oral Dis. 2016 Sep;22(6):463-93. doi: 10.1111/odi.12446. Epub 2016 Apr 14.
(Emphasis mine)
"Collagen hydroxylation
"Common symptoms of scurvy include wound dehiscence, poor wound healing and loosening of teeth, all pointing to defects in connective tissue (Crandon et al, 1940; Lind, 1953; Hirschmann and Raugi, 1999). Collagen provides connective tissue with structural strength. Vitamin C catalyzes enzymatic (Peterkofsky, 1991) posttranslational modification of procollagen to produce and secrete adequate amounts of structurally normal collagen by collagen producing cells (Kivirikko and Myllyla, 1985; Prockop and Kivirikko, 1995). Precollagen, synthesized in the endoplasmic reticulum, consists of amino acid repeats rich in proline. Specific prolyl and lysyl residues are hydroxylated, proline is converted to either 3-hydroxyproline or 4-hydroxyproline, and lysine is converted to hydroxylysine. The reactions catalyzed by prolyl 3-hydroxylase, prolyl 4- hydroxylase, and lysyl hydroxylase (Peterkofsky, 1991; Prockop and Kivirikko, 1995; Pekkala et al, 2003) require vitamin C as a cofactor. Hydroxylation aids in the formation of the stable triple helical structure of collagen, which is transported to the Golgi apparatus and eventually secreted by secretory granules. In the absence of hydroxylation, secretion of procollagen decreases (Peterkofsky, 1991) and it probably undergoes faster degradation. However, some hydroxylation can occur even in the absence of vitamin C (Parsons et al, 2006). Secreted procollagen is enzymatically cleaved to form tropocollagen that spontaneously forms collagen fibrils in the extracellular space. These fibrils form intermolecular collagen cross-links, giving collagen its structural strength. Independent of its effects on hydroxylation, ascorbate may stimulate collagen synthesis (Geesin et al, 1988; Sullivan et al, 1994). Collagen synthesis may be decreased in scorbutic animals (Peterkofsky, 1991; Kipp et al, 1996; Tsuchiya and Bates, 2003). Reduced collagen cross-links may be a marker of vitamin C deficiency in the guinea pig (Tsuchiya and Bates, 2003) but this may not be specific to vitamin C deficiency. Although many features of human scurvy appear to be due to weakening of connective tissue, it has not been shown that these lesions are due to defective collagen synthesis."
Evidence type: non-human animal experiment
J Mårtensson, J Han, O W Griffith, and A Meister
Proc Natl Acad Sci U S A. 1993 Jan 1; 90(1): 317–321.
"Guinea pigs given an ascorbate-deficient diet gained weight through day 14, but gained at a slower rate than the control animals,and then lost weight(Table1,groupA).The animals givenGSH ester(groupB)gained more weight than those of group A, and the weight gain during days 10-14 was =70% of the control group. Animals in group A became obviously sick after about day 17. They could not walk and moved very little, apparently immobilized by fractures of the hind legs and by swelling of the joints of the extremities, which were tender and had periosteal hematomas. Radiography showed major fractures of the femur in two animals. Animals in group A died or were sacrificed on day 21 or 22. Animals in group B(GSHester)did not have fractures or hematomas; 75% of these animals were indistinguishable by general appearance from controls. Histological study showed significant loss of osteoid material from long bones in group A,whereas most animals in group B had no decrease of osteoid material (Fig.1)or only a moderate decrease. In a separate experiment, several animals comparable to those of group B were kept for 40 days and showed no significant signs of scurvy (tender swollen joints,fractures);they exhibited some weight loss."
Evidence type: in vitro experiment
Li X, Qu ZC, May JM.
Antioxid Redox Signal. 2001 Dec;3(6):1089-97.
"Liver is the site of ascorbic acid synthesis in most mammals. As human liver cannot synthesize ascorbate de novo, it may differ from liver of other species in the capacity or mechanism for ascorbate recycling from its oxidized forms. Therefore, we compared the ability of cultured liver-derived cells from humans (HepG2 cells) and rats (H4IIE cells) to take up and reduce dehydroascorbic acid (DHA) to ascorbate. Neither cell type contained appreciable amounts of ascorbate in culture, but both rapidly took up and reduced DHA to ascorbate. Intracellular ascorbate accumulated to concentrations of 10-20 mM following loading with DHA. The capacity of HepG2 cells to take up and reduce DHA to ascorbate was more than twice that of H4IIE cells. In both cell types, DHA reduction lowered glutathione (GSH) concentrations and was inhibited by prior depletion of GSH with diethyl maleate, buthionine sulfoximine, and phenylarsine oxide. NADPH-dependent DHA reduction due to thioredoxin reductase occurred in overnight-dialyzed extracts of both cell types. These results show that cells derived from rat liver synthesize little ascorbate in culture, that cultured human-derived liver cells have a greater capacity for DHA reduction than do rat-derived liver cells, but that both cell types rely largely on GSH- or NADPH-dependent mechanisms for ascorbate recycling from DHA."
Evidence type: non-human animal experiment
Jarrett SG, Milder JB, Liang LP, Patel M.
J Neurochem. 2008 Aug;106(3):1044-51. doi: 10.1111/j.1471-4159.2008.05460.x. Epub 2008 May 5.
"The ketogenic diet (KD) is a high-fat, low carbohydrate diet that is used as a therapy for intractable epilepsy. However, the mechanism(s) by which the KD achieves neuroprotection and/or seizure control are not yet known. We sought to determine whether the KD improves mitochondrial redox status. Adolescent Sprague-Dawley rats (P28) were fed a KD or control diet for 3 weeks and ketosis was confirmed by plasma levels of beta-hydroxybutyrate (BHB). KD-fed rats showed a twofold increase in hippocampal mitochondrial GSH and GSH/GSSG ratios compared with control diet-fed rats. To determine whether elevated mitochondrial GSH was associated with increased de novo synthesis, the enzymatic activity of glutamate cysteine ligase (GCL) (the rate-limiting enzyme in GSH biosynthesis) and protein levels of the catalytic (GCLC) and modulatory (GCLM) subunits of GCL were analyzed. Increased GCL activity was observed in KD-fed rats, as well as up-regulated protein levels of GCL subunits. Reduced CoA (CoASH), an indicator of mitochondrial redox status, and lipoic acid, a thiol antioxidant, were also significantly increased in the hippocampus of KD-fed rats compared with controls. As GSH is a major mitochondrial antioxidant that protects mitochondrial DNA (mtDNA) against oxidative damage, we measured mitochondrial H2O2 production and H2O2-induced mtDNA damage. Isolated hippocampal mitochondria from KD-fed rats showed functional consequences consistent with the improvement of mitochondrial redox status i.e. decreased H2O2 production and mtDNA damage. Together, the results demonstrate that the KD up-regulates GSH biosynthesis, enhances mitochondrial antioxidant status, and protects mtDNA from oxidant-induced damage."
Evidence type: non-human animal experiment
Milder JB, Liang LP, Patel M.
Neurobiol Dis. 2010 Oct;40(1):238-44. doi: 10.1016/j.nbd.2010.05.030. Epub 2010 May 31.
"The mechanisms underlying the efficacy of the ketogenic diet (KD) remain unknown. Recently, we showed that the KD increased glutathione (GSH) biosynthesis. Since the NF E2-related factor 2 (Nrf2) transcription factor is a primary responder to cellular stress and can upregulate GSH biosynthesis, we asked whether the KD activates the Nrf2 pathway. Here we report that rats consuming a KD show acute production of H(2)O(2) from hippocampal mitochondria, which decreases below control levels by 3 weeks, suggestive of an adaptive response. 4-Hydroxy-2-nonenal (4-HNE), an electrophilic lipid peroxidation end product known to activate the Nrf2 detoxification pathway, was also acutely increased by the KD. Nrf2 nuclear accumulation was evident in both the hippocampus and liver, and the Nrf2 target, NAD(P)H:quinone oxidoreductase (NQO1), exhibited increased activity in both the hippocampus and liver after 3 weeks. We also found chronic depletion of liver tissue GSH, while liver mitochondrial antioxidant capacity was preserved. These data suggest that the KD initially produces mild oxidative and electrophilic stress, which may systemically activate the Nrf2 pathway via redox signaling, leading to chronic cellular adaptation, induction of protective proteins, and improvement of the mitochondrial redox state."
Evidence type: review
Meister A
J Biol Chem. 1994 Apr 1;269(13):9397-400.
"Ascorbate and GSH have actions in common and can spare each other under appropriate experimental conditions; this redundancy reflects the metabolic importance of such antioxidant activity.
[Sorry, this paper is hard to quote. It's free. Go look. :-)]
Evidence type: review
Bruce N. Ames, Richard Cathcart, Elizabeth Schwiers, and Paul Hochstein
Proc. NatL Acad. Sci. USA Vol. 78, No. 11, pp. 6858-6862, November 1981 Biochemistry
"During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate level in humans (about 300 ILM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context."
Evidence type: review
Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA.
Curr Pharm Des. 2005;11(32):4145-51.
"It has been proposed that UA may represent one of the most important low-molecular-mass antioxidants in the human biological fluids [23-26]. Ames et al. proposed in the early eighties that UA can have biological significance as an antioxidant and showed, by in vitro experiments, that it is a powerful scavenger of peroxyl radicals (RO2 . ), hydroxyl radicals (. OH) and singlet oxygen [23]. The authors speculated that UA may contribute to increased life-span in humans by providing protection against oxidative stress-provoked ageing and cancer. UA is an oxidizable substrate for haem protein/H2O2 systems and is able to protect against oxidative damage by acting as an electron donor [27]. Apart from its action as radical scavenger, UA can also chelate metal ions, like iron and copper, converting them to poorly reactive forms unable to catalyse free-radical reactions [28-30]."
"A randomized placebo-controlled double-blind study has evaluated the effects of systemic administration of 100 mg UA, in healthy volunteers compared with vitamin C 1000 mg [45]. A significant increase in serum free radical scavenging capacity from baseline was observed during UA and vitamin C infusion – but the effect of UA was substantially greater. No adverse reactions to UA administration were reported. Another clinical study indicated a significant inverse relationship between serum UA concentrations and oxidative stress during acute aerobic exercise [46], while an increase in muscle allantoin levels was detected [32]. The authors concluded that ROS are formed in human skeletal muscle during intense sub-maximal exercise and urate is used as a local antioxidant. Another clinical trial involving healthy young men showed that 50 and 80 km marches led to 25 % and 37 % rises, respectively, in plasma levels of UA, probably due to increases in the metabolic rate and consequently pyrimidine nucleotide metabolism [47]. A randomized double-blind placebo controlled crossover study evaluated the free radical properties of UA in healthy volunteers [48]. UA (0.5 g in 250 ml of 0.1 % lithium carbonate / 4 % dextrose vehicle or vehicle alone as control) was given to subjects who then performed high intensity aerobic exercise for 20 min to induce oxidative stress. A single high-intensity exercise caused oxidative stress (as reflected by increased plasma F2- isoprostanes) immediately after exercise and recovery. Administration of UA increased circulating UA concentrations, which increased serum free radical scavenging capacity and reduced the exercise-induced increases in plasma F2-isoprostanes. The authors concluded that the antioxidant properties of UA are of physiological consequence and support the view that UA has potentially important free radical scavenging effects in vivo."
Evidence type: observational
"Urate has been shown to be a major antioxidant in human serum and was postulated to have a biological role in protecting tissues against the toxic effects of oxygen radicals and in determining the longevity of primates. This possibility has been tested by determining if the maximum lifespan potentials of 22 primate and 17 non-primate mammalian species are positively correlated with the concentration of urate in serum and brain per specific metabolic rate. This analysis is based on the concept that the degree of protection a tissue has against oxygen radicals is proportional to antioxidant concentration per rate of oxygen metabolism of that tissue. Ascorbate, another potentially important antioxidant in determining longevity of mammalian species, was also investigated using this method. The results show a highly significant positive correlation of maximum lifespan potential with the concentration of urate in serum and brain per specific metabolic rate. No significant correlation was found for ascorbate. These results support the hypothesis that urate is biologically active as an antioxidant and is involved in determining the longevity of primate species, particularly for humans and the great apes. Ascorbate appears to have played little or no role as a longevity determinant in mammalian species."
Evidence Type: review
Charles V. Mobbs, Jason Mastaitis, Minhua Zhang, Fumiko Isoda, Hui Cheng, and Kelvin Yen
Interdiscip Top Gerontol. 2007; 35: 39–68.
(emphasis mine)
"Glucose Oxidation Favors Complex I, Lipid/Amino Acid Oxidation Favors Complex II
"The significance of the shift in source of carbon atoms for oxidation produced by dietary restriction may be that the oxidation of lipids and amino acids depends much more on mitochondrial complex II than on (free-radical generating) complex I, whereas glucose oxidation depends much more on complex I than on complex II. When glucose is broken down by glycolysis, the only reducing equivalents it makes are in the form of NADH. When the final carbon product of glucose, pyruvate, is metabolized in the Krebs cycle, almost all the reducing equivalents are produced in the form of NADH, except for one step at complex II (succinate dehydrogenase) that makes (then oxidizes) FADH2. Ultimately the metabolism of one molecule of glucose produces an NADH: FADH2 ratio of 5:1 [53, p. 20]. In contrast, when lipids are broken down by β-oxidation (fatty acid counterpart to glycolysis), an equal number of NADH and FADH2 molecules are formed. When the lipid-derived carbons are metabolized in the Krebs cycle, reducing equivalents are produced in the ratio of 3 NADH molecules per FADH2 molecule. Therefore ultimately lipid metabolism yields an NADH:FADH2 ratio of about 2:1 [53, p. 38] or even more if the fatty acid contains enough carbon atoms. For example, when one molecule of palmitate is oxidized, it produces 15 molecules of FADH2 and 31 molecules of NADH, which are ultimately oxidized to produce a net total of 129 ATP molecules. In contrast, production of the same number of ATP molecules from glucose would entail producing then oxidizing 8.66 FADH2 and 43.3 NADH molecules. Amino acid oxidation also proceeds by a similar 2-step mechanism yielding an NADH:FADH2 ratio between that of lipids and that of glucose, the precise number depending on the specific amino acid. The significance of this shift in the NADH:FADH2 ratio is that NADH is oxidized only at mitochondrial complex I, whereas FADH2 is oxidized only at complex II [53, p. 17]. Thus palmitate oxidation entails utilizing complex II at roughly twice the (FADH2-dependent) rate as glucose oxidation entails. Therefore shifting away from glucose utilization toward lipid and amino acid utilization would be expected to substantially reduce the production of reactive oxygen species, without necessarily reducing ATP production. As described below, other beneficial effects also occur as a result of this altered pattern of glucose fuel use, including a shift toward producing antioxidizing NADPH and increased protein and lipid turnover, which reduces the accumulation of oxidized protein and lipids."
Evidence type: experiment
Greco T, Glenn TC, Hovda DA, Prins ML
J Cereb Blood Flow Metab. 2016 Sep;36(9):1603-13
"Mechanisms of ketogenic improvement
"As mentioned previously, it is thought that much of the KD’s improvement in cellular metabolism and neuroprotection is through its ability to act as an alternative substrate. Here, we show rather that it first acts in an antioxidant manner to reverse mitochondrial dysfunction. Both Complex I and II–III are inhibited in CCISTD mice at 6 h post-injury. Increased production of lactate is a reflection of impairment of oxidative phosphorylation as well as an attempt to maintain ATP concentrations and cellular membrane potential through increased glycolytic output.13 While Complex I activity returns to sham levels by 24 h, Complex II–III activity remains inhibited. ONOO has been shown to not only inhibit Complex II–III, but also Complex V40 and suggests that the observed decline in ATP production in PND35 animals13 is due in part to impaired Complex III and/or V activity. In addition to inhibition of mitochondrial complexes, decomposition products of ONOO increase the amount of lipid peroxidation leading to thiol linkages and pore formation in the inner membrane ultimately uncoupling the mitochondria. Although Complex I activity is inhibited in CCI-KD animals, Complex II–III activity is not. This will continue to allow electron flow through the respiratory chain and production of ATP. KD not only has antioxidant properties, but may provide substrates beyond Acetyl-CoA. The reaction of AcAc with Succinyl-CoA produces succinate, and animals either fed a KD or infused with ßOHB show a significant increase in succinate concentrations.41,42 Other groups have also shown that KD increases Complex II activity (succinate dehydrogenase activity).43 By increasing Complex II activity and its substrate, KD is able to maintain mitochondrial membrane potential and ATP production and prevent bioenergetic failure. At 24 h post-injury, KD is likely to exert its affects through three mechanisms: (1) continued direct and indirect ROS/RNS scavenging, (2) increased Complex II activity and (3) increased acetyl-CoA and succinate."

Evidence type: experiment
I cannot access the original experiment, but it is referred to here in the documents used by the RDA:
"Overall, while evidence suggests that vitamin C deficiency is linked to some aspects of periodontal disease, the relationship of vitamin C intake to periodontal health in the population at large is unclear. Beyond the amount needed to prevent scorbutic gingivitis (less than 10 mg/day) (Baker et al., 1971), the results from current studies are not sufficient to reliably estimate the vitamin C requirement for apparently healthy individuals based on oral health endpoints."
Baker EM, Hodges RE, Hood J, Sauberlich HE, March SC, Canham JE. 1971. Metabolism of 14C- and 3H-labeled L-ascorbic acid in human scurvy. Am J Clin Nutr 24:444–454.
Evidence type: observation
The current recommended dietary allowance (RDA) for vitamin C for adult nonsmoking men and women is 60 mg/d, which is based on a mean requirement of 46 mg/d to prevent the deficiency disease scurvy. However, recent scientific evidence indicates that an increased intake of vitamin C is associated with a reduced risk of chronic diseases such as cancer, cardiovascular disease, and cataract, probably through antioxidant mechanisms. It is likely that the amount of vitamin C required to prevent scurvy is not sufficient to optimally protect against these diseases. Because the RDA is defined as "the average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all healthy individuals in a group," it is appropriate to reevaluate the RDA for vitamin C. Therefore, we reviewed the biochemical, clinical, and epidemiologic evidence to date for a role of vitamin C in chronic disease prevention. The totality of the reviewed data suggests that an intake of 90-100 mg vitamin C/d is required for optimum reduction of chronic disease risk in nonsmoking men and women. This amount is about twice the amount on which the current RDA for vitamin C is based, suggesting a new RDA of 120 mg vitamin C/d.


Optimal Weaning from an Evolutionary Perspective:

The evolution of our brains, meat eating, and a reliance on ketogenic metabolism

I recently had the privilege of presenting a talk, with the same title as this post, at the Ancestral Health Symposium.

I am posting the video here, with a transcript, some references, and related material.


This is what I said for each slide, with comments / clarifications in square brackets. Times are approximate.

Optimal Weaning from an Evolutionary Perspective



My talk is called Optimal Weaning from an Evolutionary Perspective and I'd like to break down that title a little bit.

'Optimal' implies best for something, and here that something is going to be brain development.

The word 'weaning' can also benefit from clarification, because we often use it to mean the end of breastfeeding, but I use the convention meaning the beginning of the end, with the introduction of first foods.

For 'evolutionary perspective', I just want to point out that what we know about our past can inform our understanding of physiology, but our physiology can also constrain the possibilities of the past.




I've concluded that weaning infants onto an animal based diet best meets their nutritional needs, and the rest of this talk will be about why.

Primarily I'll be talking about the unique properties that resulted from the evolution of our brains. I'll also give a bit of evidence from modern health studies and trials, and then finally I'll give a little bit of the how, based on my own experience in weaning one of my children onto animal based foods.

Human brains are unique



Human brains are unique in many ways, but one of the most striking things is their sheer size, especially relative to our bodies. In particular, when you take into account that we are primates, it's really quite extraordinary. Primates already have brains that are about three times as large as most other mammals, at least relative to their size [1], and then humans have again about two and a half to three times as large brains as other primates do. And we didn't always have that large a brain, that three times expansion occurred over the course of a few million years.

And a second related way that our brains are unique, is that our individual human brains do most of their growth after birth [2].

Altricial vs. Precocial



It's helpful to think about this in context of the distinction between altricial and precocial animals, which is based on their degree of development at birth. Altricial animals are underdeveloped. They tend to have a short gestation, compared to precocial animals, who have a long gestation. They're poorly developed, so they may be missing hair. They usually have underdeveloped sense organs, for example unopen eyes. They're usually born in litters, as opposed to singletons, and they have less adult-like proportions, whereas precocial animals are essentially adult-like in their proportions. They have underdeveloped limbs, which means that they can't do what precocial animals do, which is move like the adults that they're born from, and they tend to be smaller at birth, and their parents are younger when they reproduce.

Humans appear altricial but are precocial



Humans don't really fit into this paradigm very well when you look at it at first glance, because they appear to be altricial, but they're actually better understood as being precocial. Primates in general are highly precocial, and humans, when they fit that, are to the extreme, for example, we have enormous newborns, and we reproduce relatively late. Our babies appear altricial, though, because they're born helpless, they don't have adult proportions at all, and they can't walk or have the motor skills that you would expect them to have.

But it's helpful to think of them as actually precocial, but born early. And one reason to think that is because of fetal brain growth rates. We have our brains growing at the same rate as fetuses do persisting for up to a year [ should say at least ] after birth, and if you then look at our babies when they are a year old they look a lot more like you would expect them to look if they were born precocial: they have motor skills that you would expect them to have, and teeth, for example.

Human bains continue to grow postnatally



Here's [sic] a couple of graphs from the Smithsonian. There's one for chimpanzee brain growth and one for human brain growth. As you can see with the chimpanzee brain growth, they complete about half of their brain growth in gestation, and the rest over the course of a couple of years. Note that chimpanzees, like many primates wean quite late compared to us [3]; they wean at about four years of age, which is well after all their brain growth is completed.

Humans, on the other hand, have a very steep rate of growth before birth, and it continues into the second year [4], [5], and then the rate slows down some, although it's still pretty significant, and then it's followed by what looks on this graph like a levelling off, but this graph does end at age 10 and we know that there are growth spurts after that, too.

Rapid brain growth sustained beyond weaning



What I want to draw attention to with that is that the fetal-like brain growth doesn't just extend beyond birth, but it also extends beyond the end of weaning. [This is a mistake. I meant to say that the rapid brain growth continues past the end of weaning, but it is "fetal-like" only past the beginning of weaning.]

So, we have this fetal-like growth in the first year, continued rapid growth to 5 years [ Or is it 4? ] [6], continued slower growth through childhood, and then, if you combine that with the fact that we wean early [3], we realise we need to support that kind of rate of growth even beyond weaning.

[ I'm also wondering whether weight is the best measure. Volume, density, cholesterol levels are all other measures to consider, but I won't get into that here and now. ]

Our brains are really vulnerable, and they have many critical periods, each of which builds on the one before, so if you haven't completed one of your stages of brain growth, you may not be able to complete the next stage successfully, and that means that you need continuous support through a long period of time [7].

Brain growth requirements



What kind of support do we need to give growing brains? Well there are at least three kinds of ways that we need to support a growing brain.

One is that they need specific micro-nutrients. Even adult brains can suffer if they don't get enough of certain kinds of micronutrients and certainly developing brains that are missing these nutrients, if they're missing them at critical times sometimes they can't even recover from the detriment.

Secondly brains require an enormous amount of energy. At least 20% of the energy that we consume as adults goes to our brain and that's even more extreme in a newborn who has about three quarters of the energy that they consume go[ing] right to the brain [8], [9].

And then thirdly, of course we need material for the structural components, and brains are made mostly of cholesterol and fat.

Brain evolution requirements



In parallel to that, the evolving of the brain has similar requirements. We needed those micronutrients and the energy and the structural components. We needed them to be available over a period of years for each individual and then that needed to be compounded more or less continuously for millions of years for us to be able to make that three times expansion.

Brain requirements: co-adaptations



While our brains were expanding over this long evolutionary period, there were co-adaptations that allowed them to expand, particularly contributing to the extraordinarily high energy requirements.

These co-adaptations I would like to talk about in more specifics: a high quality diet (by which I mean high in animal foods), shrinking intestines, a reliance on the ketogenic metabolism, and increased body fat particularly in babies.

Co-adaptation: eating meat



First of all, meat eating. The plants that were available to us at the time that we were expanding our brains were simply too fibrous, too low in protein, too seasonal, and too low in calories to provide the needed energy. So significant fatty meat eating was necessary for the protein and the energy as well as the micro-nutrients for developing our brains to our current form.

[ See the post, Meat is best for growing brains for more detail about the implausibility of plants as a sufficient food source.]

Brain requirements: micronutrients



I'm going to just zoom in on a few of those particularly critical micronutrients.

We have the minerals iodine [10] , iron [11], and zinc [12]; the fatty acid DHA [13], which is in all your brain cells in the phospholipids. It's particularly important in vision (retinal cells) in the synapses, and vitamins A and D. If you don't get enough of these vitamins and minerals and fatty acids as your brain is developing you can suffer developmental delay, disability. There is a tendency to emotional fragility and susceptibility to psychiatric disorders and it's often not recoverable.

Micronutrient sources



For these micronutrients, animal foods are either the only, the best, or the most bioavailable source.

For DHA it's almost exclusively found in animals. It's true that there is some in microalgae, but it's not very plausible but that's where we were getting it while we were evolving.

Vitamin D is only available in animal sources. It's true you can get it from sunshine, but again if you take into account the seasonality and the various geological periods we went through, It's — we would need more.

Iron is available in plants, but it's three times more bio-available in animal sources [14]. Similarly with vitamin A, which is 12 to 24 times more bioavailable in animal sources [15], [16]. If you think about the sheer amount of plant food that you would have to eat to try to make up for that, it's just not plausible at all. For zinc it's simply — animal sources are simply the best.

And then I'd also like to note that some plants actually interfere with the absorption of those minerals, so it might not just be not a benefit to try to get them from plants but it could actually be a detriment.

[ I refer the interested reader to the blog of Dr. Georgia Ede, and in particular, her post on vegetables ]

Co-adaptation: shrinking intestines



A second co-aptation is shrinking intestines. In 1995 Aiello and Wheeler came up with a hypothesis to try to explain how it could be that these brains that we're growing which requires so much energy could have gotten that energy without giving up something else, and they noticed that we did give up something else. We gave up a drastic amount of the size of our intestines. Intestines are also really energy-intensive, so that smaller size freed up energy for the brain But there's also a feedback loop, because having less intestines reduced our ability to consume fibre. A lot of other primates get a lot of their energy by consuming fibre and putting them through the factory of bacteria that turns that fibre into fat. We no longer have much of that ability at all and so that also increased our need to get our fat directly from an animal based diet.

[ See the post, Meat is best for growing brains for more detail about the the Expensive Tissue Hypothesis, and shrinking intestines. ]

Brain requirements: structural components



Going back to brain requirements, I wanted to re-emphasize the structural components I'd said that brains are mostly fat and cholesterol. By dry weight it's about 60% lipids [17], about 40% of that which are cholesterol [18], but there's a problem because fatty acids don't cross the blood-brain barrier very easily [19], [ That is, DHA and AA enter the brain easily, but not the long chain fatty acids that white matter, gray matter, and myelin are mainly composed of. ] [20], [21] cholesterol almost not at all [22]. So all of that fat and cholesterol is reconstructed in the brain and it's reconstructed we know, out of ketone bodies [ See next two slides ].

Ketone body fates


[ This slide I inadvertently omitted! It shows the biochemical pathways of ketone bodies being made in the liver, and what is relevant for this talk, being transformed into fuel, as is familiar to many, but also into fat and cholesterol, which may be new to many in audience. ]

Co-adaptation: reliance on ketogenic metabolism



That brings me to the third co-adaptation, which is using fat for energy and for substrates in the brain with ketone bodies. Ketone bodies are directly usable by the brain for energy, unlike fatty acids. They are used to create most of the fat and all the cholesterol.

[ Correction! Most of the fat and all of the cholesterol is synthesised in the brain, and preferentially by ketone bodies, but some is also made from glucose (which, of course, can be made on demand from protein. ] [23], [24], [25]

and most importantly, they can easily and abundantly cross the blood-brain barrier.

There are other benefits to being in a ketogenic metabolism, for example, it increases the density of mitochondria in brain cells which allows more energy to flow and it also decreases the vulnerability of the growing brain to stress and trauma. You may be aware of the extreme neuroprotective properties of the ketogenic diet. For example, it mitigates drastically the damage that you would incur if you had a traumatic brain injury or stroke, so that's obviously adaptive.

[ See the post The medical-grade diet, for more on neuroprotective properties of ketogenic diets. ]

Co-adaptation: reliance on ketogenic metabolism



The fact that we use ketone bodies for brain energy and material, which we and some other species also do in gestation, explains why newborns are in mild ketosis all the time [26]. Infants use ketones three to four times more efficiently than adults [ Correction! four to five times. (Three to four is in newborn rats.) ] [27], so mild ketonemia for a baby is more like a deeper ketosis for an adult. Even children as old as 12 and probably older can become ketogenic much more quickly and easily than you might expect. We're talking about a matter of hours of fasting to develop the kind of ketosis that would take adults several days [28]. But even human adults become ketogenic more easily than other species and they do it without calorie restriction. This is really significant. I know of no other species that sustains ketosis without either starvation or semi-starvation, and it has implications for animal models of ketogenic diets therapies, because there may be cases where an animal requires caloric restriction for the therapy to be effective, whereas in humans it probably doesn't, and would be a detriment to compliance and to health outcomes.

So I wanted to emphasize that humans have co-opted this trait that was previously an adaptation to cope with periods of starvation, and it still is in other species, but we have co-opted it into a default metabolism at least for the period of childhood to support the brain growth in particular, but also to meet the brain's ongoing energy requirements.

Co-adaptation: increased body fat



Finally, the last co-adaptation I want to talk about is increased body fat, because it goes along with all the others It's striking, again, when you compare humans with other primates, how fat they are. Even adults are fat compared to other primates. Other primates and most terrestrial animals actually have less than 5% body fat, and humans have easily somewhere between 15 and 20%, even very lean ones. Human babies take that to the extreme. They start out at about 15%. That's doubled in a couple of months and it continues to increase over the first year.

Baby fat is different in character from the kind of fat you'd see in obese adults. It's subcutaneous, not visceral [29], and it's very low in polyunsaturated fatty acids even if their mother is eating a lot of polyunsaturated fatty acids, whereas obese adults tend to have a kind of roughly corresponding level and quality of fatty acids to what they're eating. So there's obviously a lot of filtering going on. And what polyunsaturated fatty acids are there are almost all DHA and arachidonic acid, which is another important brain fat, so it seems that this extreme body fat in babies is there to provide a continuous supply of fat that can be used by the brain both for energy and for materials via the ketogenic metabolism that we are relying on [30].

Summary of Evolutionary Evidence for Meat


[ This is the other slide I missed.]


I seem to be missing a slide.

I just wanted to quickly summarize what what I've said about evolution of the brain. The first is that we needed to evolve — we needed to eat meat to allow us to evolve the brains that we did. That's for energy and for micronutrients. And I also wanted to emphasize the ketogenic metabolism part, because not only is it a natural normal default state for children but it shows that it's not detrimental, it's actually a benefit. It's actually critical. It's actually part of the mechanism of how we build our brains.

And so I'm bringing that up because someone who's thinking about weaning their baby onto animal-based foods might worry: Wouldn't this make them ketogenic and could that be a problem? And I just want to emphasize that not only is it not a problem, it's the way it's supposed to be and you could hardly stop if you wanted to because even when they sleep they're going to go into ketosis.

Weaning onto meat: clinical trials



OK, so onto clinical trials. I know of two clinical trials that compared eating — weaning an infant onto the fortified cereals that we mostly recommend now, versus weaning them onto exclusively meat. The first one compared or took some measurements comparing them and the meat weaned children had a higher zinc status, which we know is very important. They had adequate iron without the benefit of supplementation that the cereal arm had. They had increased head growth which in children is a good index of brain growth, and it's also correlated with higher intelligence and that's not even taking into account the size of your head at birth so it's not just the size of their head, it's the amount of growth that happened between birth and the later time that's correlated with the higher intelligence. And the second study just showed better general growth without increased adiposity That was what the researchers were worried about was that if you wean babies onto meat they would get fat in a way that would increase the risk for modern diseases and that of course didn't happen.

Slide with refs



And I just have those references there for your reference. This kind of study is what I think has led to certain agencies like the Canadian government and the La Leche League to include meat as a recommended first food.

How? It's easy.



Finally I'm going to talk a little bit about how to do that just based on my experience from doing that with my third child. I was very influenced by Baby-Led Weaning. The core understanding from them is that you don't — you can basically give a baby the same food that an adult eats. The risk of choking has been greatly exaggerated. You don't need to buy into this whole, you know, factory-made baby food stuff. You can give them what you eat for the most part. So what I have done, for example:

I was in the habit of making bone broths that had some meat in the broth and I started by giving him broth on a spoon and increasingly over time added some fragments of meat.

I also gave him bones to teethe on from my steaks and chops, and again I increasingly left meat and fat on it, which he enjoyed a lot.

I fed him a lot of egg yolks and beef and chicken liver, which have a nice soft, silky texture. They're extremely nutrient dense and to this day — this child is almost seven and liver is one of his favourite foods which pleases me to no end.

I'm really grateful to Aaron for being the first to bring up the word pre-masticate in this conference yesterday, so I didn't have to be, and I also know from being in the audience that several people besides me did prechew their food for their babies and it's certainly plausible — I would expect that a lot of people in the past did that and I did that.

I also often made plain unseasoned beef jerky which is really good for teething — sort of reminds me of a dog with rawhide he would gum down on it and pull and then he'd suck on it for a long time and it would basically just disintegrate. Also still one of his favorite foods.

(Photo slide)



And I'll just leave you with a couple of photos of that baby who is almost 7. On the left here we have him at six months with a lamb bone that he was teething on. At the bottom: when he was two I discovered that he had liberated a stick of butter from the fridge, because that's so delicious, and by two-and-a-half he was scrambling his own eggs.

This child basically had almost no plant matter in his diet for the first two years of his life and even now his diet is primarily animal-based.

Please give me your questions. Thank you.


I've included the names of the questioners that I knew. If you are one I left out, introduce yourself!

Again, my clarifications or further comments in brackets.

Question 1 (Christopher Kelly)

C: I fully(?) subscribe to your ideas presented here and I have a very healthy two and a half year old daughter that's eaten much the same way. But I thinks there's an important point missing from your talk that is: the ketones come from medium chain triglycerides, that come from mom's milk from eating carbohydrates. So the carbohydrates are synthesised in the breast tissue that make MCTs. Those MCTs are put in the breast milk, and that's a really important ketogenic substrate, so I think that mom should be in ketosis, You see what I'm saying? The ketones should be synthesised by the baby.

A: I understand what you're saying, yes. So I just want to give a couple of counter-examples. I didn't eat any carbohydrate while I was making breast milk, and although there are medium chain triglycerides in the breast milk, that's certainly not the only reason that babies are in ketosis. Even the babies postweaning that i mentioned earlier get into ketosis very rapidly, because it's just the natural state. You can make it — that's why what I'm positing here, and I'm not — it's not my idea — but what I'm saying here is that the baby fat that is there is being turned into ketones just from the fat that's stored on the body, just the same way that I make them

C: Right

A: And I forgot to mention that, I talked about how fat babies are and how fat adults are compared to other primates, and I think it's quite significant. It would be unusual to see an animal that's that fat if you thought that we weren't naturally ketogenic animals.

C: Yeah and I've actually measured ketones, blood ketones, in my daughter when she was still an infant, breastfed only, and it was 1.6 mmol. But I can actually send you the studies that show that the the MCTs in milk, they go down and there's studies where they've looked at giving MCTS to mom and they don't go anywhere. Mom metabolizes them all. None of them appear in the breast milk, so I think like the carbohydrates for mom, It's not my opinion, I can send you the studies that show that that might be important.

A: I'd like to see that. I guess what I'm trying to say is that the ketones that are in the baby's blood don't only come for a medium chain triglycerides...

C: Right, right, I understand that. Okay, yeah. I work with a doctor, he's just finishing his PhD in neonatal neuroprotection so he's done quite a lot of research in this area so I'll send you some studies.

A: That's fantastic. I would love that.

C: Okay, thank you.

Question 2


Q: Hey, that was great talk. Thank you. Can you say something about the timeframe and you're, you know after three children and all of your research and interest in this, your thoughts on the timeframe for beginning the weaning process and then also how large that window of transition looks

A: Sure. There's a lot I don't know but I know that the recommendation currently is to start weaning at around four to six months and I think that the reason for that is because the amount of breast milk that children get, the caloric input just can't provide much more than what they need by the time they're that large and so I would say to start giving your baby food as soon as they start to express interest in it. Just, you know, let them be the ones who say "I'm ready to start eating. Give me that." And then how long it goes: Humans tend to wean a lot younger than other primates and I don't know to what degree that's enculturated and to what degree that's natural. With my experience, my first child, I, he stopped breastfeeding at about two years and then each one after that was earlier and earlier with the last one, he stopped at nine months. So, I'm sorry I don't know more about that.

Q: No, no, it's okay. I just kind of wanted to see what your thoughts are. I suppose there's some, aside from nutritional implications of how soon or early or late you you move away from breastfeeding I'm sure there's other implications as well but it's just it's hard to understand. I just have a newborn, so I was just interested.

A: Congratulations!

Q: Yeah. Thank you so much!

Question 3 (Georgia Ede)


G: Amber, thank you for an exceptionally good talk. I just had a curiosity question as a psychiatrist. You having raised three children on this unique diet, which I wish were more common, [ Clarification: Unfortunately only my third child was weaning onto meat, though our household was always generally a low carb one. ] can you comment at all about how your children fared emotionally and physically compared to their peers? As a mother I would be very curious to hear.

A: Well there's so much individuality I don't want to necessarily claim too much. I know that my youngest child does have a very even temperament, especially compared to one of his brothers, but then on the other hand his oldest brother has perhaps the most even temperament of all, so don't I don't know what to conclude about that. One interesting thing that has been commented on to me many, many times is that my youngest child was never — he never missed a single day of daycare throughout — when he started at two and, so the entire three-year period, many of his peers, all of his peers missed significant time to many illnesses and he missed not a single day, so I like to attribute that to his diet.

G: Thank you very much. It was fascinating.

A: Thank you.

Question 4 (Ben Sima)


B: Has it been difficult to maintain his diet of high-fat from a social perspective, for example, they go over to someone else's house and they have candy or something with other parents?

A: It is a challenge and the older they get the more of a challenge it is. My other children also at the time that I was weaning him, they were also transitioning to a more meat-based diet and yes it's — I mean for example there, the number of special occasions that you have when you're at school seem to be almost as numerous as the number of days Like, it's always somebody's birthday or some occasion and that's always being celebrated with some kind of gluteny, sugary snack and yeah, it's a struggle.

B: So do you find that he has a sweet tooth or does he kind of shun that

A: He loves sweet things when he gets his hands on them, but he doesn't seem to be obsessed with them.

Question 5


Q: I just wanted to offer the cross cultural perspective that the worldwide age of breastfeeding cessation is about four to five years. [ But see footnote 3 below, which argues that the natural age is about 2.5 and for important, persuasive reasons. ] It's only in the United States that it's young, around a year, but if you look cross-culturally it is actually four years in most cultures.

A: Thank you for that. So that's for the very end of breastfeeding?

Q: Yeah. So that's kind of our biological norm. It's more of a cultural thing here. The other thing that's interesting is around four to six months — infants get a big bolus of iron from the placenta especially if we allow for delayed cord clamping — and then around four to six months that initial iron starts to go down which is another reason why, like you're saying, meats are such a good first food, but that's why that four to six months seems to be a good time to start foods is because that — not that breast milk is lacking in iron and zinc, but that that's not where they're supposed to get it from. You get for placentally and then it starts to go down around four to six months which is why, traditionally the idea of "ok let's put iron in rice cereal" which we know — not a good idea but yeah that's another reason why that four to six-month window seems to be a good time for getting those iron and zinc rich foods in.

Question 6 (Nick Mailer)


Q6: Thanks for the talk, it was very good. Something that hasn't been discussed so much in this community is that weaning and continued breastfeeding is not merely about nutrition but it's also about keeping the bond between the mother and the child, and that's something that's often overlooked. I know that there are people who I know who have generally weaned but, you know, when the child is a bit ill or is feeling a little bit insecure the child will revert for a little while to getting a little bit of breast milk or maybe once at night just to say goodnight. It becomes part of a ritual and part of a bonding process rather than as an essential continuing of nutrition, which is why as long as you're comfortable with it there's no harm in weaning in that extent, finally later, and that sometimes people feel the pressure — okay it's four to six months I better stop by six months or something will happen — and people do feel that pressure which is why I think in the US and the UK people kind of feel that it's a race to the final cessation of weaning and it doesn't have to be as far as I've heard.

A: Right. Excellent point. Thank you.

Question 7


Hi. Thanks for the talk. So I have three children also. My youngest is 15 months. We thought a very similar, you know baby led weaning process, as your youngest. My question is, so my oldest is 11 too — quite a gap in between them, and you mentioned that vitamin D is one of the critical elements for brain development and prior to my son being born I had never seen like my pediatrician recommending vitamin D supplementation. So i guess my question is what are your thoughts on supplementing, like, drops as a newborn, and also what are some of the better animal sources other than I think fatty fish to get vitamin D from.

A: Yes, liver fatty fish... I'm surprised that you didn't, weren't recommended vitamin D drops because I remember that from even 15 years ago when my first son was born.

Q: Yeah I don't remember if it's possible. Five years between each of them. So, I think that's weird you know.

A: Right.

Q: Did you do those?

A: I did. I did do those with the first two children. Actually I did it with all of them, come to think of it. Yeah.

Q: Thanks.

A: I figured there's — the amount you would have to get to overdose is high enough that it wasn't going to hurt.

Q: Yeah. We did it too. I just wasn't sure. I hadn't heard it before him, and you mentioned it, so thanks. Alright.

A: Thank you.

Question 8


Q: Hi. I missed the first part your talk which I'm bummed about, but I have a four-year-old who regularly steals butter out of the fridge, and her first foods were I think egg yolk, and I don't think I did liver right away because I wasn't doing that much liver but now she loves liver too. It's like her favorite food.

A: Isn't it good!

Q: Yeah, I mean I don't particularly like it, but I eat it. But she like — she loves it.

I just wanted to add, too, maybe this will be covered in the next talk, about breastmilk and the microbiome, but one of the things that I found interesting about breastfeeding and the importance of it for the longer term is that it actually, the way that children remove milk from the breast actually helps to form the jaw and the palate, and so we see a lot today where women have to go back to work, you know six weeks, 12 weeks after giving birth and so they're pumping a lot and because we're getting bottles and that's really changing the way that our mouths are structured, I mean as are our nutrients in the womb and the palate formation.

I mean, anyone familiar with Weston Price's work knows that, right, but I just think it's an interesting piece, too, and I don't think that there's this — once kids start food they have to stop breast milk. In fact those things go together quite well for a long time because of the emotional factors and because of the palate formation and the muscle strength and the jaw formation.

A: Right.

Q: So, that I think is an interesting interesting piece, too, and yeah I've seen the same sort of statistics that hunter-gatherers usually breastfed three to four years, but they actually had a lower body fat, and so that would suppress ovulation for longer, which is why their children were spaced 4-5 years apart.

And there was no dairy. People weren't eating dairy, so only dairy that was available was breast milk and the way that that dairy produces certain vitamins...

A: Lactose in particular is broken down into glucose and galactose and galactose is used to build some the brain material as well.

Q: There's a question, so I have anoher question I'll ask you later.

Question 9 (Kevin Boyd)


Q: Okay that was interesting. Who are you? That's, it's interesting that you'd, she's — that's my whole talk this afternoon. Please come.

Nutrition is concerned with nutrients, but not mechanical aspects of food processing and what she brought up was what I was gonna talk about a little bit, but how did you learn about baby led weaning, because, that is, for people who might not know could you explain a little bit about what it is and how you learned about it and how you are executing it with your own children?

A: Well, I'm not sure where I first heard of it, but the thing that I said that was the core important idea from it is what I've taken mostly from it, and that's that babies don't necessarily need you too mush everything up you can, you can give them a chicken drumstick and they'll deal with it.

Q: Yeah. I'm going to really elaborate and so many wonderful points you made today, at one-thirty today.

A: Ok. Well, I won't steal your thunder, then!

Q: It was a great talk.

A: Thank you.

Question 10


Q: Hi, I'm the token pre-mastication question. So you know, it goes: You know, you have your first baby and you sterilize everything before it touches her mouth and by the third baby you're picking up a pacifier and you're popping it in your own mouth before you pop it in theirs, and there was some concern about that in terms of, I guess, oral hygiene and what I had heard was, you know, it's not such a wonderful thing to introduce your mouth germs to your baby, but if your pre-masticating their food perhaps you disagree with that.

A: Yes. Yes. I suppose if you had something unhealthy going on your mouth, that would be a problem, but I — I don't really think that there's anything unhygienic about the mouth, if you're healthy.

Q: OK.


OK, well, thank you.


I've never given a talk to an audience of this size and calibre before. I particularly want to thank Sean Baker, Zooko Wilcox, and Jeff Pedelty for their support and encouragement in making it happen. I'm grateful also to the patient organisers of AHS for welcoming me and helping me through the process, particularly Katherine Morrison, Grace Liu, and Ben Sima.


[1]Using EQ (encephalisation quotient), that is: a measure of relative brain size for mammals that takes into account some physical characteristics that affect the brain-body ratio.

Evidence type: experimental

Martin, Robert D.
Fifty-second James Arthur lecture on the evolution of the human brain 1982

Evidence type: review of data collection

Kennedy GE1.
J Hum Evol. 2005 Feb;48(2):123-45. Epub 2005 Jan 18.

"Although humans have a longer period of infant dependency than other hominoids, human infants, in natural fertility societies, are weaned far earlier than any of the great apes: chimps and orangutans wean, on average, at about 5 and 7.7 years, respectively, while humans wean, on average, at about 2.5 years. Assuming that living great apes demonstrate the ancestral weaning pattern, modern humans display a derived pattern that requires explanation, particularly since earlier weaning may result in significant hazards for a child. Clearly, if selection had favored the survival of the child, humans would wean later like other hominoids; selection, then, favored some trait other than the child’s survival. It is argued here that our unique pattern of prolonged, early brain growth — the neurological basis for human intellectual ability — cannot be sustained much beyond one year by a human mother’s milk alone, and thus early weaning, when accompanied by supplementation with more nutritious adult foods, is vital to the ontogeny of our larger brain, despite the associated dangers."


[On the data set:]

"Weaning is a process, not an event that can be placed at a specific point in time; therefore, it is not subject, in any meaningful way, to precise mathematical or statistical analyses or even to exact determination. Sellen’s (2001) recent paper has, perhaps, done as much as possible to overcome the inherent problems of determining human weaning time. An ‘‘average’’ age of weaning can only suggest the age at which most young in a particular group cease nursing; moreover, in humans, as the Amele demonstrate, it is not uncommon for a mother to continue to nurse an older youngster even though she has an infant as well. Data reported in Table 1 were taken from field studies, individual ethnographic reports, and from the Human Relations Area Files (HRAF: category 862, on-line edition); data points were included only when a definite age or clear range was expressed. All were pre-industrial, ‘‘natural fertility’’ populations practicing a range of subsistence economies from agriculture to foraging, and many were mixed economies."


"Although a mean weaning age can be calculated from the human data in Table 1 (30.1 months; n = 46), it seems more accurate to conclude that the ‘‘natural’’ weaning age for humans is between 2-3 years and generally occurs about midway in that range. The minimum reported weaning age was one year (Fiji, Kogicol) and the maximum was about 4 years (several native American groups); several entries, however, reported that individual children may nurse as long as 6 years. Goodall (1986) also reported that a few Gombe chimps also nursed far longer than the population average. Sellen (2001), using a slightly larger sample (n = 113) also taken from the HRAF (microfiche edition), reported a very similar mean (29 months +/- 10 months), and a very similar peak weaning period between 2 and 3 years."


"As noted below, stable nitrogen isotope analysis on bone tissue from several prehistoric societies suggests a somewhat wider range of ‘‘natural’’ weaning ages. For example, since nursing infants occupy a different (higher) trophic level than do their mothers, the isotopic composition of nursing infants’ bones and teeth should, in theory, differ from that of the adults in their group. Weaning time, therefore, should correspond to the point at which infant and adult tissues reach a similar isotopic composition ( Herring et al., 1998 ). Following Fogel et al. (1989), several authors have found an elevated level of δ15 N in infant osteological remains (relative to adults of the same group), which, they argued, constitutes a ‘‘nursing signal’’ ( Katzen- berg, 1992; Katzenberg et al., 1993, 1996; Schurr, 1994; Tuross and Fogel, 1994; White and Schwarcz, 1994 ). For example, at the Sully site in North Dakota and at the Angel site in the Ohio Valley, δ15 N reached adult levels at about 24 months (Tuross and Fogel, 1994; Schurr, 1997), suggesting rather early weaning. In Nubia, on the other hand, there was a gradual decline up to about age 6, indicating a slow introduction of adult foods ( White and Schwarcz, 1994 ). Others have used stable carbon and oxygen isotopes in dental enamel to track dietary changes in young children. Stable carbon (δ13 C), for example, may be used to detect the introduction of solid foods, and hence the beginning of the weaning period, while oxygen isotopes (δ18 O) may track the decreasing consumption of human milk (Wright and Schwarcz, 1998). Using this approach, it was found that, among the Preclassic and Postclassic Maya, solid foods were first introduced probably late in the first year, but that the weaning process was not concluded until 5 or 6 years ( Wright and Schwarcz, 1998)."

"[E]xtensive field data, collected in modern traditional societies, ancient textual references, and biochemical evidence from prehistoric societies, all suggest that in humans, the ‘‘natural’’ weaning age is generally between 2 and 3 years, although it may continue longer in some groups."


Evidence type experiment

John Dobbing and Jean Sands
Arch Dis Child. 1973 Oct; 48(10): 757–767.

"One hundred and thirty-nine complete human brains ranging in age from 10 weeks' gestation to 7 postnatal years, together with 9 adult brains, have been analysed in order to describe the human brain growth spurt quantitatively... The growth spurt period is much more postnatal than has formerly been supposed."


"The postnatal cut-off point of the sigmoid curve of weight accumulation seems to be between 18 postnatal months and 2 years for whole brain."


Evidence Type: review of experiments

Martin, Robert D.
Fifty-second James Arthur lecture on the evolution of the human brain 1982

[Emphasis ours]

"The foregoing comparisons have demonstrated that Homo sapiens shares a number of general features of brain size and its development with the other primates, most notably in producing precocial off-spring and in the shift to a distinctive relationship between brain size and body size during foetal development (fig. 8). But human beings also exhibit a number of special features which set them apart from other primates, or at least from their closest relatives the great apes. These may be listed as follows:

  1. The remarkably large size of the adult brain relative to body size.
  2. The rapid development of both brain and body during foetal development, resulting in a distinctively large brain and body size at birth, compared to great apes.
  3. The greater degree of postnatal growth of the brain, accomplished by continuation of foetal brain : body relationships for at least one year after birth and associated with the "secondary altricial condition."

[This shows pattern of brain to body weight ratio, not just brain weight]


Evidence type: experiment

Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights.
Dekaban AS.

"More than 20,000 autopsy reports from several general hospitals were surveyed for the purpose of selecting brains without a pathological lesion that had been weighed in the fresh condition. From this number, 2,773 males and 1,963 females were chosen for whom body weight, body height, and cause of death had been recorded. The data were segregated into 23 age groups ranging from birth to 86+ years and subjected to statistical evaluation. Overall, the brain weights in males were greater than in females by 9.8%. The largest increases in brain weights in both sexes occurred during the first 3 years of life, when the value quadruples over that at birth, while during the subsequent 15 years the brain weight barely quintuples over that at birth."


"[T]he largest increases in brain weight occur during the first year of life, when the weight more than doubles that at birth (see Tables 2, 3; Figs 2A, 5). Further increases in brain weight also occur quite rapidly, although the increments from the preceding age groups are smaller. At about 3 years of age in males and between 3 and 4 years in females, the brain weight reaches four times the value at birth. Further growth of the brain is considerably slower, as it takes the brain 15 years (between ages 4 and 18) to nearly quintuple its birth weight and reach its mean highest value in young adults."


Evidence Type: review of human and non-human animal experiments

CIBA Foundation Symposium
John Wiley & Sons, Sep 16, 2009 - Science - 192 pages

"The human growth spurt appears to extend throughout the last trimester of pregnancy and well into the 2nd year of postnatal life, and by analogy similar harm would be expected in the brains of humans growth-retarded during this time [as rats in reported nutrient deficiency experiment]

"There is no question but that the transient period of brain growth, known as the brain growth spurt, is more vulnerable to growth restriction than the periods both before and afterwards. Vulnerability in this sense means that quite mild restriction leads in experimental animals to permanent, irrecoverable reduction in the trajectory of bodily growth and to easily detectable distortions and deficits in the adult brain... In the present case the 'damage' consists of permanent but non-uniform reduction in the extent of brain growth. There is accumulating evidence that it has functional importance. An important feature of this type of vulnerability is that it is highly dependent on the timing of the insult, although not as finely so as the earlier teratology."


Evidence type: review of experiments

Siegel GJ, Agranoff BW, Albers RW, et al., editors.
Philadelphia: Lippincott-Raven; 1999.

"The brain consumes about one-fifth of total body oxygen utilization

"The brain is metabolically one of the most active of all organs in the body. This consumption of O2 provides the energy required for its intense physicochemical activity. The most reliable data on cerebral metabolic rate have been obtained in humans. Cerebral O2 consumption in normal, conscious, young men is approximately 3.5 ml/100 g brain/min (Table 31-1); the rate is similar in young women. The rate of O2 consumption by an entire brain of average weight (1,400 g) is then about 49 ml O2/min. The magnitude of this rate can be appreciated more fully when it is compared with the metabolic rate of the whole body. An average man weighs 70 kg and consumes about 250 ml O2/min in the basal state. Therefore, the brain, which represents only about 2% of total body weight, accounts for 20% of the resting total body O2 consumption. In children, the brain takes up an even larger fraction, as much as 50% in the middle of the first decade of life [15]."


Evidence type: review

Stephen Cunnane (Editor), Kathlyn Stewart (Editor)
ISBN: 978-0-470-45268-4
June 2010, Wiley-Blackwell

Evidence type: review

Delange F.
Proc Nutr Soc. 2000 Feb;59(1):75-9.

"I is required for the synthesis of thyroid hormones. These hormones, in turn, are required for brain development, which occurs during fetal and early postnatal life. The present paper reviews the impact of I deficiency (1) on thyroid function during pregnancy and in the neonate, and (2) on the intellectual development of infants and children. All extents of I deficiency (based on I intake (microgram/d); mild 50-99, moderate 20-49, severe > 20) affect the thyroid function of the mother and neonate, and the mental development of the child. The damage increases with the extent of the deficiency, with overt endemic cretinism as the severest consequence. This syndrome combines irreversible mental retardation, neurological damage and thyroid failure. Maternal hypothyroxinaemia during early pregnancy is a key factor in the development of the neurological damage in the cretin. Se deficiency superimposed on I deficiency partly prevents the neurological damage, but precipitates severe hypothyroidism in cretins. I deficiency results in a global loss of 10-15 intellectual quotient points at a population level, and constitutes the world's greatest single cause of preventable brain damage and mental retardation."


Evidence type: review

Micronutrient Deficiencies in the First Months of Life
edited by F. Delange, Keith P. West

"Iron plays a critical role in brain development, including its postnatal stages. Youdim et al., Youdim, Rouault and Beard reviewed the biological mechanisms whereby iron deficiency could possibly affect brain structure and functioning. The accumulation and distribution of iron in various regions of the brain depend on the stage of its development. This might indicate that brain regions vary in their vulnerability to iron deprivation, and suggests that the effect of iron deficiency on brain iron content could depend on the timing of the exposure. Animal studies indicate that low dietary intake of iron in the neonatal or preweaning period (before postnatal days 14-21 [ this must be rodents? ] may reduce whole-brain iron content that is not reversible by dietary repletion and produce irreversible effects. In rats, such effects occur before completion of brain organization and myelination and establishment of dopaminergic tracts. By contrast, dietary depletion in the postweaning period can also reduce brain iron content but this might be reversible upon dietary repletion. This illustrates that the timing of exposure to iron deficiency must be carefully considered when examining possible effects of iron deficiency on mental performance.

"Iron is not only required for brain growth and differentiation of neuronal cells, but also for protein synthesis, hormone production and other aspects of cellular enrgy metabolism and functioning. When sufficiently severe to reduce hemoglobin concentrations or cause anemia, iron deficiency might adversely affect oxygen delivery, thereby leading to reduced functioning of the central nervous system. Such deletrious effects of iron deficiency might be partially or completely reverese by iron repletion.

"Effects of iron deficiency might also be determined by other mechanisms. For example, it has been hypothesized that anemic children experience delayed acquisition of skills because they explore and interact less with their environment than nonanemic children, and they induce less stimulating behavior in their caretakers. Additionally, several studies have indicated that anemic children tend to be more fearful, withdrawn and tense, have reduced ability to focus their attention [25, 26], and are therefore less exposed to environmental stimuli that may promote mental and motor development."


Evidence type: review (mostly non-human animal experiments)

Bhatnagar S, Taneja S.
Br J Nutr. 2001 May;85 Suppl 2:S139-45.


"Cognition is a field of thought processes by which an individual processes information through skills of perception, thinking, memory, learning and attention. Zinc deficiency may affect cognitive development by alterations in attention, activity, neuropsychological behavior and motor development. The exact mechanisms are not clear but it appears that zinc is essential for neurogenesis, neuronal migration, synaptogenesis and its deficiency could interfere with neurotransmission and subsequent neuropsychological behavior. Studies in animals show that zinc deficiency during the time of rapid brain growth, or during the juvenile and adolescent period affects cognitive development by decreasing activity, increasing emotional behavior, impairing memory and the capacity to learn. Evidence from human studies is limited. Low maternal intakes of zinc during pregnancy and lactation were found to be associated with less focused attention in neonates and decreased motor functions at 6 months of age. Zinc supplementation resulted in better motor development and more playfulness in low birth weight infants and increased vigorous and functional activity in infants and toddlers. In older school going children the data is controversial but there is some evidence of improved neuropsychological functions with zinc supplementation. Additional research is required to determine the exact biological mechanisms, the critical periods, the threshold of severity and the long-term effects of zinc deprivation on cognitive development."


Evidence type: review

McNamara RK, Carlson SE.
Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):329-49. Epub 2006 Sep 1.

"There is now good evidence suggesting that DHA is accrued in rodent, primate, and human brain during active periods of perinatal cortical maturation, and that DHA plays an important role in neuronal differentiation, synaptogenesis, and synaptic function. In animal studies, prenatal deficits in brain DHA accrual that are not corrected via postnatal dietary fortification are associated with enduring deficits in neuronal arborization, multiple indices of synaptic pathology, deficits in mesocorticolimbic dopamine neurotransmission, deficits in hippocampal serotonin and acetylcholine neurotransmission, neurocognitive deficits on hippocampus and frontal cortex-dependent learning tasks, and elevated behavioral indices of anxiety, aggression, and depression. Human and primate infants born preterm or fed diets without DHA postnatally exhibit lower cortical DHA accrual compared to infants born at term or fed human milk postnatally. Children/adolescents born preterm exhibit deficits in cortical gray matter expansion, neurocognitive deficits, and are at increased risk for attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. Individuals diagnosed with ADHD or schizophrenia exhibit peripheral indices of lower DHA status and exhibit deficits in cortical gray matter expansion and deficits in cortical dopamine neurotransmission. Based on this body of evidence, it is hypothesized that perinatal deficits in brain DHA accrual represents a modifiable neurodevelopmental risk factor for the emergence of neurocognitive deficits and subsequent psychopathology. Evaluation of this hypothesis is currently feasible."


Evidence type: review

J D Cook
Am J Clin Nutr February 1990 vol. 51 no. 2 301-308

[ Emphasis mine ]

"Dietary iron supply encompasses both the total amount of ingested iron and its bioavailability. Before 1950, nutritionists emphasized only total iron intake as a measure of dietary adequacy. Wider application of isotopic techniques during the l9SOs and l960s led to the realization that the bioavailability of ingested iron may be more important than total intake. There are two separate pathways of iron entry into the mucosal cell. The largest fraction of dietary iron is in the form of inorganic or nonheme iron, the absorption of which is determined largely by the nature of the meal. Nonheme-iron absorption occurs mainly from the duodenum because of the greater solubility of luminal iron in the proximal, more acid, region of the small intestine. Isotopic studies with extrinsic labeling demonstrated that all dietary forms of nonheme iron ingested in the same meal form a common pool within the intestinal lumen. Absorption from this pool is determined not by the type of the iron ingested but by enhancers, which promote absorption by maintaining iron in a reduced soluble form, and inhibitors, which bind iron or make iron insoluble and prevent its uptake by the brush border (29-32). The bioavailability of nonheme iron is enhanced by ascorbic acid and various tissue foods, such as meat, fish, and poultry, but not dairy products (33). A large number of dietary constituents impair iron absorption and these factors have been the major focus of absorption studies during the past decade. The most important inhibitors include tea, coffee, bran, calcium phosphate, egg yolk, polyphenols, and certain forms of dietary fiber. The extremes in bioavailability of nonheme iron as measured from isotopically labeled single meals served in a laboratory setting is nearly 15-fold (Fig 2). If tea is eliminated, absorption will increase about threefold. If meat is added, absorption will again increase 2-3 times. Maximal enhancement absorption occurs when a large quantity of ascorbic acid (eg, 2g) is taken with the meal.

"The second dietary iron fraction is heme, which is absorbed into the intestinal cell as an intact porphyrin complex. Specific receptors for heme iron have been identified in laboratory animals (34) but not in humans. After heme iron enters the cell it is rapidly degraded by heme oxygenase (35), and the released iron then enters the common intracellular iron pool. Subse- quent mucosal handling ofthis iron appears to be identical to that of inorganic iron. Because heme iron remains protected within the porphyrin complex before its uptake by the mucosa, it does not interact with dietary ligands and is therefore unaffected by the nature of the meal. Percentage absorption of heme iron is 5-10-fold higher than from nonheme iron. Although heme represents only 10-15% of dietary iron in meat-eating populations, it may account for nearly one-third of absorbed iron (36). Because absorption of heme iron is constant and independent of meal composition, the contribution of heme iron can be readily calculated from dietary records. This is in distinction to marked differences in the availability of non-heme iron."


Evidence type: review

Clive E. West*,†,2, Ans Eilander*, and Machteld van Lieshout*
J. Nutr. September 1, 2002 vol. 132 no. 9 2920S-2926S

"The bioefficacy of β-carotene in plant foods is much less than was previously thought. Intervention studies enrolled schoolchildren in Indonesia (10) and breast-feeding women in Vietnam (11) (Table 1). In each study there were four dietary groups: low-retinol, low-carotenoid diet (negative control); dark-green leafy vegetables (as well as carrots in the Indonesian study); yellow and orange fruits; and a retinol-containing diet (positive control). For dark-green leafy vegetables, the bioefficacy was 1:26 and 1:28; while for fruit, the bioefficacy was 1:12. This suggests that, with a mixture of vegetables and fruits in a ratio of 4:1, which is typical for both developing and developed countries, the bioefficacy of β-carotene from a mixed diet is 1:21. Chinese children aged 5–6.5 y yielded similar results for green and yellow vegetables (1:27) (14). Van Lieshout et al. (15), using the plateau isotopic enrichment method, also found relatively poor bioefficacy of β-carotene in dark-green leafy vegetables. β-Carotene in pumpkin was 1.7 times as potent as that in spinach (Table 1)."

[16]See also the extensive review in the Vitamin A chapter of Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Panel on Micronutrients, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, which is accessible and would take a lot of space to include here.

Evidence type: review

Crawford MA.
Am J Clin Nutr. 1993 May;57(5 Suppl):703S-709S; discussion 709S-710S.

"The brain is 60% structural lipid, which universally uses arachidonic acid (AA; 20:4n6) and docosahexaenoic acid (DHA; 22:6n-3) for growth, function, and integrity. Both acids are consistent components of human milk. Experimental evidence in animals has demonstrated that the effect of essential fatty acid deficiency during early brain development is deleterious and permanent. The risk of neurodevelopmental disorder is highest in the very-low-birth-weight babies. Babies born of low birth weight or prematurely are most likely to have been born to mothers who were inadequately nourished, and the babies tend to be born with AA and DHA deficits. Because disorders of brain development can be permanent, proper provision should be made to protect the AA and DHA status of both term and preterm infants to ensure optimum conditions for the development of membrane-rich systems such as the brain, nervous, and vascular systems."


Evidence type: experiment

O'Brien JS, Sampson EL.
J Lipid Res. 1965 Oct;6(4):537-44.

Evidence type: review

William M. Pardridge
Chapter in Fuel Homeostasis and the Nervous System, Volume 291 of the series Advances in Experimental Medicine and Biology pp 43-53

[ Emphasis mine ]

"Although free fatty acids are an important carbon source for cellular combustion in tissues such as skeletal muscle, fat, or liver in the postabsorptive state, brain does not significantly combust circulating free fatty acid, even after several weeks of prolonged starvation.(32) This failure to oxidize circulating free fatty acids is not due to a deficiency of the relevant free fatty acid oxidizing enzymes in brain since labeled free fatty acids are readily converted to CO 2 following the intracerebral administration of [14Cj-labeled free fatty acid,(33) and small amounts of circulating free fatty acids are converted to Krebs cycle intermediates (34). Rather, the failure of brain to utilize circulating free fatty acids as an important source of combustible carbon is due, in part, to a slow transport through the BBB. In the absence of plasma proteins, both medium chain and long chain free fatty acids are rapidly transported through the BBB. (35) However, free fatty acids are more than 99% bound by high affinity binding sites on circulating albumin, and only approximately 5% of plasma free fatty acid is unidirectionally extracted by brain on a single pass through the cerebral microcirculation .(36) Moreover, there is a prominent enzymatic barrier to the utilization of the circulating free fatty acids,3 as depicted in Figure 5. There is rapid esterification into membrane-bound triglyceride of circulating free fatty acid at either the endothelial membrane or the brain cell membrane. Thus, in the steady state, an equal amount of free fatty acid taken up by brain and esterified in the endothelial or brain cell membranes is released to blood via hydrolysis of membrane-bound triglyceride via brain microvascular lipoprotein lipase. 3 This enzymatic barrier protecting brain intracellular space from circulating free fatty acids is very well developed and breaks down only under pathologic conditions in brain."

[ As far as I can tell, it has only recently been discovered that there are some mechanisms for transporting fatty acids across the blood brain barrier, but how much and under what circumstances is poorly understood. This statement expresses that candidly: ]

Murphy EJ.
J Neurochem. 2015 Dec;135(5):845-8. doi: 10.1111/jnc.13289. Epub 2015 Sep 17.

"How do fatty acids enter the brain and what role, if any, do membrane and cytosolic fatty acid binding proteins have on facilitating this process? This is a fundamental question that many lipid neurochemists will freely admit they cannot answer in any kind of definitive manner."


Evidence type: experiment

O'Brien JS, Sampson EL.
J Lipid Res. 1965 Oct;6(4):537-44.

[ palimitic = 16:0, stearic = 18:0, oleic = 18:1 ]


Evidence type: non-human animal experiment

Fatty acid transport and utilization for the developing brain.
Edmond J, Higa TA, Korsak RA, Bergner EA, Lee WN.
J Neurochem. 1998 Mar;70(3):1227-34.

[ Emphasis mine ]

"To determine the transport and utilization of dietary saturated, monounsaturated, and n-6 and n-3 polyunsaturated fatty acids for the developing brain and other organs, artificially reared rat pups were fed a rat milk substitute containing the perdeuterated (each 97 atom% deuterium) fatty acids, i.e., palmitic, stearic, oleic, linoleic, and linolenic, from day 7 after birth to day 14 as previously described. Fatty acids in lipid extracts of the liver, lung, kidney, and brain were analyzed by gas chromatography-mass spectrometry to determine their content of each of the deuterated fatty acids. The uptake and metabolism of perdeuterated fatty acid lead to the appearance of three distinct groups of isotopomers: the intact perdeuterated, the newly synthesized (with recycled deuterium), and the natural unlabeled fatty acid. The quantification of these isotopomers permits the estimation of uptake and de novo synthesis of these fatty acids. Intact perdeuterated palmitic, stearic, and oleic acids from the diet were found in liver, lung, and kidney, but not in brain. By contrast, perdeuterated linoleic acid was found in all these organs. Isotopomers of fatty acid from de novo synthesis were observed in palmitic, oleic, and stearic acids in all tissues. The highest enrichment of isotopomers with recycled deuterium was found in the brain. The data indicate that, during the brain growth spurt and the prelude to myelination, the major saturated and monounsaturated fatty acids in brain lipids are exclusively produced locally by de novo biosynthesis. Consequently, the n-6 and n-3 polyunsaturated fatty acids must be transported and delivered to the brain by highly specific mechanisms."


Evidence type: review

Brain Cholesterol: Long Secret Life Behind a Barrier
Ingemar Björkhem, Steve Meaney
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004; 24: 806-815

"Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation.Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation."


Evidence type: review

Morris AA
J Inherit Metab Dis. 2005;28(2):109-21.

"The second function of KBs in the brain is to provide substrates for the synthesis of various molecules. KBs are particularly important for the synthesis of lipids, such as cholesterol in myelin. Studies in 18-day-old rats found that KBs are incorporated into brain cholesterol and fatty acids much more readily than glucose is incorporated (Webber and Edmond 1977). Studies of cultured mouse astrocytes and neurons gave similar results (Lopes-Cardozo et al 1986). The preferential use of KBs for lipid synthesis probably occurs because they can be converted directly to acetoacetyl-CoA in the cytoplasm by acetoacetyl-CoA synthetase (EC, see Figure 1). Cytosolic acetoacetyl-CoA thiolase can then convert acetoacetyl-CoA to acetyl-CoA. Cytosolic acetyl-CoA can be generated from glucose (via the tricarboxylic acid cycle and ATP-citrate lyase, Figure 1) but this is a less direct pathway due to the inability of acetyl-CoA to cross the mitochondrial inner membrane. KBs are incorporated into fatty acids in the brain but they are primarily used for cholesterol synthesis (Koper et al 1981). Acetoacetyl-CoA synthetase expression in human brain parallels that of HMG-CoA reductase (EC, providing further evidence for the importance of this pathway in sterol synthesis (Ohgami et al 2003). Although KBs are the preferred substrates for brain lipogenesis, they appear not to be essential. Thus, rats fed a hypoketogenic diet develop normally (Auestad et al 1990). Development is also normal in most human patients with defects of ketogenesis (Morris et al 1998; van der Knaap et al 1998), though imaging sometimes shows white-matter abnormalities (see Clinical Considerations below)."


Evidence type: review

Yeh YY, Sheehan PM.
Fed Proc. 1985 Apr;44(7):2352-8.

[ Emphasis mine ]

"Persistent mild hyperketonemia is a common finding in neonatal rats and human newborns, but the physiological significance of elevated plasma ketone concentrations remains poorly understood. Recent advances in ketone metabolism clearly indicate that these compounds serve as an indispensable source of energy for extrahepatic tissues, especially the brain and lung of developing rats. Another important function of ketone bodies is to provide acetoacetyl-CoA and acetyl-CoA for synthesis of cholesterol, fatty acids, and complex lipids. During the early postnatal period, acetoacetate (AcAc) and beta-hydroxybutyrate are preferred over glucose as substrates for synthesis of phospholipids and sphingolipids in accord with requirements for brain growth and myelination. Thus, during the first 2 wk of postnatal development, when the accumulation of cholesterol and phospholipids accelerates, the proportion of ketone bodies incorporated into these lipids increases. On the other hand, an increased proportion of ketone bodies is utilized for cerebroside synthesis during the period of active myelination. In the lung, AcAc serves better than glucose as a precursor forbiddingly the synthesis of lung phospholipids. The synthesized lipids, particularly dipalmityl phosphatidylcholine, are incorporated into surfactant, and thus have a potential role in supplying adequate surfactant lipids to maintain lung function during the early days of life. Our studies further demonstrate that ketone bodies and glucose could play complementary roles in the synthesis of lung lipids by providing fatty acid and glycerol moieties of phospholipids, respectively. The preferential selection of AcAc for lipid synthesis in brain, as well as lung, stems in part from the active cytoplasmic pathway for generation of acetyl-CoA and acetoacetyl-CoA from the ketone via the actions of cytoplasmic acetoacetyl-CoA synthetase and thiolase."


Evidence type: non-human animal experiment

Koper JW, Zeinstra EC, Lopes-Cardozo M, van Golde LM.
Biochim Biophys Acta. 1984 Oct 24;796(1):20-6.

"We have compared glucose and acetoacetate as precursors for lipogenesis and cholesterogenesis by oligodendrocytes and astrocytes, using mixed glial cultures enriched in oligodendrocytes. In order to differentiate between metabolic processes in oligodendrocytes and those in astrocytes, the other major cell type present in the mixed culture, we carried out parallel incubations with cultures from which the oligodendrocytes had been removed by treatment with anti-galactocerebroside serum and guinea-pig complement. The following results were obtained: 1. Both oligodendrocytes and astrocytes in culture actively utilize acetoacetate as a precursor for lipogenesis and cholesterogenesis. 2. In both cell types, the incorporation of acetoacetate into fatty acids and cholesterol exceeds that of glucose by a factor of 5-10 when the precursors are present at concentrations of 1 mM and higher. 3. Glucose stimulates acetoacetate incorporation into fatty acids and cholesterol, whereas acetoacetate reduces the entry of glucose into these lipids. This suggests that glucose is necessary for NADPH generation, but that otherwise the two precursors contribute to the same acetyl-CoA pool. 4. Both with acetoacetate and with glucose as precursor, oligodendrocytes are more active in cholesterol synthesis than astrocytes. 5. Using incorporation of 3H2O as an indicator for total lipid synthesis, we estimated that acetoacetate contributes one third of the acetyl groups and glucose one twentieth when saturating concentrations of both substrates are present."


Evidence type: experiment

"A total of 272 venous blood samples was obtained from umbilical cord and from children of varying ages from birth to 8 years. All were analysed for blood glucose and either FFA, glycerol or ketone bodies." [ Fasted overnight ]


Evidence type: experiment

Kraus H, Schlenker S, Schwedesky D.
Hoppe Seylers Z Physiol Chem. 1974 Feb;355(2):164-70.

"Removal of circulating ketone bodies by the brain is greater in newborns than in infants. Both values are higher than those reported in adults [14]. This is demonstrated by the differences in the slopes of the'regression lines. From these data, however, the conclusion cannot be drawn that there is a specific enhancement of ketone body metabolism in the brains of young individuals. The total metabolic rate could be increased in the infant brain due to denser arrangement of blood capillaries, shorter diffusion distances and a higher cerebral blood flow. In order to avoid objections arising from these differences the contribution of ketone bodies to the total oxidative metabolism of the brain was calculated (last row of Table 1). Hence it follows that the brain's capacity to utilize ketone bodies is specifically increased in newborns in comparison with infants. These values in turn are five and four times higher respectively than those reported in adults [14]. This conclusion is also justified by the finding that the contribution of glucose is not significantly altered throughout the different age groups. Corresponding relative values in newborns, infants and adults are 0.26, 0.27, and 0.33. The results of the present paper are confirmed by the report that the estimated cerebral uptake of ketone bodies in a group of older children (aged up to 14 years) was about three to four times higher than values observed in adults [19]. As cited above it was shown in different animals that the capacity to utilize ketone bodies is higher in the infant than in the adult brain [2, 20]. The increased ketone utilization by the animal brain during the neonatal period resulted from higher activities of the enzymes of ketone body utilization. Whether this also applies to the human infant brain remains to be tested.


Evidence type: experiment

P F Bougneres, C Lemmel, P Ferré, and D M Bier
J Clin Invest. 1986 Jan; 77(1): 42–48.

[ Emphasis ours ]

"Using a continuous intravenous infusion of D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3 +/- 1.4 mumol kg-1 min-1 in the neonates, a value not different from that of 20.6 +/- 0.9 mumol kg-1 min-1 measured in the older infants. This rate was accelerated to 32.2 mumol kg-1 min-1 in the diabetic and slowed to 5.0 mumol kg-1 min-1 in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased. Compared with the adult, however, ketone body turnover rates of 12.8-21.9 mumol kg-1 min-1 in newborns fasted for less than 8 h, and rates of 17.9-26.0 mumol kg-1 min-1 in older infants fasted for less than 10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate's basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans."


Evidence type: experiment

Harrington TA, Thomas EL, Modi N, Frost G, Coutts GA, Bell JD.
Lipids. 2002 Jan;37(1):95-100.

"The role of body fat content and distribution in infants is becoming an area of increasing interest, especially as perception of its function appears to be rapidly evolving. Although a number of methods are available to estimate body fat content in adults, many are of limited use in infants, especially in the context of regional distribution and internal depots. In this study we developed and implemented a whole-body magnetic resonance imaging (MRI)-based protocol that allows fast and reproducible measurements of adipose tissue content in newborn infants, with an intra-observer variability of <2.4% and an inter-observed variability of <7%. The percentage total body fat for this cohort of infants ranged from 13.3-22.6% (mean and standard deviation: 16.6 +/- 2.9%), which agrees closely with published data. Subcutaneous fat accounted for just over 89% of the total body fat, whereas internal fat corresponded to almost 11%, most of which was nonabdominal fat. There were no gender differences in total or regional body fat content. These results show that whole-body MRI can be readily applied to the study of adipose tissue content and distribution in newborn infants. Furthermore, its noninvasive nature makes it an ideal method for longitudinal and interventional studies in newborn infants."


Evidence type: review

[ Emphasis ours ]

"The likelihood that the composition of fatty acids delivered to the fetus can affect the quality of fetal development is more compelling. The concentration of DHA in the brain of neonates is dependent on the intake of pre-formed DHA (Farquharson et al., 1993; Jamieson et al., 1999; Makrides et al., 1994) and many workers have reported beneficial effects of LCPUFA intake in early post-natal life in particular (Birch et al., 1992 ; Hoffman et al., 1993; Horwood, Darlow and Mogridge, 2001; Lucas et al., 1992, 1998). In this context, much has been made of the relatively high concentration of DHA in the fetal brain at term and the importance of in utero DHA supply but this is not specifically a fetal/placental issue as the human brain, including that of the pregnant mother, maintains a high concentration of DHA throughout life. Furthermore the total amount of DHA present in the fetal brain at term is not much greater than that in the placenta itself. An issue that is much more clearly specific to the fetus and placenta is the very high concentration of DHA and AA achieved in the fetal adipose tissue and the fact that 16 times more DHA is stored in the adipose tissue than is deposited in the fetal brain during in utero life. Within a few hours of birth there is a dramatic rise in plasma TG and NEFA indicating mobilization of adipose tissue stores ( Van Duyne & Havel, 1959 ) such that the concentration of DHA in the adipose tissue is undetectable after two months of post-natal life on a diet devoid of pre-formed DHA ( Farquharson et al., 1993). Thus the importance of this adipose store of LCPUFA may be to protect processes such as brain and retinal development against a poor dietary supply of LCPUFA during the critical first months of post-natal life. The fact that most of the LCPUFA such as DHA which is accrued by the fetus is actually stored in fetal adipose tissue also implies that there is normally an excess availability in utero for development of the fetal organs and tissues and that it is only in low birth weight babies, where the body fat content may be very low (Sparks et al., 1980), that the supply of LCPUA may become limiting for fetal requirements during in utero life."