The human brain confronts two major challenges during its development: (i) meeting a very high energy requirement, and (ii) reliably accessing an adequate dietary source of specific brain selective nutrients needed for its structure and function. Implicitly, these energetic and nutritional constraints to normal brain development today would also have been constraints on human brain evolution. The energetic
constraint was solved in large measure by the evolution in hominins of a unique and significant layer of body fat on the fetus starting during the third trimester of gestation. By providing fatty acids for ketone production that are needed as brain fuel, this fat layer supports the brain’s high energy needs well into childhood. This fat layer also contains an important reserve of the brain selective omega-3 fatty acid, docosahexaenoic acid (DHA), not available in other primates.
Certain nutrients must be present in the diet to assure optimal mammalian development, maturation and reproduction. These nutrients include a number of amino acids, vitamins, minerals and fatty acids. ‘Brain selective nutrients’ is a term that was coined to signify those nutrients that are needed for optimal brain development and that would therefore have facilitated human brain evolution (Cunnane and Crawford, 2003). Of course, it does not imply that these nutrients exist only in the brain or that they have no role in other organs. Brain selective nutrients can be divided into three groups: (i) brain selective minerals, (ii) brain selective fatty acids, and (iii) brain selective vitamins. There are at least five brain selective minerals: iodine, iron, zinc, copper and selenium. There is probably only one brain selective fatty acid: DHA. The brain selective vitamins are less well studied but there are probably at least two: vitamins A and D. At present, none of the indispensable (essential) amino acids are known to be a brain selective nutrient.
Three features characterise brain selective nutrients (Cunnane,2010):
(i) A minimum amount of each brain selective nutrient is required in the diet on a regular basis to permit normal development of the human brain. If these nutrients are not present in the diet in sufficient amounts, brain development will be suboptimal in proportion to the degree of their dietary deficiency.
(ii) There is a cluster of brain selective nutrients, each with a separate and distinct role in brain development and function. Inadequate intake of any one brain selective nutrient results in specific symptoms regardless of the sufficiency of the others. Severity of the symptoms of deficiency of a brain selective nutrient depends on the body’s ability to conserve it in the face of its deficient intake. The best known brain selective nutrients are DHA, iodine and iron, so, for the moment, they form the nucleus of this nutrient cluster. Iodine and iron both control different aspect of energy metabolism (see Iodine and iron: The two main brain selective nutrients, below). Docosahexaenoic acid is important in neuron-to-neuron communication (see Docosahexaenoic acid: The brain selective omega-3 fatty acid, below) and its synthesis is iron-dependent.
(iii) A generous supply of brain selective nutrients supported, indeed, was probably essential for, hominin brain expansion. The corollary is that inadequate intake of the cluster of brain selective nutrients would have been a significant impediment to human brain evolution.
Inadequate intake of brain-selective nutrients is more severe in some geographical regions than others but, on a global scale, it is a massive public health problem. Low intake of brain selective nutrients is much less prevalent in populations regularly consuming fish and shellfish, a point crucial for the link between brain selective nutrients, shore-based diets and human brain evolution (Crawford et al., 1997; Crawford, 2010; Cunnane, 2010). The extensive prevalence of suboptimal brain development in humans subsisting on diets providing inadequate amounts of brain selective nutrients underlies the ongoing developmental vulnerability of the human brain; this vulnerability was clearly not eliminated but rather probably increased as the brain expanded during its evolution.
Docosahexaenoic acid: the brain selective omega-3 fatty acid Docosahexaenoic acid is an integral part of membrane phospholipids of neurons throughout the brain. Synapses, the contact points between neurons, are particularly enriched in DHA. It is in this structural role that DHA participates in processes linked to learning and memory, but the specific molecular mechanism by which this occurs is still poorly understood. Learning and memory are almost always compromised under clinical or experimental conditions causing lower brain DHA. These conditions may be genetic in origin, i.e., low DHA synthesis in Zellweger Syndrome, or may be induced by experimental dietary depletion of omega-3 fatty acids. All stages of the life cycle seem to be affected, though more so during vulnerable periods such as infancy and old age.
There are three reasons why DHA is probably the only brain selective fatty acid:
(i) A specific and irreplaceable lipid component: The unique specificity of DHA in photoreceptor function is well known throughout the animal kingdom. No other polyunsaturated fatty acid, not even DHA’s two closest homologues, the omega-3 and the omega-6 docosapentaenoic acids (22:5n-3 and 22:5n-6, respectively), can replace DHA in the highly specialized photoreceptor membrane (Crawford, 2010). The specific requirement for DHA is best known in the photoreceptor but the analogous situation occurs in the neuronal synapse.
(ii) DHA synthesis is insufficient: Humans possess functional forms of the enzymes used to make DHA from shorter chain omega-3 fatty acids so in theory can make some DHA endogenously. However, numerous studies show that humans are capable of converting less than 0.5% of the precursor omega-3 fatty acids, alpha-linolenic acid or eicosapentaenoic acid, to DHA (reviewed by Plourde and Cunnane, 2007). Infants are reportedly better able to synthesize DHA from its omega-3 precursors than adults, but the brain of a six month old infant not consuming pre-formed DHA still accumulates about 50% less DHA than the brain of a breastfed infant (Farquharson et al., 1992; Makrides et al., 1994; Cunnane et al., 2000, Fig. 3). Since the brain of human infants accumulates so much less DHA if pre-formed DHA is not provided in the diet (or milk), the synthesis route alone is clearly not able to meet the brain’s DHA requirement. Thus, the developing human brain unequivocally needs to be provided with pre-formed DHA.
(iii) A complicated route to DHA synthesis: DHA synthesis depends on an alternating series of desaturation and chain elongation of enzymes that are catalysed by a number of different cofactor nutrients, including iron, zinc, vitamin B6, and magnesium (Plourde and Cunnane, 2007). As a result, in all mammals (not just humans), DHA synthesis depends on the nutritional adequacy of these cofactors as well as on the amount of precursor omega-3 fatty acid in the diet. As explained in point 2 above, assuming for the sake of argument that the low rate of DHA synthesis (0.5%) was adequate to meet the DHA requirements of the adult, the dependence of this pathway on multiple nutrient cofactors still makes DHA synthesis a much less reliable way to get DHA into the body than consuming it directly. The need for iron in this pathway combined with the extremely widespread prevalence of iron deficiency in the world today makes it even less plausible that the increasing requirement for DHA for the evolving human brain would have been provided by its synthesis route as opposed to obtaining it pre-formed in the diet.
Baby fat: the brain’s DHA and fuel reserve
At birth, body fat contains very low amounts of polyunsaturated fatty acids; at most 1-2% of all the fatty acids present (Farquharson et al.,1992). However, this small depot includes significant amounts of DHA, which, when multiplied by 500-600 g of fat normally present at birth, represents a reserve of about 1000 mg of DHA (Fig. 3). Docosahexaenoic acid accumulation in the brain during the first six months of life occurs at a rate of about 10 mg per day, and in the whole body at about 20 mg per day. Hence, pre-formed DHA in body fat at birth represents a supply for the infant that could last for at least 50 days in the absence of any other source of DHA (Cunnane et al., 2000).
Some DHA synthesis occurs in the infant and, if breastfed, maternal milk is also a major source of pre-formed DHA. This redundancy in the availability of DHA (in fat stores, milk and some synthesis) serves to virtually assure sufficient DHA accumulation by the developing brain. Premature or low birth weight infants have a much lower reserve of pre-formed DHA because they have much less body fat at birth, which contributes to their risk of neurodevelopmental delay. Chimpanzee infants have no body fat and hence no known reserve of pre-formed DHA.
...the ‘shore-based paradigm’ fully accepts that the hominins destined to become humans probably obtained much of what they ate by gathering, but gathering foods found mostly on or near the shores rather than fruits, vegetables, grains and tubers as commonly suggested. Foods gathered on the shores included not only aquatic and marsh plants but also fish, shellfish, amphibians, crustaceans, eggs, etc.
The new paradigm: a shore-based habitat and diet.
The shore-based paradigm proposes that one or more australopithecine populations in eastern and southern Africa came to occupy a habitat and consume a diet that provided solutions to both the energetic and nutritional constraints on primate brain size and function. This paradigm has four principal features:
(i) Ketones and ketogenesis: Increasing energy and structural lipid (e.g., cholesterol) requirements of the expanding brain were met in large part by ketones.
(ii) Subcutaneous fat: The evolution of neonatal body fat probably occurred before evolution of the bigger brain (see previous section: Body fat: The infant brain’s unique energy reserve). Subcutaneous fat not only supplies the fatty acids that are substrates for ketone production but also stores key structural fatty acids for the developing brain, particularly DHA.
(iii) Brain selective nutrients: A diet providing a richer and more reliable source of brain selective nutrients was needed for optimum brain development and function in adult life. These nutrients include not only DHA but also several brain selective minerals and vitamins. for brain structure and function, Iodine and iron, Docosahexaenoic acid).
(iv) Shore-based habitat and diet: A shore-based habitat and diet provided a secure and abundant food supply richer in brain selective nutrients than any other diet (Cunnane, 2005). Sustained access to a shore-based diet occurred before significant brain expansion and tool-making started. Access to a reliable food supply also provided an opportunity to develop more fixed habitats in which fat deposition could gradually evolve in the human fetus and neonate. Some brain selective nutrients contributed to relieving the metabolic (energetic) constraint on the developing brain, i.e., iodine and iron. Others helped relieve the nutritional constraint, i.e., DHA, zinc, copper and selenium. Some brain selective nutrients played both roles, i.e., iron and copper, which are essential structural components of enzymes needed for efficient energy metabolism (Fig. 4). Evolution of neonatal body fat also contributed to relieving both of these constraints. It provided a reserve of DHA for neuronal membrane structure but also other saturated and monounsaturated fatty acids that are good ketone precursors, which could be used both for the synthesis of other brain lipids and as an alternative brain fuel to glucose. For 40 years now, attention has been drawn to the importance of DHA in human brain development and evolution (Crawford and Sinclair, 1972; Crawford and Marsh, 1989). Indeed, the idea that DHA is a brain selective nutrient is now widely endorsed. Notwithstanding the fact that DHA is the poster nutrient for successful brain development and function throughout the life cycle, it alone could not have stimulated brain evolution in hominins without a concomitant increase in availability of either the full cluster of brain selective nutrients or a way to reliably ramp up brain fuel supply as the brain expanded.
Brain selective nutrients in the shore-based diet
A shore-based diet provided a richer supply of brain selective nutrients and thus helped relieve the nutritional constraint on hominin brain expansion because foods available on or near shores are generally excellent sources of DHA, iodine, iron, zinc, copper, selenium, vitamin A, and vitamin D. Shore-based foods include a large variety of nutritious plants, shallow freshwater fish such as catfish, crustaceans, shellfish, amphibians, and eggs of birds nesting on or near shorelines. Most shore-based foods can be obtained
without needing either highly developed cognitive and manual skills or manufacture of cutting stone implements or other fishing technology.
Most if not all nutrients known to be important for the developing brain are present in higher amounts in foods found on freshwater and marine shores than in foods not associated with lakes, marshes or waterways. The daily requirements for brain selective minerals can therefore be met by less shellfish or fish than by any other food groups, including pulses, fruits, vegetables, nuts, or meat (Cunnane, 2005). Thus, any amount of fish and/or shellfish contributes very significantly to meeting the dietary needs of humans for brain selective nutrients (Broadhurst et al., 1998; Cunnane, 2005, 2010). Conversely, the less one eats foods found along the shores, the harder it is to get sufficient intake of iodine, selenium, iron and DHA.
