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Abstract

Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B₃ /nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the ‘de novo’ tryptophan-to-kynurenine-nicotinamide ‘immune tolerance’ pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital.

Keywords

Meat nicotinamide evolution NAD(H)Malthus fertility immunological tolerance longevity

Rich fellas . . .their kids die out but we keep a-comin . . .we’ll go on forever, Pa, cos we’re the people

The Grapes of Wrath, Steinbeck, 1939.

Introduction

Malthusian demographic projections predict that the rate of population increase will inevitably (postponed in man by improvements in agricultural and medical technology) lead to intense competition between individuals for food resources and reproductive success.^1–4 This led Darwin to his theory of natural selection and the concept of the survival of the fittest. However, was this competition just about calories? We will argue that it was really about an optimal supply of nicotinamide/nicotinamide adenine dinucleotide (NAD) important not only for the energy supply but also for the metabolic and genetic regulation and growth of big brains. The demographic success of humans relative to other omnivorous primates, or, as individuals or groups competing with each other, being down to success in obtaining this supply, largely from meat. Nicotinamide adenine dinucleotide powered brains with cognitive workspaces and the physical wherewithal to obtain NAD precursors in an ‘NAD World’.^5,6

Demographic events that we discuss in the light of meat intake closely relate to Cohen’s ‘Four Evolutions in human population growth’ covering hunter-gatherers whose populations doubled over hundreds of thousands of years to early agriculturists that doubled over thousands of years to later agriculturists that doubled over hundreds of years to the modern day when populations in developing countries can treble within lifetimes.⁷

Taking an ecological view of human history was first proposed by Aldo Leopold⁸ in A Sand County Almanac and taken up by Alfred Crosby⁹ in The Columbian Exchange and his followers^10–13 including Anthony McMichael’s¹⁴ recent Climate Change and the Health of Nations. These authors emphasise historical exchanges of food and disease, particularly infectious disease, and the effect of climate on crop yield: here, we expand on the effect of changing nutrition on intelligence, longevity, and reproductive behaviour in more specific detail.^15–17 A very long perspective helps our argument beginning with the original rise of the animal kingdom and costly brains.

Meat, NAD, and the Cambrian

Our argument begins with the Cambrian explosion^18,19 (Figure 1). This era is known as Darwin’s dilemma as evolution progressed so fast – a veritable gallop of morphological complexity and genomic variation. The Cambrian was, in essence, an explosion of (vertebrate) brains and mineralised skeletons allowing calculated movement and burrowing for food. Consciousness, sentience, primal emotions, qualia, high arousal, and mental maps whether visual, tactile, sound, pain, taste, and lingering smells leading to memory maps, and so on, necessarily evolved for predation, as did raptorial appendages, in an escalatory arms race. (This evolutionary route was not used by all species as many survived on genetically programmed reflex actions that avoid the high costs of complex nervous systems.) Bacteria that eat worms use NAD as a ‘food signal’ to open their mouths, but if NAD is unavailable they stop reproducing and enter a developmental and reproductive arrest phase, mediated by serotonin, to survive.²⁰ The next evolutionary step was macropredator worms hunting worms and arthropods hunting fish and included widespread cannibalism, often at defined developmental phases.^21,22 Carnivory became pervasive and our own evolution can be traced from these times.^23,24 Even the clever invertebrates, such as octopi, hunted and they had been preceded in the long Precambrian by the earliest animals with recognisable heads, and ancestral neurones and ganglia, some of whom developed prey capture as their foraging style.²⁵

Figure 1.

Evolution seen as the acquisition of NAD. Mitochondrial usage and rising O₂ levels followed by animals hunting for NAD followed by even bigger human brains. NAD indicates nicotinamide adenine dinucleotide.

Rising oxygen levels in the atmosphere would have allowed better adenosine triphosphate (ATP) production from NAD(H) + O₂ reactions but preceded the Cambrian.^26–30 One can take this ‘metabolic acceleration’ argument over the importance of hydrogen metabolism and NAD(H) availability back further to the origins of life, given that it is a redox cofactor used by all living organisms, and this fits with ideas over the importance of the endosymbiotic acquisition of mitochondria and the arrival of visible multicellular eukaryocytes.^31–33

Well after the Cambrian, dinosaurs flourished, but a series of volcanic eruptions followed by a large asteroid struck the Yucatan 65 million years ago and caused widespread climate change and extinctions; this is thought to have first affected herbivorous prey and consequently the demise of clever ‘red in tooth and claw’ carnivorous dinosaurs such as Tyrannosaurus rex.^34,35 Amniotes, then mammals and primates then took the lead again with improving nutrition (more nicotinamide-riboside in milk and early weaning to animal products) for their young building big brains in an increasingly complex and variable environment requiring problem-solving skills aided by social learning and cooperation.^36,37 Strategic and social hunters have to take account of the habits of their prey and competitive groups whether other carnivores or ‘Machiavellian’ members of their own species. Whether one is a proponent of the ecological, social, technological, or general intelligence hypothesis for the evolution of high energy requiring high neuronal count brains, ideas overlap if the original task was clever foraging for difficult-to-obtain micronutrients and high-quality energy in a variable environment with new opportunities and new dangers.^38–43

Meat, NAD, and Human Evolution

Archaeological and palaeo-ontological evidence indicate that hominins increased meat consumption and developed the necessary fabricated stone tools while their brains and their bodies evolved for a novel foraging niche and hunting range, at least 3 million years ago. This ‘cradle of mankind’ was centred around the Rift Valley in East Africa where the variable climate and savannah conditions, with reductions in forests and arboreal living for apes, may have required clever and novel foraging in an area where overall prey availability but also predator dangers were high^44–50 (Figure 2). Tools helped hunting and butchery and reduced time and effort spent chewing as did cooking later.⁵¹ Another crucial step may have been the evolution of a cooperative social unit with divisions of labour, big enough to ensure against the risks involved in hunting large game and the right size to succeed as an ambush hunter – with the requisite prosocial and altruistic skills to also share the spoil across sexes and ages.⁵² The ambitious transition from prey to predator hunting the then extensive radiation of megaherbivores so big that they are normally considered immune to carnivores, needed advanced individual and social cognition as humans do not have the usual physical attributes of a top predator.^53–59 Adult human requirements to run such big brains are impressive enough, but during development, they are extraordinarily high with 80% to 90% of basal metabolic rate necessary in neonates – this is probably not possible after weaning without the use of animal-derived foods.^51,60,61

Figure 2.

Our early evolution in a nutshell. Steadily increasing nicotinamide powered biological and cultural evolution.

Such a climb up the food chain is unusual as most species go for the easy calories as they increase in body size.^52,62,63 Sometimes, this climb down the food chain can be extreme with some, for instance, in the order Carnivora becoming specialist herbivores.^64–66 Close examples among primates that have taken this approach are gorillas and orangutans and extinct robust hominids such as Paranthropus – none known for their particularly big brains or sociality relative to chimpanzees. Chimpanzees went for a high-quality diet as did early Homo. Homo sapiens whose brains enlarged markedly simultaneously managed high reproductive rates with large dependent children with long developmental periods and high longevity.^67–69 Energy constraints were lifted to achieve this suite of costly traits without always having large trade-offs, at least when the NAD supply allowed.^60,70

As a consequence, man may have been part responsible for the wave of megafaunal herbivore extinctions starting in Australasia some 50 000 years ago in a diaspora out of Africa probably driven by hunting parties in search of meat –even if climate and loss of high-protein clover-like foods caused some of the die-off of animals such as the wooly mammoths.^71,72 Later came the technically more difficult over-fishing and near extinctions or extinctions of oceanic megafauna and fauna such as the dodo and giant tortoises less than 20 years after they were discovered by meat-hungry sailors. Present-day near extinctions of other primates and meso-carnivores for bushmeat leave ‘empty forests’. All this meat eating changed the geological and physical nature of the world long before the onset of agriculture and marks the true beginning of the Anthropocene where now 90% of mammals are either human or our domesticates⁷³ (Figure 3).

Figure 3.

Our later evolution in the light of oscillations in the nicotinamide supply. Variances provoked population booms and some busts with friction over meat resources between populations and between social classes.

Omnivorous man

Omnivory, such as by farming, first evolved in insects and later by convergent evolution in Eocene primates and is their defining trait^74–76 (Figure 4). Our more remote ancestors were herbivores eating grasses, digested by gut symbionts, then frugivores and insectivores eating enough animal protein to supply vitamin B₁₂ and some nicotinamide – either by chance on fruit or more actively, such as fishing for termites. Hominids and early Homo increased meat intake but remained omnivores not carnivores, despite being top predators.^77,78 Finding new plant foods and the tension between neophobia vs neophilia (as laid out in the ‘omnivore’s dilemma’) involved dangers that need avoiding to avoid plant toxicity from secondary compounds evolved to deter herbivores.^79–82 We were helped by evolving a complex detoxification enzymic system (such as cytochrome P450 now also used to metabolise many drugs) that includes detoxification from excess nicotinamide by nicotinamide N-methyltransferase and culturally acquired cooking methods to avoid toxicity, for example, from cyanogens and improve extraction of calories and some micronutrients (including nicotinamide).^83–85 Cooking helped tenderise meat and made plants more edible and nutritionally available – such as the culturally learnt alkalinisation of maize that releases nicotinamide from its bound form niacytin – a process known as nixtamalization.⁸⁶ Processes for storage and preserving, such as smoking, drying, and salting of meat, or fermentation, whether with co-evolved yeasts and lactobacilli (of cereals to produce bread and beer or of milk to produce cheeses), also improved the nicotinamide supply.^87,88 Tolerance of milk drinking throughout adult life – a genetic change that followed the culturally lead domestication of animals for their milk and the potent nicotinamide-riboside in particular – may speak for strong selection pressures for nicotinamide.³¹

Figure 4.

Omnivores and domesticated diets. Domestication of animals and plants but also of ourselves, our microbiome, and the microbiomes of our domesticates whether of ruminant cattle or the mycorrhiza of legumes.

Being omnivorous has several advantages, an obvious one being switching diet depending on availability, rather than starving. Diet (and altered nutri-microbiomes) can affect individual behaviour and increase variability within a population – striking in isogenomic social insect castes but also generally true.^89–91 Omnivores can use diet to self-regulate behaviour – Argentine ants change from protein-rich to carbohydrate-rich diets when they settle down and increase population size – just as we did).⁹²

Plant and animal cultivation

A key series of plant and animal pre-domestication gardening or pet-like relationships followed by co-evolved domestication happened, including of ourselves.^93,94 This transition was slower than previously thought – 3000 years to fix the non-shattering spikelet of wheat – but still speaks for significant selection pressures – not convincingly explained^95–98 (Figure 5). Only a tiny proportion of available plants were selected – some 3% of 5000 species with less than 20 plants now providing most of the world’s food supply. Some selection must have been unconscious from metabolic needs and some conscious based on taste, toxicity, harvesting characteristics, or tameness.^99–101

Figure 5.

Steady rise of meat/nicotinamide in surviving hominids until the Neanderthals. Homo sapiens survived, but only just, and then we subjected ourselves to large meat variances with demographic consequences.

Why there is sudden interest in plants is unclear even if the when, where, and how is becoming clearer. Farming, for instance, was facilitated by a benign climate at the end of the recent ice age and the warmer, wetter, higher carbon dioxide early Holocene 9000 to 12 000 years ago. This heralded the dawn of food production rather than food gathering and urban civilisation – almost simultaneously, and independently, in 8 to 10 major centres. In the context of our 200 000-year history (‘an eerie synchronicity’), this suggests a single driving evolutionary advantage adapted to local circumstances.^102–105

We make the case that the change to an agricultural lifestyle co-evolved as the change in diet changed our (tryptophan-nicotinamide) biochemistry and immunology favouring tolerance of the foetus, increased fertility and higher, denser, populations. Population size and density are important to a social species. More people particularly young people enable more division of labour while avoiding labour shortages – even if the price is hard work, more disease, inter-group stress, and social stratification with rich elites.¹⁰⁶ Perhaps, an earlier evolutionary pressure for bigger brains relaxed (brains did atrophy) under domestication in favour of interactive social brains and specialisation.^107,108

Change in diet changes serotonin and other neurotransmitters directly and indirectly through altering the gut microbiome (an overall trend from Bacteroides to Prevotella enterotype on more plant-based diets) influencing cognition and mood and potentially increasing social cohesion, collectivism, and sedentism.^109–117 Cross infection with symbionts is an advantage when they add to the supply of nutrients of living closer together with less than perfect hygiene, but risks dysbioses. Increased transmission of pathogens and species jumping from domesticates’ vectors led to then emerging ‘crowd’ diseases, such as measles and smallpox, and slash and burn agriculture encourages mosquitoes and malaria explaining why many of these diseases became common at this time.^118–120 Pathogens and dysbioses have a ‘Malthusian’ role in reducing population size particularly and may target NAD-deficient individuals on a poor diet.¹²¹ This could, seen from one perspective, be beneficial and better than starving and damaging the ecological and farming niche or eating seed corn in desperation – putting eventual recovery at risk. Ecological damage made deliberately and politically by empires being a major factor in their population collapses, although once a popular alternative hypothesis, has proven difficult to confirm.^70,122,123

Demographic Transitions

The key features of demographic transitions comprise usually (but not always) improving economics followed by decreased mortality, first in adults and then in infants.^124–126 Then, nearly always, this is followed by a delayed decline in fertility from up to 8 births per woman to replacement levels of around 2 (this lag causes the disequilibrium and the population explosion). Population then stabilises but can implode as fertility drops below replacement levels (if not bolstered by immigration or infertility treatment).^127–130 This pattern has been and still is being replicated in all parts of the world – even if circumstances and timescales differ in detail. The pattern is almost a demographic law even though the mechanism remains hotly disputed.^131–133 During the transition period, population increases often over a century – although some recently have been faster. A historical minimum is a 2-fold increase with an average of an 8-fold increase. Fourfold increases are predicted for China and India, but record-breaking 10-fold to 18-fold increases or more (up to 30-fold) are projected in several countries mainly in sub-Saharan Africa where meat intake remains very low.^134,135

Thomas Doubleday¹³⁶ in his Great General Law made while contemporaneously observing the United Kingdom’s 19th century transition stated that the first decline in fertility happened in the wealthy, whose food habits at that time included far more meat eating, and led him to favour a biological cause for the relative sterility of the rich. We will take his argument a step further and argue that more meat in diet provides the biochemical basis for increased longevity; then the usual (but not inevitable) further improvement in dosage leads to a decrease in fertility as well as improved cognition and education – that then play their part in further decreases in fertility. The length of the lag between increased longevity and decreased fertility is critical to the size of the population explosion and depends, we think, on the speed at which the meat intake (and nicotinamide dose) increases.^137–139

Meat – The Key Ingredient is Nicotinamide

Is meat special? In some cultures, they recognise a ‘meat hunger’ and it is a prized food in all cultures with cattle capital often used as a sign of wealth and used for dowries. Great effort and costs are made to hunt and obtain hunting grounds or pastureland, through raids or warfare when necessary. Domesticated animals include omnivores at the cost of them eating human animal product fodder let alone crops. We have argued, as have others, that there have always been easier and safer ways of obtaining calories, such as foraging for tubers.^48,140 Vitamin B₁₂ can only be obtained from meat, but an insectivorous diet, even one obtained inadvertently from eating fruit, would have sufficed. Similarly, iron, zinc, and vitamin A are best sourced from meat, but not much is enough to satisfy requirements. Certainly, one does not need to hunt big game. An argument for protein has been found wanting as most essential amino acid needs can be met from plants. However, a case can be made for needing animal protein for tryptophan that is otherwise hard to obtain – tryptophan is a source of nicotinamide, and dietary deficiency also has effects on serotonin and therefore social behaviour.^141–144 We have made the case for vitamin B₃ – nicotinamide – as this is the key vitamin that is missing in cases of over-reliance on a single plant, usually maize, and little or no meat. Nicotinamide as an essential component of NAD/NADH (reduced NAD) drives the electron transport chain converting the free energy of the electromotive force in to a proton gradient across the mitochondrial inner membrane driving ATP production and controlling pH and other voltage-coupled processes.^145–148 Simultaneously, many NAD-coupled redox reactions as well as more recently discovered NAD-consuming reactions are known to be important for cell development, repair, and ageing: NAD is a master controller of much of metabolism necessary for running large bodies and brains and restoring stem cells.^70,149–155

High energy has long been recognised as crucial for expanding ape brain size but has often been considered to be paid for by reducing energy spent on large guts, inefficient locomotion, and less chewing.^156–158 Storing more fat – another human feature – would be a reserve store of calories and nicotinamide without having to use auto-carnivory of muscle, liver, or other organs where the longer term price is high. Our metabolism runs faster with higher energy expenditure measured as calories burnt (27% more than chimps and more than that in gorillas): this can only happen by boosting mitochondrial function. Increasing the supply of NAD would be a way of accomplishing such a feat.^159,160

Lessons From Pellagra – The Forgotten Meat Deficiency State

The past is never dead. It’s not even past. (William Faulkner)

Pellagra causes brain atrophy and subsequent low IQ/dementia, poor social behaviour, and gut dysbiosis.^161–163 It has often been considered an atavistic model of human evolution¹⁶⁴; in other words, evolution running in reverse as a truly degenerative phenomenon – homo without the sapiens. Pellagra was known as the ‘lazy’ disease with emotional, cognitive, and physical stunting alongside many degenerative disease mimics (as we define them now) (Figure 6). Comments about pellagrins as degenerates were made in the early European literature and the more recent American literature describing the pellagra-prone southern states around a century ago. Clinically undiagnosed cases had impaired IQ with average army Confederate recruits being in the ‘moron’ group (unlike Union recruits) and been felt to be in part responsible for the ‘white trash’ phenomenon with racial differences being both an additional factor in causing the Civil War and in determining the outcome. Such views fuelled the eugenic movement as genetics were thought to be causal and it was believed that such people had too many children.¹⁶⁵ The high fecundity observed among sub-clinical pellagrins that caused much of this friction may be relevant to our argument.

Figure 6.

Pellagra has an extra-ordinary wide phenotype. Many mimic modern diseases of ageing. Premature ageing may have been traded off against greater fecundity when the diet is poor. NAD disruption may be a final common pathway of ageing diseases whether from dietary under- or over-dosage or high NAD consumption from stressors. NAD indicates nicotinamide adenine dinucleotide.

Golberger proved that pellagra was dietary in origin and due to a lack of meat and milk, not genetic or infectious, and that eventually influenced thinking that southerners were not genetically degenerate and deserved help.^166,167 Finally, the biochemical basis and treatment with replacement nicotinic acid was discovered in the 1940s.¹⁶⁸

1850 – UK Data

We now take the data available from the demographic transition in the United Kingdom, 1850-1950, to look at correlations between meat and both fertility and longevity alongside height and IQ as a general marker of health to advance our hypothesis. The period from around 1800 had led to the population doubling to 18 million, despite conditions deteriorating culminating in the ‘hungry 1840s’ (perhaps, a boom with a bust narrowly avoided as conditions improved as the buoyant economy allowed high meat imports). This period had very poor harvests probably triggered by the eruption of Mt Tambora in Indonesia in 1815 with falls in average temperatures and lost summers and El Niño consequences.¹⁶⁹ This period is well documented in literature with Charles Dickens Hard Times and William Cobbett’s Rural Rides describing the plight of both city and rural poor as did Freidrich Engels’ The Condition of the Working Class in England. Relevant legislation such as the repeal of the corn laws and new poor and education laws was enacted: relevantly for us the Births and Registration Act culminated in William Farr’s classification system and means that we have clean data from a time when modern medical or contraceptive interventions were not possible.

Methods

Sources for data

All meat data were collated from The Meat Trade in Britain 1840-1914 by Perren,¹⁷⁰ Eating Meat: Evolution, Patterns, and Consequences by Smil,¹⁷¹ and The Atlas of Food Who Eats What, Where, and Why by Millstone and Lang.¹⁷² Raw data sets for fertility and death were sourced from OPCS (1995),¹⁷³ The Health of Adult Britain 1841-1994 Charlton and Murphy,¹⁷⁴ and Millstone and Lang.¹⁷² Life expectancy circa 1850 data were from The Population History of England 1541–1871 by Wrigley and Schofield¹⁷⁵ and Ecological Public Health: The 21st Century’s Big Idea?’ by Rayner and Lang.¹⁷⁶ Birth rate data was from Hardy.¹⁷⁷ Data for diarrhoea were derived from Mortality in England and Wales from 1848 to 1947 by Logan¹⁷⁸ and Millstone and Lang.¹⁷² IQ and literacy data were from Some British Pioneers of Social Medicine by Greenwood¹⁷⁹ and ‘National IQS predict differences in scholastic achievement’ in 67 countries by Lynn et al.¹⁸⁰ Fertility data were collated from The Central Intelligence World Factbook.¹⁸¹ World Population Growth Rates data were collated from World Population Prospects in McMichael¹⁴ and correlated to recent meat data taken from Weis in Pritchard et al¹⁸² and nicotinamide trends from Hiza and Bente.

Statistics

Exploratory analysis was conducted on these data to identify relationships between meat consumption and other variables by conducting scatter plots. The correlation between meat consumption and other variables was analysed using the Pearson correlation coefficient. All statistics were conducted using SPSS (version 21).

Results

During the period 1850-1950, in the United Kingdom, birth rates fell very significantly as did overall death rates and with a short lag infant mortality rates (Table 1).

Table 1.

Birth rates (B/R), crude death rates (D/R), and infant mortality rates (IMR), England and Wales, 1851–1950.

Years	B/R	D/R	IMR
Years	Per 1000 living		Per 1000 births
1851–1860	35.5	21.3	148
1861–1870	35.8	21.5	160
1871–1880	35.4	21.4	149
1881–1890	32.4	19.1	142
1891–1900	29.9	18.2	153
1901–1910	27.2	15.4	128
1911–1920	21.8	14.4	100
1921–1930	18.3	12.1	72
1931–1940	14.9	12.3	61
1941–1950	17.0	12.3	43

All fell during the period 1851–1950 – crude death rates first followed by birth rates and infant mortality.

Life expectancy increased very significantly and trended with increased meat consumption P > .065 and correlates more strongly across the world today P > .0001 (Table 2; Figures 7 and 8).

Table 2.

Life expectancy in England and Wales, 1838–1952.

1838–1854	40.9
1871–1880	43
1881–1890	45.4
1891–1900	46
1901–1910	50.5
1920–1922	57.6
1930–1932	60.8
1950–1952	69

Life expectancy increased over time and has continued to increase since (as has meat intake).

Figure 7.

Life expectancy plotted against meat consumption 1820-1960. Overall life expectancy increased and positively trended with increased meat consumption (r = 0.685; P = .067).

Figure 8.

Life expectancy plotted against meat consumption now is significant (r = 0.641; P < .001).

Death rates falling between 1850 and 1960 in the United Kingdom correlate with meat consumption P > .001, as does the drop in fertility rate P > .001 (Figure 9). The death rate falls first and the fertility rate continues to fall until it reaches just above or below the replacement rate. Fertility and meat or nicotinamide intake across the contemporary world correlates negatively (P < .01) (Figure 10). Measures of good physical and mental health whether height or literacy correlate with meat intake in the United Kingdom between 1850 and 1950 and in the contemporary world – all P<0.001 (Figures 11 to 14).

Figure 9.

Death and fertility rates plotted against meat consumption. Overall death rates and infant mortality fell and correlated strongly with increased meat consumption (for fertility rate vs meat r = −0.815; P < .001; for death rate vs meat r = −0.864; P < .001).

Figure 10.

Fertility and meat across the contemporary world (P < .01) .

Figure 11.

Literacy rates plotted against meat consumption in the United Kingdom 1850-1900 (r = −0.988; P < 0.001).

Figure 12.

Literacy rates plotted against meat consumption in the contemporary world across nations (r = 0.531; P < .001).

Figure 13.

Increased height correlates strongly with higher meat intake in the past (r = 1; P < .001).

Figure 14.

Increased height correlates strongly with higher meat intake currently (r = 0.635; P < .001).

Recent percentage declines in population growth rates significantly correlate with average rise in meat and nicotinamide intake (P < .01) (Figure 15).

Figure 15.

Recent percentage population growth rates correlate with average rise in meat and nicotinamide intake (P < .01).

Having seen these supportive correlations between meat and therefore nicotinamide intake and lower fertility and markers of health and intelligence and therefore longevity during this modern period for which there are data, we now return to our 100 000-200 000 years of evolution and history with meat intake and population growth in mind and then will propose a biologically plausible biochemical mechanism.

Hunter-gatherer times

Meat intake was high in all hunter-gatherer groups beginning some 700 000 years ago and only ending relatively recently on evolutionary timescales, assuming that contemporary studies reflect the conditions under which early humans obtained meat with a relatively light workload.¹⁸³ Dietary animal protein intake among the San of the Kalahari Desert is approximately 30 to 50 g per person per day (developing countries now average 7-10 g per person per day) derived from 17 of 55 edible animals along with an eclectic yet selective collection of wild fresh vegetables consuming 23 of 85 plant species that they know to be edible.¹⁸⁴ The Hadza of Tanzania may be a better model for pre-history as they live in the same kinds of environments, ie, game-rich savannas, steppes, and open forests – not deserts and jungles.¹⁸⁵ On this analogy, early human beings are estimated to get 50 to 250 g of meat protein per person per day – high even by modern affluent standards.

Population size by the time that humans had gone global around 50 000 years ago suggests a total of maybe 3 to 4 million people and densities of around 1 person/km². Given the long time periods involved, this suggests a very gentle rate of population growth, at no time having exponential phases. It has, up till now, been considered a mystery as to why this was so low, given that it is well below the carrying capacity of the land.¹⁸⁶ High meat intake during this very long time period was linked with low fertility supporting our hypothesis. Kung San hunter-gatherers who turn to sedentism and agriculture increase their fertility rates.¹⁸⁷

Neolithic agricultural revolution

Plant domestication began in the Jordan Valley around 9500 bc with rye, barley, and wheat in the ‘fertile crescent’ using the waters and flood plains from the Euphrates, Tigris, and the Nile. Animal husbandry started a little later in the Zagros Mountains of Iran/Iraq and in North Africa.¹⁸⁸ Goats were first domesticated, then pigs and sheep around 7000 years ago, and the largest bovids domesticated from aurochs into cattle herds 6000 years ago with signs of dairy farming between the Sahara and Mesopotamia between 4 and 3000 bc.^189–192 Despite domestication of animals, there is general agreement that the increased use of plant foods decreased the dependence on animal protein by around 50%^193–197 (Figure 16).

Figure 16.

Decreased meat availability from climate change or over-hunting may have pushed the agriculture revolution, but a bigger pull may have come from increased fecundity.

Populations exploded once the area under crops was large enough to have an effect around 5000 bc doubling every 1000 years, and populations became denser as a consequence.¹⁹⁸ Estimates, including from sets of mitochondrial genomes, suggest some 4 to 5 million in 10 000 bc rising to 190 million by ad 500 largely at the first birthplaces of agriculture in Europe and Asia and later within the Roman and Chinese (Han) empires.^199,200 The latter is possible due to a benign climate known as the ‘Roman Warm’ from around 300 bc lasting some 800 years.

Evidence suggests that this demic explosion caused the diffusion of agriculture and farmers rather than that the idea, through cultural diffusion, spread. Indeed, the idea may not have been popular as agriculture by all accounts is harder work than being a hunter-gatherer and there are highly significant detrimental consequences for height and health.^201–205 Many tooth and bone infections (including tuberculosis [TB]) along with stunting show up in the palaeopathological record and are all associated with deficient animal proteins or iron deficiency – although pellagra itself has no diagnostic features in bone.^206–208 Despite all of this, farmers outreproduced hunter-gatherers supporting our argument and in a biological sense were ‘fitter’.^209–211

Roman empire to the middle ages: decline and fall – of fertility

The origins of the Middle Ages were one with the decline and fall of the Roman Empire. Rome’s population peaked at 500 000 persons – numbers not to be attained again for several centuries in European cities.^212–219 Augustus was so concerned about the falling birth rate among the wealthy, who ate large amounts of meat that in 19 bc, he penalised the childless; the overall phenomenon (later picked up by Doubleday) is well documented by Polybius who predicted that this loss of fertility would affect the ability of Rome to remain masters of the world. Declining numbers across the Western Empire were evident from the spread of agri deserti (‘abandoned fields’) and abandoned villas.²²⁰ Finlay, a 19th century American historian of Rome, repeated this analysis coming to the same conclusion and pointed out that it was also true of his contemporary oligarchy in France and was implicit in the use of the Latin term proletariat (proles = offspring) that the poorest had the higher fertility attesting to the antiquity of the observation (described even earlier by writers in Sparta and later again in explanations of the decline of the Habsburg and Egyptian empires).^221,222

Rome was highly dependent on imported grain much from ‘bread-baskets’ in Egypt. The diet of the average person, unlike the wealthy, was not heavily meat dependent. Others have wondered if poor diet later pre-disposed Romans to the bubonic plague whose long pandemic lasted from 541 to 750 during the reign of Justinian. Exhausted soil and poor summers may have played a part leaving the empire prone to exogenous attacks whether from plague or Vandals from the west and the rise of Islam in the East. Byzantine eyewitness accounts by Procopius during the Gothic War suggest pellagra: ‘skin livid to black faces with a dreadful sort of insane stare and flesh consumed by starvation – such was the manner in which famine visited the land’. ‘Barbarians’ were mixed farmers (such as the Goths) or nomadic tribes (such as the Huns) with livestock playing a more prominent role in their culture and diet.

We propose that the rise of the Roman empire and its population boom was related to a successful crop agriculture feeding the proletariat. High meat intake among wealthy roman citizens eventually led to their low fertility, and simultaneously among the poor, eventually pellagra-like conditions led to a population bust from disease. Finally, they were overcome by formidable meat–eating barbarians.

Domesday Book to Black Death and its aftermath

The 300-year period up to 50 years before the Black Death in 1348 benefited from good climatic conditions with high solar irradiance and positive El Niño conditions fuelling good harvests and high cereal crop yields.²²³ Population boomed from approximately 1.5 million in England to a medieval peak of 5 million. Southeast Asian and Indian empires along with Song China population booms were similar and were famously very cereal dependent.^224–228

Meat intake was very low just before the plague as rough pasture was turned to arable and climate change to cold wet dark summers led to harvest failures with famines – such as the famine of 1314.^{223,229–231} Poor pastureland triggered diseases in sheep (scab) and cattle plagues (probably rinderpest) that decimated the meat supply before the plagues. Yersinia pestis had evolved remarkably quickly from Yersinia pseudotuberculosis in around 20 000 years and has a very active NAD metabolism. It is spread by fleas normally on rodents, the natural host, advancing from Asia to Europe causing massive mortality rates with the major outbreak in 1348 and at least 4 sequels before the end of the century.^232–234

Because of the resultant population decline to 2 million people, arable land was turned back to pasture (as so much grain was no longer required).^235,236 Meat became more available to the survivors as production stayed stable or increased with the invention of the plough. Meat and milk intake doubled between 1300 and 1450 but varied within Europe (Figure 17). Despite a survivor benefit that included higher wages and more housing for couples contemplating marriage, fertility remained paradoxically low and the population did not rebound taking two centuries to climb back to the medieval peak.²³⁷ This is a good example of a high meat diet leading to low fertility rates and an increase in human capital.

Figure 17.

Meat intake was not the same in every European country. This may explain the relative success of England during this long period up to the industrial revolution.

Geographic variation: the New World

The ‘fertile crescent’ was lucky having significant choice of both domesticable plants and animals, but other parts of the world were less fortunate.²³⁸ Diets often became dependent on single cereal staples all with problems that are usually solved by adequate meat or dairy intake. Wheat is deficient in lysine/isoleucine, rice in protein and vitamin A, millet or sorghum deficient in protein. Maize is deficient in nicotinamide and tryptophan.

As the last habitable continent colonised, the Americas were slower (4000 rather than 10 000 years ago) to take up crops with several reverses (elsewhere unusual except in marginal zones sensitive to climate change such as for the Norse in Greenland) back to hunter-gathering lifestyles – suggesting that the risk-benefit ratio of the agricultural revolution was tighter than in the Old World.

The pre-Columbian New World became reliant on maize once the minute cobs attracted human interest and became the principal focus of artificial selection and domestication. Maize first appeared around 9000 years ago in Mexico having descended from teosinte and may have been first attractive for its sugary stalks that could be chewed or fermented. Maize has advantages as it grows in difficult hydrological conditions and returns 25 to 100 (1000 in modern times) grains per grain planted (compared with 5 grains for wheat),²³⁹ relevant as the continent was prone to droughts and poor soils that did not make agriculture easy.²⁴⁰ Micronutrient deficiencies were partly corrected by adding beans and squash to the diet and co-evolved cooking measures involving alkali releasing some nicotinamide from maize. Despite this cultural adaptation, presumably under strong selection pressure, the risk of sub-clinical or clinical pellagra must have always higher than in other parts of the world – as it would have been if maize was exported without the learnt cooking adaptation.

The original Americans had potato, squash, beans, chillies, tomatoes, peanuts, avocado, and manioc (cassava) and plants with medicinal, eg, quinine, and hallucinogenic potential for ritual or recreational purposes, e.g., cocaine, mescaline, chocolate and tobacco.^241,242 Tobacco is of interest as nicotine is so closely related to nicotinic acid and other hallucinogenic compounds intersect with tryptophan – serotonin metabolism perhaps acting as pharmacological meat/nicotinamide substitutes.^243–245

Their agricultural revolution was also harder as there were few herbivorous animal species, namely, the turkey, lhama, guinea pig, and dog suitable for domestication. Unlike the New World, this domestication of animals happened with a lag of 1000 to 2000 years after plants putting the whole society at risk of an unbalanced diet. Impressive though, the Aztec, Inca, and Mayan empires were they were considerable, later than equivalent cultures, in the Middle East and some never developed full literacy – a gap of approximately 2000 years – and when the two worlds eventually clashed the older culture with a long history of higher availability of meat and earlier successful domestication ‘won’. Columbus first noted these discrepancies ‘I saw neither sheep nor goats nor any other beast’.

Such plant-based pre-Columbian societies such as the Maya are well known for population booms and busts adding to our argument.^246–248 Pre-Columbian archaeology suggests large but often unstable populations with evidence of disease in bony material. Tuberculosis was certainly present, and bone pathology shows chronic infection, iron deficiency, and stunting suggesting a deficiency of animal products in diet – pellagra itself is not known to have any specific bony changes.^249,250

Capturing human slaves for cannibalism are well-documented.^251,252 This speaks for a meat shortage and a meat hunger. The enigma is explained of Aztec human sacrifice and wars taking prisoners –rather than the more usual land for agricultural usage – as there were no domesticated herbivores, so there was no point. This was a politically and religiously sanctioned form of human cannibalism fronted by meat-requiring gods. Meat went preferentially to the nobles, and the commoners only obtained meat at feasts or if they were responsible for human captures gaining the right to eat human flesh as a reward.

The heavy dependence of the Americas on plants and a boom-bust population history with poor human capital supports our hypothesis.

The great divergence and enrichment: the smart European ‘Miracle’

Although some think of the roots of economic growth (perhaps 100 times that of the agricultural era) and the dominance or Europe and Great Britain in particular as being a product of the Industrial Revolution, its roots date from the aftermath of the Black Death.^253,254 This could not have happened without high intellectual function with perhaps 10 000 very well-educated Europeans with enough time and longer lives to participate in the search for useful knowledge about nature and the environment.^255–257 Others have wondered if the rise of the British and later American empires was related to diet with some implicating a sugar or caffeine ‘rush’ but others pointing to ‘beef-eaters’ – certainly, both empires consumed high quantities of meat.^258–260 Earlier and relative to other parts of the world, Europeans commanded more working capital in the form of livestock that they ate often in prodigious quantities especially if rich. Literacy rates were considerably higher than elsewhere and technological and decision-making superiority played significant roles in the conquest of America. Superior health may have been just as decisive.^261,262

The Columbian Exchange

This major global event is well known to have caused population busts in the New World but population explosions in Europe.²⁶³ The New World populations were decimated by imported disease, but their own poor constitution from their relatively poor low meat/high maize diet may have contributed. Livestock were later imported and populations eventually stabilised, although not fast, suggesting that the extra meat did not lead to another population boom.^264,265

Maize was imported to Europe, and although often considered a food fit for animals, not humans (by decree in France), it did not stop its popularity and later spread to Asia and particularly Africa. Population booms followed. Maize was directly held responsible for the outbreaks and first descriptions of Pellagra in Spain and Italy in the 18th century in poor people on a very low meat diet.²⁶⁶

Easter Island

For those who prefer case studies from microcosms, the story of Easter Island may be relevant: islands cannot support big game, and as plant agriculture developed strongly, Easter islanders’ population boomed. Few animal domesticates, however, resulted in them becoming reliant on eating rats that are, however, competing omnivores, eg, over seagull eggs. This desperate meat poverty may have caused booms and busts followed by a final collapse.²⁶⁷

Ireland

The Irish famine around mid-19th century may also have been a low meat population boom with too high a reliance on the potato and little meat. Although potato blight was blamed (alongside the attitude of the British Government), this was ultimately another Malthusian population bust.^268,269 Interestingly, even within Ireland, the Irish ate the most potatoes and had the highest population growth and later declines – such exceptional fertility rates continued after emigration to New England and reliance on Indian maize.^270,271

China

China’s demographics have been considered, even by Malthus, to be different. But we would argue a country well known (until very recently) to have had a low meat diet and exceptional population growth – 200 to 1400 million people between 1700 and 2000 – supports our hypothesis.²⁷² Differences claimed for China include a collective rather than an individualistic attitude but that in itself may be influenced by a low meat diet. Collective and coercive attitudes have been prominent from high use of late marriages and at times female infanticide or state intervention with one child policies. These preventive checks may have kept fertility rates below the maximum of 8 but were still high at around 6 children per eligible woman. Malthusian checks with multiple famines up till the Great Leap Forward 1958-1961 causing severe population busts are well recorded demonstrating that this is another cereal-dependent boom-bust population.

Meat intake has improved markedly in recent times and mortality has fallen from 1950 with fertility following from 1970.²⁷³ We argue that more meat, with its biological effect on fertility and higher IQ not primarily moral restraint or state intervention, is now responsible for this more controlled demographic transition.

1950

Meat and demographic transitions continue across the world, such as in China, but stall or fail to complete in other places, notably Africa.^274–276 Africa, despite being the ‘cradle of mankind’ subsequently, was unlucky in both the availability of good animal and plant domesticates and its climate. Africa has many parasites and the aridity that helped initially became too extreme with much of the continent becoming desert. Tsetse fly and trypanosomiasis were the bane of cattle and man and with rinderpest could decimate the meat supply with outbreaks of pellagra described in the south.^277–281 Malaria of course was, and is, a major issue and has known interactions with NAD metabolism as do the evolved protective haemoglobinopathies: high meat areas appear to escape human-biting mosquitoes (who bite the animals instead) and individuals have a better constitution so see a decline in disease rates as a result.^282–289 Low meat areas prone to pellagra or famines are prone to malaria in the past even in temperate zones in Europe and America a century ago (even though other dietary deficiencies such as that of iron protect).²⁹⁰ Meat intake is still very low in many parts of Africa, and over-reliance on maize remains a prominent feature.²⁹¹ One has to consider Africa as a high-risk area for nicotinamide deficiency with resultant classic boom-bust demographics as history repeats itself, currently, in spades.^292–296

Correlation to mechanism: the nicotinamide/tryptophan/kynurenine immune tolerance pathway and fertility – maternal acceptance of the foetus

So, in broad consistent but somewhat anecdotal historical terms, with more specific data from one transition period in the United Kingdom, 1850-1950, our hypothesis is supported, but is there a mechanism? (Figure 18).

Figure 18.

Low nicotinamide in diet biases the ‘de novo’ pathway towards catabolising tryptophan to nicotinamide. This increases tolerance of the foetus but risks illness and deaths from dysbioses and pathogens.

Nicotinamide, though, classified as a vitamin is more complicated than just looking to diet as some is provided by the microbiome (in gut or perhaps from TB) and also as there is an intrinsic ‘de novo’ pathway as it is synthesised, rather inefficiently, as a degradation product of the essential amino acid tryptophan.²⁴³ Both these backup sources are used when the diet is poor. Activation of the ‘de novo’ pathway affects the immune system and thus is also known as the ‘immune tolerance’ or ‘disease tolerance’ pathway. This pathway allows symbionts to flourish – that produces nicotinamide/nicotinic acid – but affects adversely the ability to resist pathogens.^297,298 This pathway can be neurotoxic, although this ‘autocarnivory’ may release precursors to nicotinamide as another short-term fix.^{144,299–302}

This pathway is the biochemical site of immune privilege.^303–310 Importantly, for our argument, this immune privilege includes transgenerational tolerance to the allogenic foetus that one would normally expect to be rejected by the mother as ‘foreign’. When this pathway is suppressed, inflammation is followed by spontaneous abortion (as can also happen for some cancers and organ transplants).³¹¹ Indoleamine 2,3-dioxygenase 1 (IDO-1), the rate-limiting enzyme in this pathway, is produced in trophoblast cells that result in selective apoptosis of T cells.³¹² Systemic inhibition of IDO in pregnant mice results in immune abortion of allogenic foetuses through mechanisms that involve Tregs.³¹³ Adoptive transfer of pregnancy-induced Tregs prevent fetal rejection in murine abortion models, and human pregnancy is associated with an increased number of immunosuppressive Tregs.³¹⁴ Indoleamine 2,3-dioxygenase is highly expressed in the placenta and serum during pregnancy and encourages trophoblast proliferation, migration, and invasion essential to placental and fetal development, and its inhibition whether by pharmacological blockade or high nicotinamide in diet will result in an inflammatory reaction causing early abortion or later pre-eclampsia and fetal loss.^315–319 Dietary interactions with fertility have indeed been recognised, although not specifically in the context of nicotinamide that may have a regulatory role affecting fertility in a positive or negative direction depending on dietary and other contexts.^320–331

This mechanism using the ‘de novo’ pathway evolved long before humans being present in all animals (affecting how much nicotinamide is needed from diet) and may be a method of population control. It might explain why top-predator/carnivore populations do not relentlessly expand to the estimated carrying capacity of the land even when prey is plentiful – the ‘prudent predator’ (as we were in hunter-gatherer days). This avoids species abusing keystone status and exponential growth of populations with eventual extinction from decimation of prey. This pathway also allows a switch from quantity (what ecologists call ‘r’ selection hedging bets with large numbers of offspring) to quality (‘K’ selection) of fewer offspring depending on ecological context. Namely, the latter higher quality route is used when there is a better diet with more nicotinamide – a defining feature of our history.^332,333

NAD and fertility

NAD itself when extracellular and working through adenosine diphosphate ribosylation of surface proteins such as CD38 and the ART2 and prinoreceptors can shape regulatory T cells and immune tolerance at times killing T cells and working on host-symbiont, host-tumour, and host-fetal interactions.^{152,313,314,334–340} NAD influences the endocrine system and oxytocin affecting social and sexual interactions.³⁴¹ Central oxytocin release through a NAD-CD38 pathway affects mating and social/sexual pair bonding, maternal nurturing, and therefore, chances of infant survival and their own later (parental) behaviour – let alone having peripheral effects on labour and lactation.^342–345 NAD consumers such as SIRTs are associated with the hypothalamic-pituitary-gonadotrophin and stress axis and developmental oocyte and spermatogenesis and with both male and female infertility.^346,347 SIRTs are involved as sensors and guardians of the redox state in the key issue of oocyte ageing and the natural decline in fertility with age ending with the menopause – given that ovarian lifespan is the main determinant of reproductive lifespan.^348,349 Poly (ADP-ribose) polymerases (PARPs) upregulated by oestrogen in the uterus have an important role in implantation of an embryo.^350,351

Dietary Aversions

Pregnancy dietary aversions are also of interest as the commonest single aversion is of animal products, particularly meat.³⁵¹ Morning sickness and meat aversion could during the first trimester affect the outcome of pregnancy and fertility rates. Cravings usually involve non-meat items and when they do involve animal products may be influenced by evolution having to balance the suppressed immunological needs of pregnancy with the nutritional needs of both the mother and the foetus if seriously deficient.^{318,352–355}

In summary, we therefore have biochemical mechanisms (there may be others such as the rise of polycystic ovary syndrome) whereby those on a low-nicotinamide diet could have a higher fertility due to lower chances of rejection at many stages of pregnancy (Figure 19). Clearly if taken too far to frank pellagra or starvation fertility falls – in the famine in 1940-1942 in occupied Athens for instance births declined by nearly 50% as it does in frank pellagrins.²⁶⁹

Figure 19.

High nicotinamide could influence fertility rates by various compounding mechanisms.

NAD, survival, and ageing

Fertility is a key issue in demographics but so is survival and ageing.³⁵⁶ Ageing, in general, as in oocytes in particular, have long been associated with declining mitochondrial function and free radical production.³⁵⁷ Pellagra caused premature death and premature ageing. Much recent research supports a major role for good mitochondrial function and the NAD-sirtuin axis in ageing. Dietary intake of nicotinamide, nicotinamide-riboside, and nicotinamide mononucleotide improves metabolic health and restores mitochondrial function whether measured by respiration, membrane potential, ATP production apoptosis, autophagy, or the unfolded response with less degeneration and more active stem cells.³⁵⁸ Supplementation works for genetic versions of premature ageing and defects in DNA repair with resulting SIRT inactivation. NAD levels decline with age in part due to diet and in part due to increased requirements to repair damage particularly to DNA, using PARPs.³⁵⁸ High nicotinamide in diet and therefore NAD levels reduces the need for symbionts and the risk of the relationship becoming dysbiotic and improves resistance to pathogens. All improve the chances of survival to older ages.³⁵⁹

Conclusions

Meat eating and high nicotinamide dose have been important throughout our evolution and may explain why when we are on an optimal diet, we have enough energy and the mechanisms to run big costly brains as well as high reproductive rates and long lives without always having to trade one off against the other.^360–362 Meat eating correlates with low fertility. This was true in the long pre-Neolithic and has remained a consistent trend in all the examples that we can find. With the exception of the pre-Neolithic when trauma (rather than disease) caused many deaths at all ages, high meat eating also correlates with physical and mental health and longevity, the other main driver of population growth.

We have drawn attention to a biochemical mechanism whereby high nicotinamide in diet switches off the ‘de novo’ pathway stopping in-house production of nicotinamide from tryptophan and causing immune intolerance, including of the foetus and dietary-induced infertility (Figure 19). The population explosion related to the Neolithic agricultural revolution and lower meat and higher cereal diets and high fertility was just the first example of this commonplace and causative correlation that continues to this day³⁶³. High fertility and enlarging populations when nicotinamide dose is low had many advantages (at least in the past) but is traded off against poorer health with more chronic infections and lack of resistance to pathogens and reduced height and cognitive skills.³⁶⁴ Picking quantity or quality offspring to survive has depended on diet throughout our demographic history and remains the main driver of inequality between nations and individuals.^365,366

There is a general consensus that there are too many exceptions to link any one aspect of progress and social modernity such as educational or economic improvements or even birth control to be truly causative of the decline in fertility.³⁶⁷ The incontravertible law is that the mortality decrease happens first with the logical implication that the then apparently inevitable fall in fertility occurs by the same basic mechanism. We argue that modest improvements in home economics allows poor families to improve diet and they will prioritise spending on animal products (Engel’s law). An improved nicotinamide dose first decreases mortality from gut infections, TB, and classic pathogens, and then at a higher dose reduces fertility creating a natural lag responsible for the population increase. The length of the lag depends on whether the meat/nicotinamide supply continues to improve and at what tempo. Many propose increasing literacy and access to better birth control devices to speed demographic transitions. We argue that diet needs dealing with first and the rest will follow^367–369 (Figure 20 & 21).³⁷⁰

Figure 20.

A summary of the demographic effects of nicotinamide dose on fecundity Moderation works.

Figure 21.

Classic Malthusian trap and deadlock on low-nicotinamide diet. Malthusian escape on a moderate nicotinamide diet. Affluence trap on a high-nicotinamide diet – rise of fertility clinics and necessary immigration.

Such ‘Enlightenments’ that also come with scientific and technological change, democracy, and emancipation may always have related first to better diet not better institutions or markets.^367–370 Many think that our economic and intellectual breakthrough started in the period after the Black Death. Meat intake was high then fell but got a second wind after 1850. In contrast, other countries such as China had a much lower meat intake and although made promising scientific starts, and indeed may have been ahead for a while, never quite managed to pull off an early industrial or cultural revolutions or demographic transition.³⁷¹

Better diet with more meat/nicotinamide closer to our evolutionary norm helps cognition. The French anthropologist Lévi-Strauss commented that foods must be ‘good to think’ before they can be ‘good to eat’.^372,373 Usually, the emphasis has been on the social, symbolic, and cultural nature of our food-consuming behaviour – rarely positive in the case of meat eating. Meat eating as one gets richer is often seen as a penchant, or worse, for example gutting linked to, ‘demonic males’ or violence for violence’s sake rather than that there is a real ‘meat hunger’.³⁷⁴ Being in denial about our need for animal products and not accepting that ‘meat hunger’ is biological and not a matter of taste, or cultural history, or perversity, or to signal status/wealth/masculinity or our war-like nature does not help³⁷⁵.

Meat is expensive requiring many resources whether land, water, or grain affecting the ‘green-house’ effect, so increasing meat in diet looks highly counter-intuitive on a sustainability agenda given its ecological ‘hoofprint’.^376–378 Traditional farming for animal husbandry used grassland not suitable for crops.³⁷⁹ Those days are being re-visited as part of value ‘farm to fork’ local chains, but other technologies need to be developed. Agroecology is an established field and aims to nourish not just feed populations on evidence-based rather than ideological grounds.³⁸⁰ This has to be better than driving a desperate market for bushmeat that is as damaging to forests as clearing them for agriculture – or one that leads to poor game management where human hunters eliminate all fauna larger than rats. Poverty is the biggest polluter borne out by Kuznets curves showing that as countries develop pollution increases but then decreases.³⁸¹

Re-distributing micronutrient supplements or preferably meat as a meat ‘entitlement’ would be a parallel approach. Clean water in countries in the past was introduced as an entitlement for rich and poor, not really from good social motives but because the poor were thought of as a source of typhoid and cholera: better food for the poor is not yet considered in the light of reducing risks for the rich but if it was, being a clear source of (emerging) infection or violence, this could provide the motivation to share more, as we did in our evolutionary past.³⁸² Mitigation of environmental effects could come from re-distribution of meat, eliminating the extremes, or advances in artificial meat production or other sources of animal protein not commonly used, such as insects.^383,384 Meat moderation and ‘flexitarian’ diets are, after all, a policy already followed by the ‘healthy-wealthy’ in a life cycle approach that should begin with concentrating on the first 1000 days of life - and may be both the healthiest and the one most likely to be environmentally and economically sustainable.^385–389 We make the case that history has taught us that a dietary approach modestly increasing animal products for the poor rather than cereal subsidies work and may be the necessary and sufficient approach to control population size and improve human capital even if there is a conceptual and political mountain to climb.³⁹⁰

Footnotes

Acknowledgements

A.C.W. would like to thank Mike Hammond and the Richardson family for their support and Robin Dunbar for earlier discussions.

Peer review:

Five peer reviewers contributed to the peer review report. Reviewers’ reports totalled 1091 words, excluding any confidential comments to the academic editor.

Funding:

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is funded by QEHB Charities.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

ACW and LJH analysed the data, agree with manuscript results and conclusions, and made critical revisions and approved final version. ACW wrote the first draft of the manuscript. LJH contributed to the writing of the manuscript.

References

Kaack

Katul

. Fifty years to prove Malthus right. Proc Natl Acad Sci U S A. 2013;110:4161–4162.

Nakamura

Bhatnagar

Sadoshima

. Overview of pyridine nucleotides review series. Circ Res. 2012;111:604–610.

Clutton-Brock

. Mammal Societies. Hoboken, NJ: Wiley; 2016.

Mayhew

. Malthus. Cambridge, MA: Harvard University Press; 2014.

Morowitz

. Energy Flow in Biology: Biological Organization as a Problem in Thermal Physics. Woodbridge, CT: Ox Bow Press; 1979.

Shipman

. Metabolism: totally addicted to NAD+. Nat Rev Cancer. 2016;16:70.

Cohen

. The Food Crisis in Prehistory: Overpopulation and the Origins of Agriculture. New Haven, CT: Yale University Press; 1977.

Leopold

. A Sand County Almanac, and Sketches Here and There. Oxford, UK: Oxford University Press; 1949.

Crosby

. The Columbian Exchange: Biological and Cultural Consequences of 1492. Westport, CT: Greenwood Publishing Group; 2003.

10.

McNeill

. The Human Web: A Bird’s-Eye View of World History. New York, NY: W.W. Norton; 2003.

11.

Acemoglu

Robinson

. Why Nations Fail: The Origins of Power, Prosperity and Poverty. London, England: Profile Books; 2012.

12.

Barnes

. Diseases and Human Evolution. Albuquerque, NM: University of New Mexico Press; 2007.

13.

Fernández-Armesto

Kulshrestha

. Food: A History. London, England: Macmillan; 2001.

14.

McMichael

. Climate Change and the Health of Nations. Oxford, UK: Oxford University Press; 2017.

15.

Nutrition and Metabolism . Hoboken, NJ: John Wiley & Sons; 2004.

16.

Cockburn

. The Evolution and Eradication of Infectious Diseases. Baltimore, MD: Johns Hopkins Press; 1963.

17.

Ewald

. Evolution of Infectious Disease. New York, NY: Oxford University Press; 1994.

18.

Abouheif

Zardoya

Meyer

. Limitations of metazoan 18S rRNA sequence data: implications for reconstructing a phylogeny of the animal kingdom and inferring the reality of the Cambrian explosion. J Mol Evol. 1998;47:394–405.

19.

Fox

. What sparked the Cambrian explosion? Nature. 2016;530:268–270.

20.

Mylenko

Boland

Penkov

. NAD+ is a food component that promotes exit from dauer diapause in Caenorhabditis elegans. PLoS ONE. 2016;11:e0167208.

21.

Crook

Mcreynolds

Wang

Hanna-Rose

. An NAD(+) biosynthetic pathway enzyme functions cell non-autonomously in C. elegans development. Dev Dyn. 2014;243:965–976.

22.

Schutt

. Eat Me: A Natural and Unnatural History of Cannibalism. London, England: Profile Books; 2017.

23.

Wray

. Molecular clocks and the early evolution of metazoan nervous systems. Phil Trans R Soc B. 2015;370:20150046.

24.

Brown

Prendergast

Swalla

. Man is but a worm: chordate origins. Genesis. 2008;46:605–613.

25.

Han

Morris

Shu

Huang

. Meiofaunal deuterostomes from the basal Cambrian of Shaanxi (China). Nature. 2017;542:228–231.

26.

Battistuzzi

Billing-Ross

Murillo

Filipski

Kumar

. A protocol for diagnosing the effect of calibration priors on posterior time estimates: a case study for the Cambrian explosion of animal Phyla. Mol Biol Evol. 2015;32:1907–1912.

27.

Bell

. Origin of metazoan phyla: Cambrian explosion or proterozoic slow burn? Trends Ecol Evol. 1997;12:1–2.

28.

Lane

. Power, Sex, Suicide: Mitochondria and the Meaning of Life. Oxford, UK: Oxford University Press; 2006.

29.

Lane

. Life Ascending: The Ten Great Inventions of Evolution. London, England: Profile Books; 2010.

30.

Thomas

. The breath of life – did increased oxygen levels trigger the Cambrian explosion? Trends Ecol Evol. 1997;12:44–45.

31.

Sulovari

Chen

Hudziak

. Atlas of human diseases influenced by genetic variants with extreme allele frequency differences. Hum Genet. 2017;136:39–54.

32.

Lane

. Bioenergetic constraints on the evolution of complex life. Cold Spring Harb Perspect Biol. 2014;6:a015982.

33.

Lane

Martin

. Eukaryotes really are special, and mitochondria are why. Proc Natl Acad Sci U S A. 2015;112:E4823.

34.

Brusatte

Luo

Z-X

. Ascent of the Mammals. Sci Am. 2016;314:28–35.

35.

Brusatte

Butler

Barrett

. The extinction of the dinosaurs. Biol Rev. 2015;90:628–642.

36.

McNally

Brown

Jackson

. Cooperation and the evolution of intelligence. Proc R Soc B: Biol Sci. 2012;279:3027–3034.

37.

Briggs

. The Cambrian explosion. Curr Biol. 2015;25:R864–R868.

38.

Dunbar

Shultz

. Evolution in the social brain. Science. 2007;317:1344–1347.

39.

van der Bijl

Kolm

. Why direct effects of predation complicate the social brain hypothesis. Bioessays. 2016;38:568–577.

40.

Leonard

Robertson

. Comparative primate energetics and hominid evolution. Am J Phys Anthropol. 1997;102:265–281.

41.

Isler

Van Schaik

. How our ancestors broke through the gray ceiling. Curr Anthropol. 2012;53:S453–S465.

42.

Sayol

Maspons

Lapiedra

Iwaniuk

Székely

Sol

. Environmental variation and the evolution of large brains in birds. Nat Commun. 2016;7.

43.

Stankowich

Romero

. The correlated evolution of antipredator defences and brain size in mammals [published online ahead of print January 11, 2017]. Proc R Soc B: Biol Sci. doi:10.1098/rspb.2016.1857

44.

Klein

. The Human Career: Human Biological and Cultural Origins. 3rd ed. Chicago, IL: University of Chicago Press; 2009.

45.

Grine

Fleagle

Leakey

. The First Humans: Origin and Early Evolution of the Genus Homo. Dordrecht, The Netherlands: Springer; 2009.

46.

Laird

Vogel

Pontzer

. Chewing efficiency and occlusal functional morphology in modern humans. J Hum Evol. 2016;93:1–11.

47.

Nowell

Davidson

. Stone Tools and the Evolution of Human Cognition. Boulder, CO: University Press of Colorado; 2010.

48.

Milton

. The critical role played by animal source foods in human (Homo) evolution. J Nutr. 2003;133:3886S–3892S.

49.

Pickering

. Rough and Tumble: Aggression, Hunting, and Human Evolution. Berkeley, CA: University of California Press. 2013.

50.

Maslin

. The Cradle of Humanity: How the Changing Landscape of Africa Made Us So Smart. Oxford, UK: Oxford University Press; 2017.

51.

Crittenden

Schnorr

. Current views on hunter-gatherer nutrition and the evolution of the human diet. Am J Phys Anthropol. 2017;162:84–109.

52.

Bowles

Gintis

. A Cooperative Species: Human Reciprocity and Its Evolution. Princeton, NJ: Princeton University Press; 2011.

53.

Ardrey

. The Hunting Hypothesis: A Personal Conclusion Concerning the Evolutionary Nature of Man. New York, NY: Fontana Press; 1977.

54.

Cornélio

de Bittencourt-Navarrete

de Bittencourt Brum

Queiroz

Costa

. Human brain expansion during evolution is independent of fire control and cooking. Front Neurosci. 2016;10:167.

55.

Hart

Sussman

. Man the Hunted: Primates, Predators, and Human Evolution. Expanded ed. Boulder, CO: Westview Press; 2008.

56.

Jones

. Feast: Why Humans Share Food. Oxford, UK: Oxford University Press; 2008.

57.

McCorriston

Harrower

Martin

Oches

. Cattle cults of the Arabian Neolithic and early territorial societies. Am Anthropol. 2012;114:45–63.

58.

Tattersall

. Masters of the Planet: The Search for Our Human Origins. New York, NY: St. Martin’s Press; 2012.

59.

Terborgh

Estes

. Trophic Cascades: Predators, Prey, and the Changing Dynamics of Nature. Washington, DC: Island Press; 2013.

60.

Marean

. The transition to foraging for dense and predictable resources and its impact on the evolution of modern humans [published online ahead of print June 13, 2016]. Proc R Soc B: Biol Sci. doi:10.1098/rstb.2015.0239

61.

Hublin

Richards

. The Evolution of Hominin Diets: Integrating Approaches to the Study of Palaeolithic Subsistence. Dordrecht, The Netherlands: Springer; 2009.

62.

Herculano-Houzel

. The Human Advantage: A New Understanding of How Our Brain Became Remarkable. Cambridge, MA: MIT Press; 2016.

63.

Wynn

Coolidge

. Archeological insights into hominin cognitive evolution. Evol Anthropol. 2016;25:200–213.

64.

. Comparative genomics reveals convergent evolution between the bamboo-eating giant and red pandas. Proc Natl Acad Sci U S A. 2017;114:1081–1086.

65.

Hohmann

Robbins

Boesch

. Feeding Ecology in Apes and Other Primates. Cambridge, UK: Cambridge University Press; 2012.

66.

Sussman

Tab Rasmussen

Raven

. Rethinking primate origins again. Am J Primatol. 2013;75:95–106.

67.

Smaers

Gómez-Robles

Parks

Sherwood

. Exceptional evolutionary expansion of prefrontal cortex in great apes and humans. Curr Biol. 2017;27:714–720.

68.

Lyras

Giannakopoulou

Kouvari

Papadopoulos

. Evolution of gyrification in carnivores. Brain Behav Evol. 2017;88:187–203.

69.

Gómez-Robles

Smaers

Holloway

Polly

Wood

. Brain enlargement and dental reduction were not linked in hominin evolution. Proc Natl Acad Sci U S A. 2017;201608798.

70.

Pontzer

Brown

Raichlen

. Metabolic acceleration and the evolution of human brain size and life history. Nature. 2016;533:390–392.

71.

Wroe

Field

Archer

. Climate change frames debate over the extinction of megafauna in Sahul (Pleistocene Australia-New Guinea). Proc Natl Acad Sci U S A. 2013;110:8777–8781.

72.

Willerslev

Davison

Moora

. Fifty thousand years of Arctic vegetation and megafaunal diet. Nature. 2014;506:47–51.

73.

Johnson

Earle

. The Evolution of Human Societies: From Foraging Group to Agrarian State. Stanford, CA: Stanford University Press; 2000.

74.

Harding

RSO

Teleki

. Omnivorous Primates: Gathering and Hunting in Human Evolution. New York, NY: Columbia University Press; 1981.

75.

Krebs

. The gourmet ape: evolution and human food preferences. Am J Clin Nutr. 2009;90:707S–711S.

76.

Allen

. The Omnivorous Mind: Our Evolving Relationship with Food. Cambridge, MA: Harvard University Press; 2012.

77.

Rindos

. The Origins of Agriculture: An Evolutionary Perspective. New York, NY: Academic Press; 1984.

78.

Marlowe

. The Hadza: Hunter-Gatherers of Tanzania. Berkeley, CA: University of California Press; 2010.

79.

Armelagos

. Brain evolution, the determinates of food choice, and the omnivore’s dilemma. Crit Rev Food Sci Nutr. 2014;54:1330–1341.

80.

Freedman

. Food: The History of Taste. Berkeley, CA: University of California Press; 2007.

81.

Levenstein

. Fear of Food: A History of Why We Worry about What We Eat. Chicago, IL: University of Chicago Press; 2012.

82.

Shepherd

. Neurogastronomy: How the Brain Creates Flavor and Why It Matters. New York, NY: Columbia University Press; 2013.

83.

Jackson

. Two evolutionary models for the interactions of dietary organic cyanogens, hemoglobins, and falciparum malaria. Am J Hum Biol. 2002;2:521–532.

84.

Danielson

. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab. 2002;3:561–597.

85.

Nebert

Wikvall

Miller

. Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci. 2013;368:20120431.

86.

Carmody

Weintraub

Wrangham

. Energetic consequences of thermal and nonthermal food processing. Proc Natl Acad Sci U S A. 2011;108:19199–19203.

87.

Tamang

Kailasapathy

. Fermented Foods and Beverages of the World. New York, NY: CRC Press; 2010.

88.

Carmody

Dannemann

Briggs

. Genetic evidence of human adaptation to a cooked diet. Genome Biol Evol. 2016;8:1091–1103.

89.

Ernst

Van Hiel

Depuydt

Boerjan

De Loof

Schoofs

. Epigenetics and locust life phase transitions. J Exp Biol. 2015;218:88–99.

90.

Kapheim

Rao

Yeoman

. Caste-specific differences in hindgut microbial communities of honey bees (Apis mellifera). PLoS ONE. 2015;10:e0123911.

91.

Strachecka

Olszewski

Bajda

Demetraki-Paleolog

. Natural larval diet differently influences the pattern of developmental changes in DNA 5-methylcytosine levels in Apis mellifera queens as compared with workers and drones. Biochemistry (Mosc). 2015;80:1019–1025.

92.

Kay

Zumbusch

Heinen

Marsh

Holway

. Nutrition and interference competition have interactive effects on the behavior and performance of Argentine ants. Ecology. 2010;91:57–64.

93.

Wilson

. The Domestication of the Human Species. New Haven, CT: Yale University Press; 1991.

94.

Perez

Postillone

Rindel

. Domestication and human demographic history in South America. Am J Phys Anthropol. 2017.

95.

Balick

Cox

. Plants, People, and Culture: The Science of Ethnobotany. New York, NY: Scientific American Library; 1997.

96.

Harlan

. Crops and Man. Madison, WI, USA: American Society of Agronomy & Crop Science Society of America; 1975.

97.

Harris

. What Have Plants Ever Done for Us? Western Civilization in Fifty Plants. Oxford, UK: Bodleian Library; 2015.

98.

Hodder

. The Domestication of Europe. London, England: Blackwell; 1990.

99.

Budiansky

. The Covenant of the Wild: Why Animals Chose Domestication. New York, NY: William Morrow; 1992.

100.

Larson

Piperno

Allaby

. Current perspectives and the future of domestication studies. Proc Natl Acad Sci U S A. 2014;111:6139–6146.

101.

Kurihara

. Umami the fifth basic taste: history of studies on receptor mechanisms and role as a food flavor. Biomed Res Int. 2015;2015:189402.

102.

Heiser

. Seed to Civilization: The Story of Food. Cambridge, MA: Harvard University Press; 1990.

103.

Cauvin

Watkins

. The Birth of the Gods and the Origins of Agriculture. Cambridge, UK: Cambridge University Press; 2000.

104.

Hsu

Harris

. Plants, Health And Healing: On the Interface of Ethnobotany and Medical Anthropology. Oxford, UK: Berghahn Books; 2012.

105.

Mazoyer

Roudart

Membrez

. A History of World Agriculture: From the Neolithic Age to the Current Crisis. London, England: Earthscan; 2006.

106.

Boyd

Richerson

. Culture and the Evolutionary Process. Chicago, IL: University of Chicago Press; 1988.

107.

Bednarik

. Doing with less: hominin brain atrophy. Homo. 2014;65:433–449.

108.

Henriksen

Johnsson

Andersson

Jensen

Wright

. The domesticated brain: genetics of brain mass and brain structure in an avian species. Sci Rep. 2016;6:34031.

109.

Arumugam

Raes

Pelletier

. Enterotypes of the human gut microbiome. Nature. 2011;473:174–180.

110.

Crockett

Clark

Hauser

Robbins

. Serotonin selectively influences moral judgment and behavior through effects on harm aversion. Proc Natl Acad Sci U S A. 2010;107:17433–17438.

111.

Cryan

. Microbial Endocrinology. Dordrecht, The Netherlands: Springer; 2014.

112.

Heijtz

Wang

Anuar

. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108:3047–3052.

113.

McAuliffe

. This Is Your Brain on Parasites: How Tiny Creatures Manipulate Our Behavior and Shape Society. Boston, MA: Houghton Mifflin Harcourt; 2016.

114.

Trammell

Brenner

. NNMT: a bad actor in fat makes good in liver. Cell Metab. 2015;22:200–201.

115.

Vickers

Breier

McCarthy

Gluckman

. Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am J Physiol Regul Integr Comp Physiol. 2003;285:R271–R273.

116.

Moeller

Caro-Quintero

Mjungu

. Cospeciation of gut microbiota with hominids. Science. 2016;353:380–382.

117.

Valle Gottlieb

Closs

Junges

Schwanke

CHA

. Impact of human aging and modern lifestyle on microbiota [published online ahead of print January 13, 2016]. Crit Rev Food Sci Nutr. doi:10.1080/10408398.2016.1269054

118.

Spencer

Zuk

. For host’s sake: the pluses of parasite preservation. Trends Ecol Evol. 2016;31:341–343.

119.

Start

Gilbert

. Host-parasitoid evolution in a metacommunity. Proc Biol Sci. 2016;283:20160477.

120.

Shah

. The Fever: How Malaria Has Ruled Humankind for 500,000 years. New York, NY: Farrar, Straus and Giroux; 2010.

121.

Brown

Inhorn

. The Anthropology of Infectious Disease: International Health Perspectives. Abingdon, UK: Taylor & Francis; 2013.

122.

Diamond

. COLLAPSE: How Societies Choose. New York, NY: Penguin Books; 2005.

123.

McAnany

Yoffee

. Questioning Collapse: Human Resilience, Ecological Vulnerability, and the Aftermath of Empire. Cambridge, UK: Cambridge University Press; 2009.

124.

Landry

. La révolution démographique:études et essais sur les problèmes de la population. Librairie du Recueil Sirey, société anonyme. Oxford, UK: Oxford, Blackwell publishing; 1934.

125.

Teitelbaum

. The British Fertility Decline: Demographic Transition in the Crucible of the Industrial Revolution. Princeton, NJ: Princeton University Press; 2014.

126.

Titmuss

. Parents Revolt: A Study of the Declining Birth-rate in Acquisitive Societies. London, England: Secker and Warburg; 1947.

127.

Caldwell

. Demographic Transition Theory. Dordrecht, The Netherlands: Springer; 2006.

128.

Demeny

McNicoll

. Encyclopedia of Population. New York, NY: Macmillan; 2003.

129.

Dyson

. Population and Development: The Demographic Transition. London, England: Zed Books; 2010.

130.

Hollingsworth

. Historical Demography. London, England: Hodder and Stoughton; 1969.

131.

Kirk

. Demographic transition theory. Pop Stud. 1986;50:361–387.

132.

Banks

. Prosperity and Parenthood: A Study of Family Planning Among the Victorian Middle Classes. London, England: Routledge & Kegan Paul; 1954.

133.

Soloway

. Demography and Degeneration: Eugenics and the Declining Birthrate in Twentieth-Century Britain. Chapel Hill, NC: University of North Carolina Press; 2014.

134.

Omran

. The epidemiologic transition theory. A preliminary update. J Trop Pediatr. 1983;29:305–316.

135.

Szreter

. The idea of demographic transition and the study of fertility change: a critical intellectual history. Popul Dev Rev. 1993;19:659–701.

136.

Doubleday

. The True Law of Population: Shewn to Be Connected With the Food of the People. London, England: Smith, Elder & Co.; 1853.

137.

Fraser

EDG

Rimas

. Empires of Food: Feast, Famine and the Rise and Fall of Civilizations. London, England: Arrow Books; 2011.

138.

Livi-Bacci

. Population and Nutrition: An Essay on European Demographic History. Cambridge, UK: Cambridge University Press; 1991.

139.

Ponting

. A New Green History of the World: The Environment and the Collapse of Great Civilizations. New York, NY: Random House; 2011.

140.

Rothman

Raubenheimer

Bryer

Takahashi

Gilbert

. Nutritional contributions of insects to primate diets: implications for primate evolution. J Hum Evol. 2014;71:59–69.

141.

Hulsken

Martin

Mohajeri

Homberg

. Food-derived serotonergic modulators: effects on mood and cognition. Nutr Res Rev. 2013;26:223–234.

142.

Lemieux

Cunningham

Lin

Mayer

Werb

Ashrafi

. Kynurenic acid is a nutritional cue that enables behavioral plasticity. Cell. 2015;160:119–131.

143.

Strasser

Gostner

Fuchs

. Mood, food, and cognition: role of tryptophan and serotonin. Curr Opin Clin Nutr Metab Care. 2016;19:55–61.

144.

Zhang

Smolik

Barba-Escobedo

. Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains. Neuropharmacology. 2015;90:1–8.

145.

Chini

Tarragó

Chini

. NAD and the aging process: role in life, death and everything in between [published online ahead of print November 5, 2016]. Mol Cell Endocrinol. doi:10.1016/j.mce.2016.11.003

146.

Guarente

. The resurgence of NAD+. Science. 2016;352:1396–1397.

147.

Pétriacq

Ton

Patrit

Gakiere

. NAD acts as an integral regulator of multiple defense layers. Plant Physiol. 2016;172:1465–1479.

148.

Preyat

Leo

. Reassessing the role of NAD as a prosurvival factor. Mol Cell Oncol. 2016;3:e1062591.

149.

Son

Kwon

Son

Cho

. Restoration of mitochondrial NAD+ levels delays stem cell senescence and facilitates reprogramming of aged somatic cells. Stem Cells. 2016;34:2840–2851.

150.

Sinclair

. Restoring stem cells – all you need is NAD+. Cell Res. 2016;26:971–972.

151.

Yin

Voorhees

Genova

. Acute axonal degeneration drives development of cognitive, motor, and visual deficits after blast-mediated traumatic brain injury in mice. Eneuro. 2016;3:ENEURO. 0220-16.2016.

152.

Montserrat-de

Paz

Naranjo

Lopez

Abia

Muriana

FJG

Bermudez

. Niacin and its metabolites as master regulators of macrophage activation. J Nutr Biochem. 2017;39:40–47.

153.

Bonkowski

Sinclair

. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016;17:679–690.

154.

Srivastava

. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clin Transl Med. 2016;5:25.

155.

Park

Long

Owens

Kristian

. Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol Dis. 2016;95:102–110.

156.

Isler

van Schaik

. The expensive brain: a framework for explaining evolutionary changes in brain size. J Hum Evol. 2009;57:392–400.

157.

Aiello

Wheeler

. The expensive-tissue hypothesis: the brain and the digestive system in human and primate evolution. Curr Anthropol. 1995;36:199–221.

158.

Navarrete

van Schaik

Isler

. Energetics and the evolution of human brain size. Nature. 2011;480:91–93.

159.

Isler

. Metabolic acceleration in human evolution. Cell Metab. 2016;24:5–6.

160.

Gibbons

. Why humans are the high-energy apes. Science. 2016;352:639.

161.

Harris

. Pellagra. BiblioBazaar. Los Angeles, USA: Hardpress; 2016.

162.

Niles

GMC

. Pellagra: An American Problem. Philadelphia, PA: W.B. Saunders Company; 1912.

163.

Williams

Ramsden

. Hydrogen symbioses in evolution and disease. QJM. 2007;100:451–459.

164.

Turnbull

. Mountain People. New York, NY: Simon & Schuster; 1987.

165.

Woodward

. The Medical and Surgical History of the War of the Rebellion, 1861–1865. Washington, DC: U.S. Government Printing Office; 1879.

166.

Daniels

. A Southerner Discovers the South. London, England: Macmillan; 1938.

167.

Rajakumar

. Pellagra in the United States: a historical perspective. South Med J. 2000;93:272–277.

168.

Elvehjem

Madden

Strong

Wolley

. The isolation and identification of the anti-black tongue factor. 1937. J Biol Chem. 2002;277:e22.

169.

Oppenheimer

. Eruptions That Shook the World. Cambridge, UK: Cambridge University Press; 2011.

170.

Perren

. The Meat Trade in Britain, 1840-1914. London, England: Routledge & Kegan Paul; 1978;

171.

Smil

. Eating meat: evolution, patterns. and consequences. Popul Dev Rev. 2002;28:599–639.

172.

Millstone

Lang

. The Atlas of Food Who Eats What, Where, and Why. London, England: Earthscan; 2008.

173.

Office of Population Censuses and Surveys. Updates. London: OPCS; 1995.

174.

Charlton

Murphy

. The Health of Adult Britain 1841-1994. London, UK: Stationery Office Books; 1997.

175.

Wrigley

Schofield

. The Population History of England 1541–1871. Cambridge, UK: Cambridge University Press; 1989.

176.

Lang

Rayner

. Ecological public health: the 21st century’s big idea? BMJ. 2012;345:17–20.

177.

Hardy

. Health and Medicine in Britain Since 1860. New York, NY: Palgrave Macmillan; 2001.

178.

Logan

WPD

. Mortality in England and Wales from 1848 to 1947: a survey of the changing causes of death during the past hundred years. Popul Stud. 1950;4:132–178.

179.

Greenwood

. Some British pioneers of social medicine. Br J Soc Med. 1948;2:74.

180.

Lynn

Meisenberg

Mikk

Williams

. National IQS predict differences in scholastic achievement in 67 countries. J Biosoc Sci. 2007;39:861–874.

181.

Agency

. The World Factbook 2014–15. Washington, DC: U.S. Government Printing Office; 2015.

182.

Pritchard

Ortiz

Shekar

. Routledge Handbook of Food and Nutrition Security. Abingdon, UK: Taylor & Francis; 2016.

183.

Kelly

. The Lifeways of Hunter-Gatherers: The Foraging Spectrum. Cambridge, UK: Cambridge University Press; 2013.

184.

Scott

Duncan

. Demography and Nutrition: Evidence from Historical and Contemporary Populations. Hoboken, NJ: John Wiley & Sons; 2008.

185.

Kiple

. The Cambridge World History of Food: 2. Cambridge, UK: Cambridge University Press; 2000.

186.

Bettinger

. Hunter-Gatherer Foraging: Five Simple Models. Clinton Corners, NY: Eliot Werner Publications; 2009.

187.

Betzig

. Eusociality: from the first foragers to the first states. Introduction to the special issue. Hum Nat. 2014;25:1–5.

188.

Childe

. Man Makes Himself. London, England: Watts; 1936.

189.

Clutton-Brock

. Animals as Domesticates: A World View Through History. East Lansing, MI: Michigan State University Press; 2012.

190.

Clutton-Brock

. The Walking Larder: Patterns of Domestication, Pastoralism, and Predation. Abingdon, UK: Taylor & Francis; 2014.

191.

O’Connor

. Animals as Neighbors: The Past and Present of Commensal Animals. East Lansing, MI: Michigan State University Press; 2014.

192.

Zeuner

. A History of Domesticated Animals. London, England: Hutchinson; 1963.

193.

Armstrong

. How the Earth Turned Green: A Brief 3.8-Billion-Year History of Plants. Chicago, IL: University of Chicago Press; 2014.

194.

Atkins

Bowler

. Food in Society: Economy, Culture, Geography. London, England: Arnold; 2001.

195.

Brothwell

. Food in Antiquity: A Survey of the Diet of Early Peoples. Baltimore, MD: Johns Hopkins University Press; 1969.

196.

Grigg

. The Agricultural Systems of the World: An Evolutionary Approach. Cambridge, UK: Cambridge University Press; 1974.

197.

Murphy

. People, Plants & Genes: The Story of Crops and Humanity. Oxford, UK: Oxford University Press; 2007.

198.

Bocquet-Appel

Bar-Yosef

. The Neolithic Demographic Transition and Its Consequences. Dordrecht, The Netherlands: Springer; 2008.

199.

Thorpe

. The Origins of Agriculture in Europe. Abingdon, UK: Taylor & Francis; 2003.

200.

Llamas

Willerslev

Orlando

. Human evolution: a tale from ancient genomes. Phil Trans R Soc B. 2017;372:20150484.

201.

Sanders

Reddy

. Nutritional implications of a meatless diet. Proc Nutr Soc; 1994;53:297–307.

202.

Sauer

. Agricultural Origins and Dispersals – Primary Source Edition. Charleston, USA: BiblioLife; 2014.

203.

Wells

. Prehistoric and historical changes in nutritional diseases and associated conditions. Prog Food Nutr Sci. 1975;1:729–779.

204.

Wells

. Pandora’s Seed: The Unforeseen Cost of Civilization. New York, NY: Penguin Books; 2011.

205.

Gignoux

Henn

Mountain

. Rapid, global demographic expansions after the origins of agriculture. Proc Natl Acad Sci U S A. 2011;108:6044–6049.

206.

Warinner

Rodrigues

JFM

Vyas

. Pathogens and host immunity in the ancient human oral cavity. Nat Genet. 2014;46:336–344.

207.

Webb

. Palaeopathology of Aboriginal Australians: Health and Disease Across a Hunter-Gatherer Continent. Cambridge, UK: Cambridge University Press; 2009.

208.

Aufderheide

Rodríguez-Martín

Langsjoen

. The Cambridge Encyclopedia of Human Paleopathology. Cambridge, UK: Cambridge University Press; 1998.

209.

Bourke

AFG

. Principles of Social Evolution. Oxford, UK: Oxford University Press; 2011.

210.

Zohary

Hopf

Weiss

. Domestication of Plants in the Old World: The Origin and Spread of Domesticated Plants in Southwest Asia, Europe, and the Mediterranean Basin. Oxford, UK: Oxford University Press; 2012.

211.

Cavalli-Sforza

. The Great Human Diasporas: The History of Diversity and Evolution. New York, NY: Addison-Wesley; 1995.

212.

Brown

. The Rise of Western Christendom: Triumph and Diversity, A.D. 200–1000. Hoboken, NJ: Wiley; 2012.

213.

Heather

. The Fall of the Roman Empire: A New History of Rome and the Barbarians. Oxford, UK: Oxford University Press; 2005.

214.

Hornblower

Spawforth

. The Oxford Companion to Classical Civilization. Oxford, UK: Oxford University Press; 1998.

215.

Little

. Plague and the End of Antiquity: The Pandemic of 541–750. Cambridge, UK: Cambridge University Press; 2007.

216.

Mitchell

. A History of the Later Roman Empire, AD 284–641. Hoboken, NJ: Wiley; 2014.

217.

Sarris

. Empires of Faith: The Fall of Rome to the Rise of Islam, 500–700. Oxford, UK: Oxford University Press; 2011.

218.

van Bath

. The Agrarian History of Western Europe, A.D. 500-1850. London, England: Arnold; 1963.

219.

Wickham

. Framing the Early Middle Ages: Europe and the Mediterranean, 400–800. Oxford, UK: Oxford University Press; 2006.

220.

DeMolen

Herlihy

. One thousand years; Western Europe in the Middle Ages. Boston, MA: Houghton Mifflin Harcourt; 1974.

221.

Wilkinson

. The Rise and Fall of Ancient Egypt. London, England: Bloomsbury Publishing; 2013.

222.

Finlay

. Greece Under the Rome. London, England: J.M. Dent & Sons; 1907.

223.

Darby

. Domesday England. Cambridge, UK: Cambridge University Press; 1986.

224.

Abel

. Agricultural Fluctuations in Europe: From the Thirteenth to the Twentieth Centuries. London, England: Methuen; 1935.

225.

Moote

. The Great Plague: The Story of London’s Most Deadly Year. Baltimore, MD: Johns Hopkins University Press; 2008.

226.

Cohn

. The Black Death Transformed: Disease and Culture in Early Renaissance Europe. New York, NY: Bloomsbury Academic; 2003.

227.

Cantor

. In the Wake of the Plague: The Black Death and the World It Made. New York, NY: Simon & Schuster; 2015.

228.

Slack

. The Impact of Plague in Tudor and Stuart England. London, England: Routledge & Kegan Paul; 1985.

229.

Dyer

. Standards of Living in the Later Middle Ages: Social Change in England C.1200–1520. Cambridge, UK: Cambridge University Press; 1989.

230.

Jordan

. The Great Famine: Northern Europe in the Early Fourteenth Century. Princeton, NJ: Princeton University Press; 1997.

231.

Lamb

. Climate, History and the Modern World. London, England: Routledge; 1995.

232.

Herlihy

Cohn

. The Black Death and the Transformation of the West. Cambridge, MA: Harvard University Press; 1997.

233.

Ziegler

. The Black Death. Boston, MA: Faber & Faber; 2013.

234.

Zinsser

. Rats, Lice and History. Boston, MA: Little Brown; 1934.

235.

Freeman

. The Black Death: History’s Most Effective Killer. CreateSpace Independent Publishing Platform; New York, USA: Hourly History; 2016.

236.

Horrox

. The Black Death. Manchester, UK: Manchester University Press; 1994.

237.

Ashworth

. An Economic History of England 1870–1939. Abingdon, UK: Taylor & Francis; 2013.

238.

Dillehay

. From Foraging to Farming in the Andes: New Perspectives on Food Production and Social Organization. Cambridge, UK: Cambridge University Press; 2011.

239.

Fussell

. The Story of Corn. Albuquerque, NM: University of New Mexico Press; 1992.

240.

Gill

. The Great Maya Droughts: Water, Life, and Death. Albuquerque, NM: University of New Mexico Press; 2000.

241.

Black

. Psychopathic Cultures and Toxic Empires. Books Noir, Limited; Scotland: Frontline Noir; 2015.

242.

Schultes

Raffauf

. The Healing Forest: Medicinal and Toxic Plants of the Northwest Amazonia. Portland, OR: Dioscorides Press; 1990.

243.

Bollwerk

Tushingham

. Perspectives on the Archaeology of Pipes, Tobacco and other Smoke Plants in the Ancient Americas. Dordrecht, The Netherlands: Springer; 2015.

244.

Furst

. Hallucinogens and Culture. San Francisco, CA: Chandler & Sharp; 1976.

245.

Wilbert

. Tobacco and Shamanism in South America. New Haven, CT: Yale University Press; 1993.

246.

Culbert

. The Classic Maya Collapse. Albuquerque, NM: University of New Mexico Press; 1983.

247.

Demarest

. Ancient Maya: The Rise and Fall of a Rainforest Civilization. Cambridge, UK: Cambridge University Press; 2004.

248.

Fernández-Armesto

. The Americas: A Hemispheric History. New York, NY: Modern Library; 2006.

249.

Buikstra

. Prehistoric Tuberculosis in the Americas. Northwestern University Archeological Program. IL, USA: Center for Amer Archeology Pr; 1981.

250.

Grob

. The Deadly Truth: A History of Disease in America. Cambridge, MA: Harvard University Press; 2009.

251.

Bremmer

. The Strange World of Human Sacrifice. Belgium: Peeters; 2007.

252.

Carrasco

. City of Sacrifice: The Aztec Empire and the Role of Violence in Civilization. Boston, MA: Beacon Press; 1999.

253.

Allen

. The British Industrial Revolution in Global Perspective: How Commerce Created the Industrial Revolution and Modern Economic Growth. Oxford, UK: Oxford University Press; 2006.

254.

Braudel

. Capitalism and Material Life, 1400-1800. London, England: Fontana; 1974.

255.

Pomeranz

. The Great Divergence: China, Europe, and the Making of the Modern World Economy. Princeton, NJ: Princeton University Press; 2009.

256.

Berg

Muscat

. The Nutrition Factor: Its Role in National Development [By] Alan Berg (Portions With Robert J. Muscat). Washington, DC: Brookings Institution; 1973.

257.

Drummond

Wilbraham

. The Englishman’s Food; Five Centuries of English Diet. London, England: Pimlico; 1957.

258.

Ferguson

. Empire: How Britain Made the Modern World. London, England: Allen Lane; 2003.

259.

Bennett

Peirce

. Change in the American national diet, 1879-1959. Food Res I Stud. 1961;2:95–119.

260.

Preston

Haines

. Fatal Years: Child Mortality in Late Nineteenth-Century America. Princeton, NJ: Princeton University Press; 2014.

261.

Carrasco

. The History of the Conquest of New Spain by Bernal Diaz del Castillo. Albuquerque, NM: University of New Mexico Press; 2009.

262.

Castillo

Cohen

. The Conquest of New Spain. New York, NY: Penguin Books; 2003.

263.

Cook

. Demographic Collapse: Indian Peru, 1520–1620. Cambridge, UK: Cambridge University Press; 1981.

264.

Earle

. The Body of the Conquistador: Food, Race and the Colonial Experience in Spanish America, 1492–1700. Cambridge, UK: Cambridge University Press; 2012.

265.

Melville

. A Plague of Sheep: Environmental Consequences of the Conquest of Mexico. Cambridge, UK: Cambridge University Press; 1997.

266.

Bryan

Mull

. Pellagra Pre-Goldberger: Rupert Blue, Fleming Sandwith, and The ‘Vitamine Hypothesis’. Trans Am Clin Climatol Assoc. 2015;126:20–45.

267.

Flenley

Bahn

. The Enigmas of Easter Island. Oxford, UK: Oxford University Press; 2003.

268.

Goss

Tabima

Cooke

. The Irish potato famine pathogen Phytophthora infestans originated in central Mexico rather than the Andes. Proc Natl Acad Sci U S A. 2014;111:8791–8796.

269.

Gráda

CÓ

. Famine: A Short History. Princeton, NJ: Princeton University Press; 2009.

270.

Foster

. Modern Ireland, 1600–1972. New York, NY: Penguin Books; 1989.

271.

Bollet

. Plagues & Poxes: The Impact of Human History on Epidemic Disease. Dordrecht, The Netherlands: Springer; 2004.

272.

. Studies on the Population of China, 1368–1953. Cambridge, MA: Harvard University Press; 1959.

273.

Dikötter

. Mao’s Great Famine: The History of China’s Most Devastating Catastrophe, 1958-62. London, England: Bloomsbury Publishing; 2010.

274.

Canning

Raja

Yazbeck

. Africa’s Demographic Transition: Dividend Or Disaster? Washington, DC: World Bank Publications; 2015.

275.

Daunton

. Progress and Poverty: An Economic and Social History of Britain, 1700-1850. Oxford, UK: Oxford University Press; 1995.

276.

Caballero

Popkin

. The Nutrition Transition: Diet and Disease in the Developing World. New York, NY: Academic Press; 2002.

277.

Roeder

Mariner

Kock

. Rinderpest: the veterinary perspective on eradication. Phil Trans R Soc B. 2013;368:20120139.

278.

Krafsur

. Tsetse flies: genetics, evolution, and role as vectors. Infect Genet Evol. 2009;9:124–141.

279.

Simo

Njiokou

Mbida

. Tsetse fly host preference from sleeping sickness foci in Cameroon: epidemiological implications. Infect Genet Evol. 2008;8:34–39.

280.

Ilemobade

. Tsetse and trypanosomosis in Africa: the challenges, the opportunities. Onderstepoort J Vet Res. 2009;76:35–40.

281.

Nash

TAM

. Africa’s Bane: The Tsetse Fly. London, England: Collins; 1969.

282.

Zerez

Tanaka

. Impaired erythrocyte NAD synthesis: a metabolic abnormality in thalassemia. Am J Hematol. 1989;32:1–7.

283.

Mesquita

Varela

Belinha

. Exploring NAD+ metabolism in host-pathogen interactions. Cell Mol Life Sci. 2016;73:1225–1236.

284.

O’Hara

Kerwin

Cobbold

. Targeting NAD+ metabolism in the human malaria parasite Plasmodium falciparum. PLoS ONE. 2014;9:e94061.

285.

Perry

. Parasites and human evolution. Evol Anthropol. 2014;23:218–228.

286.

Sabbatani

Manfredi

Fiorino

. Malaria infection and human evolution. Infez Med. 2010;18:56–74.

287.

Loy

Liu

. Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Int J Parasitol. 2017;47:87–97.

288.

van Zwieten

Verhoeven

Roos

. Inborn defects in the antioxidant systems of human red blood cells. Free Radic Biol Med. 2014;67:377–386.

289.

Magnani

Stocchi

Canestrari

. Redox and energetic state of red blood cells in G6PD deficiency, heterozygous beta-thalassemia and the combination of both. Acta Haematol. 1986;75:211–214.

290.

Kiple

. The Cambridge World History of Human Disease. Cambridge, UK: Cambridge University Press; 1999.

291.

Warman

. Corn & Capitalism: How a Botanical Bastard Grew to Global Dominance. Chapel Hill, NC: University of North Carolina Press; 2003.

292.

Fanelli

. Asymmetric Demography and the Global Economy: Growth Opportunities and Macroeconomic Challenges in an Ageing World. New York, NY: Palgrave Macmillan; 2015.

293.

Davis

. Late Victorian Holocausts: El Niño Famines and the Making of the Third World. London, England: Verso Books; 2002.

294.

Collier

. The Bottom Billion: Why the Poorest Countries are Failing and What Can Be Done About It. Oxford, UK: Oxford University Press; 2007.

295.

Floud

Humphries

Johnson

PAJ

. The Cambridge Economic History of Modern Britain. Cambridge, UK: Cambridge University Press; 2014.

296.

Goldstone

Kaufmann

Toft

. Political Demography: How Population Changes Are Reshaping International Security and National Politics. New York, NY: Oxford University Press; 2012.

297.

Jaronen

Quintana

. Immunological relevance of the coevolution of IDO1 and AHR. Front Immunol. 2014;5:521.

298.

Katz

Muller

Prendergast

. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206–221.

299.

Breda

Sathyasaikumar

Sograte Idrissi

. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites. Proc Natl Acad Sci U S A. 2016;113:5435–5440.

300.

Engin

. Tryptophan Metabolism: Implications for Biological Processes, Health and Disease. Dordrecht, The Netherlands: Springer; 2015.

301.

Yeung

Terentis

King

Thomas

. Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci (Lond). 2015;129:601–672.

302.

Bessede

Gargaro

Pallotta

. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature. 2014;511:184–190.

303.

Adar

Grisaru-Granovsky

Ben Ya’acov

Goldin

Bar-Gil Shitrit

. Pregnancy and the immune system: general overview and the gastroenterological perspective. Dig Dis Sci. 2015;60:2581–2589.

304.

Badawy

. Tryptophan metabolism, disposition and utilization in pregnancy. Biosci Rep. 2015;35:e00261.

305.

Liu

Tian

Xie

Zhang

Liu

Yang

. Fyn plays a pivotal role in fetomaternal tolerance through regulation of Th17 cells. Am J Reprod Immunol. 2016;75:569–579.

306.

Gobert

Lafaille

. Maternal-fetal immune tolerance, block by block. Cell. 2012;150:7–9.

307.

Mellor

Munn

. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20:469–473.

308.

Mellor

Munn

. Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. J Rreprod Immunol. 2001;52:5–13.

309.

Mellor

Sivakumar

Chandler

. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol. 2001;2:64–68.

310.

Munn

Zhou

Attwood

. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–1193.

311.

Nilsen

Bjørke-Monsen

Midttun

. Maternal tryptophan and kynurenine pathway metabolites and risk of preeclampsia. Obstet Gynecol. 2012;119:1243–1250.

312.

Bongaarts

Potter

. Fertility, Biology, and Behavior: An Analysis of the Proximate Determinants. London, England: Elsevier Science; 2013.

313.

Zong

Luo

. Dysregulated expression of IDO may cause unexplained recurrent spontaneous abortion through suppression of trophoblast cell proliferation and migration. Sci Rep. 2016;6:19916.

314.

Routy

Graziani

Mehraj

. The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer: implications for immunotherapy. IJTR. 2016;9:67–77.

315.

Sperber

Mathieu

Wang

. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nature Cell Biology. 2015;17:1523–1535.

316.

Mor

Kwon

. Trophoblast-microbiome interaction: a new paradigm on immune regulation. Am J Obstet Gynecol. 2015;213:S131–S137.

317.

Barnea

Almogi-Hazan

. Immune regulatory and neuroprotective properties of preimplantation factor: from newborn to adult. Pharmacol Ther. 2015;156:10–25.

318.

Fushima

Oyanagi

. Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia. Proc Natl Acad Sci U S A. 2016;201614947.

319.

Lash

Ernerudh

. Decidual cytokines and pregnancy complications: focus on spontaneous miscarriage. J Reprod Immunol. 2015;108:83–89.

320.

Maklakov

Hall

Simpson

. Sex differences in nutrient-dependent reproductive ageing. Aging Cell. 2009;8:324–330.

321.

Solon-Biet

Walters

Simanainen

. Macronutrient balance, reproductive function, and lifespan in aging mice. Proc Natl Acad Sci U S A. 2015;112:3481–3486.

322.

Simpson

Le Couteur

Raubenheimer

. Putting the balance back in diet. Cell. 2015;161:18–23.

323.

Han

Dingemanse

. You are what you eat: diet shapes body composition, personality and behavioural stability. BMC Evol Biol. 2017;17:8.

324.

D’Ippolito

Tersigni

Marana

. Inflammosome in the human endometrium: further step in the evaluation of the ‘maternal side’. Fertil Steril. 2016;105:111–118.e1-4.

325.

Di Simone

. Insights into the role of Helicobacter pylori infection in preeclampsia: from the bench to the bedside. Immun Interact Reprod Cycle. 2015. https://doi.org/10.3389/fimmu.2014.00484.

326.

Tersigni

Castellani

De Waure

. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update. 2014;20:582–593.

327.

Karayiannis

Kontogianni

Mendorou

Douka

Mastrominas

Yiannakouris

. Association between adherence to the Mediterranean diet and semen quality parameters in male partners of couples attempting fertility. Hum Reprod. 2016;32:215–222.

328.

Riley

Jungheim

. Is there a role for diet in ameliorating the reproductive sequelae associated with chronic low-grade inflammation in polycystic ovary syndrome and obesity? Fertil Steril. 2016;106:520–527.

329.

Chiu

Afeiche

Gaskins

. Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men. Hum Reprod. 2014;29:1575–1584.

330.

Gaskins

Colaci

Mendiola

Swan

Chavarro

. Dietary patterns and semen quality in young men. Hum Reprod. 2012;27:2899–2907.

331.

Pearce

Tremellen

. Influence of nutrition on the decline of ovarian reserve and subsequent onset of natural menopause. Hum Fertil. 2016;19:173–179.

332.

Stearns

. The Evolution of Life Histories. Oxford, UK: Oxford University Press; 1992.

333.

Charnov

Berrigan

. Why do female primates have such long lifespans and so few babies? Or life in the slow lane. Evol Anthropol. 1993;1:191–194.

334.

Grahnert

Klein

Schilling

Wehrhahn

Hauschildt

. Review: NAD+: a modulator of immune functions. Innate Immun. 2011;17:212–233.

335.

Hubert

Rissiek

Klages

. Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. J Exp Med. 2010;207:2561–2568.

336.

Zhou

. SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling. J Ovarian Res. 2014;7:97.

337.

Marino

Paster

Benichou

. Allorecognition by T lymphocytes and allograft rejection. Front Immunol. 2016;7:582.

338.

Vasiljevic

Poreau

Bouvier

. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and recurrent intrauterine fetal death. Lancet. 2015;385:2120.

339.

Fushima

Sekimoto

. Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure. Am J Physiol: Renal. 2016;312:F366–F372.

340.

Tissier

Handrich

Dallongeville

Robin

J-P

Habold

. Diets derived from maize monoculture cause maternal infanticides in the endangered European hamster due to a vitamin B3 deficiency [published online ahead of print January 18, 2017]. Proc R Soc B: Biol Sci. doi:10.1098/rspb.2016.2168

341.

Bartz

McInnes

. CD38 regulates oxytocin secretion and complex social behavior. Bioessays. 2007;29:837–841.

342.

Feldman

Monakhov

Pratt

Ebstein

. Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol Psychiatry. 2016;79:174–184.

343.

Garten

Schuster

Penke

Gorski

de Giorgis

Kiess

. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol. 2015;11:535–546.

344.

Krol

Monakhov

Lai

Ebstein

Grossmann

. Genetic variation in CD38 and breastfeeding experience interact to impact infants’ attention to social eye cues. Proc Natl Acad Sci U S A. 2015;112:E5434–E5442.

345.

Young

. Regulating the social brain: a new role for CD38. Neuron. 2007;54:353–356.

346.

Bell

Nagamori

Williams

. SirT1 is required in the male germ cell for differentiation and fecundity in mice. Development. 2014;141:3495–3504.

347.

Nair

Verma

Singh

. Immune-endocrine crosstalk during pregnancy. Gen Comp Endocrinol. 2016;242:18–23.

348.

Porter

Babbar

Maulik

. The role of nicotinamide phosphoribosyltransferase in pregnancy: a review. Am J Perinatol. 2016;33:1327–1336.

349.

Tatone

Di Emidio

Vitti

. Sirtuin functions in female fertility: possible role in oxidative stress and aging. Oxid Med Cell Longev. 2015;2015:659687.

350.

Joshi

Mahfooz

Maurya

. PARP1 during embryo implantation and its upregulation by oestradiol in mice. Reproduction. 2014;147:765–780.

351.

Fessler

. Reproductive immunosupression and diet. An evolutionary perspective on pregnancy sickness and meat consumption. Curr Anthropol. 2002;43:19–61.

352.

Belzer

Smulian

Tepper

. Food cravings and intake of sweet foods in healthy pregnancy and mild gestational diabetes mellitus. A prospective study. Appetite. 2010;55:609–615.

353.

Cardwell

. Pregnancy sickness: a biopsychological perspective. Obstet Gynecol Surv. 2012;67:645–652.

354.

Hill

Cairnduff

McCance

. Nutritional and clinical associations of food cravings in pregnancy. J Hum Nutr Diet. 2015;29:281–289.

355.

McKerracher

Collard

Henrich

. Food aversions and cravings during pregnancy on Yasawa Island, Fiji. Hum Nat. 2016;27:296–315.

356.

Riley

. Rising Life Expectancy: A Global History. Cambridge, UK: Cambridge University Press; 2001.

357.

James

Lane

Michalek

Karoly

Parkinson

. Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD+ and nicotinamide metabolism. Sci Rep. 2016;6:38489.

358.

Bennett

Kaeberlein

. The mitochondrial unfolded protein response and increased longevity: cause, consequence, or correlation? Exp Gerontol. 2014;56:142–146.

359.

Bjedov

Partridge

. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans. 2011;39:460–465.

360.

Fogel

. The Escape From Hunger and Premature Death, 1700–2100: Europe, America, and the Third World. Cambridge, UK: Cambridge University Press; 2004.

361.

Karlen

. Man and Microbes: Disease and Plagues in History and Modern Times. New York, NY: Simon & Schuster; 1996.

362.

Mercer

. Infections, Chronic Disease, and the Epidemiological Transition: A New Perspective. Rochester, NY: University of Rochester Press; 2014.

363.

Lutz

Butz

Samir

. World Population and Human Capital in the Twenty-First Century. Oxford, UK: Oxford University Press; 2014.

364.

Lynn

. Race Differences in Intelligence: An Evolutionary Analysis. Athens, Greece: Washington Summit Books; 2006.

365.

Bailey

West

Jr Black

. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015;66:22–33.

366.

Marmot

. The Health Gap: The Challenge of an Unequal World. London, England: Bloomsbury Publishing; 2015.

367.

Boulding

. The Meaning of the Twentieth Century: The Great Transition. New York, NY: Harper & Row; 1964.

368.

Bengtsson

Campbell

Lee

. Life Under Pressure: Mortality and Living Standards in Europe and Asia, 1700–1900. Cambridge, MA: MIT Press; 2009.

369.

Mokyr

. A Culture of Growth: The Origins of the Modern Economy. Princeton, NJ: Princeton University Press; 2016.

370.

Athanasiou

. Divided Planet: The Ecology of Rich and Poor. Athens, GA: University of Georgia Press; 1998.

371.

Needham

. The Grand Titration: Science and Society in East and West. London, England: Routledge; 2013.

372.

Baggini

. The Virtues of the Table: How to Eat and Think. London, England: Granta Publications; 2014.

373.

Lévi-Strauss

. Des Symboles et leurs doubles. Paris: Plon; 1989.

374.

Wrangham

Peterson

. Demonic Males: Apes and the Origins of Human Violence. Boston, MA: Houghton Mifflin Harcourt; 1996.

375.

Sahn

. The Fight Against Hunger and Malnutrition: The Role of Food, Agriculture, and Targeted Policies. Oxford, UK: Oxford University Press; 2015.

376.

D’Silva

Webster

. The Meat Crisis: Developing More Sustainable Production and Consumption. London, England: Earthscan; 2010.

377.

Friel

Dangour

Garnett

. Public health benefits of strategies to reduce greenhouse-gas emissions: food and agriculture. Lancet. 374:2016–2025.

378.

McMichael

Powles

Butler

Uauy

. Food, livestock production, energy, climate change, and health. Lancet. 2007;370:1253–1263.

379.

Alexandratos

Bruinsma

. World agriculture towards 2030/2050: the 2012 revision. ESA Working paper Rome, FAO. http://www.fao.org/docrep/016/ap106e/ap106e.pdf. Published 2012.

380.

Anderson

. Globalization’s effects on world agricultural trade, 1960–2050. Proc R Soc B: Biol Sci. 2010;365:3007–3021.

381.

Lorente

Alvarez-Herranz

. Economic growth and energy regulation in the environmental Kuznets curve. Environ Sci Pollut Res Int. 2016;23:16478–16494.

382.

Troesken

. Water, Race, and Disease. Cambridge, MA: MIT Press; 2004.

383.

Brunori

Galli

Barjolle

. Are local food chains more sustainable than global food chains? considerations for assessment. Sustainability. 2016;8:449.

384.

Global Panel on Agriculture and Food Systems for Nutrition. Food Systems and Diets: Facing the Challenges of the 21st Century. London, UK: Global Panel on Agriculture and Food Systems for Nutrition; 2016.

385.

Black

Victora

Walker

. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013;382:427–451.

386.

Bhutta

Das

Rizvi

. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382:452–477.

387.

Agus

. The Lucky Years: How to Thrive in the Brave New World of Health. New York, NY: Simon & Schuster; 2016.

388.

Acharya

Fanzo

Gustafson

. Assessing sustainable nutrition security: the role of food systems. Washington, DC. http://ilsirf.org/wp-content/uploads/sites/5/2016/07/2014_Acharya_et_al-SNS.pdf. Published 2014.

389.

Bucher

Collins

Rollo

. Nudging consumers towards healthier choices: a systematic review of positional influences on food choice. Br J Nutr. 2016;115:2252–2263.

390.

May

. World Population Policies: Their Origin, Evolution, and Impact. Dordrecht, The Netherlands: Springer; 2012.

Meat and Nicotinamide: A Causal Role in Human Evolution,History,and Demographics

Abstract

Keywords

Introduction

Meat, NAD, and the Cambrian

Meat, NAD, and Human Evolution

Omnivorous man

Plant and animal cultivation

Demographic Transitions

Meat – The Key Ingredient is Nicotinamide

Lessons From Pellagra – The Forgotten Meat Deficiency State

1850 – UK Data

Methods

Sources for data

Statistics

Results

Hunter-gatherer times

Neolithic agricultural revolution

Roman empire to the middle ages: decline and fall – of fertility

Domesday Book to Black Death and its aftermath

Geographic variation: the New World

The great divergence and enrichment: the smart European ‘Miracle’

The Columbian Exchange

Easter Island

Ireland

China

1950

Correlation to mechanism: the nicotinamide/tryptophan/kynurenine immune tolerance pathway and fertility – maternal acceptance of the foetus

NAD and fertility

Dietary Aversions

NAD, survival, and ageing

Conclusions

Footnotes

Acknowledgements

Peer review:

Funding:

Declaration of conflicting interests:

Author Contributions

References