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Evolution of skin colour in different human populations Olav Albert ChristophersenFwd : Asim K. Duttaroy Published on February 13, 2007
Evolution of skin colour in different human populations Olav Albert Christophersen, Norway
Light skin colour must be understood as an evolutionary adaptation that has helped to increase the photochemical synthesis of vitamin D (by solar ultraviolet radiation) in the skin among people who were living at higher latitudes and/or under cold climatic conditions at the same time as their dietary intake of vitamin D was low. Most foods eaten by humans (with some few exceptions, like cod liver and cod liver oil, or foods that have been fortified with this vitamin) contain very little vitamin D, and the requirements for the vitamin are most commonly – when we consider populations living at not too high latitudes - covered not by the diet, but by ultraviolet-B light-induced photochemical degradation of a precursor molecule, 7-dehydrocholesterol, in the skin.[1] UVB light is absorbed by ozone in the atmosphere, and the amount of UVB light reaching the ground depends both on the path-length of the solar light through the atmosphere before it reaches the ground (being shortest when the sun is in zenith) and on the concentrations of ozone in the air, especially in the stratosphere.[2] The amounts of ozone in the stratosphere are highest at middle latitudes, from where they decrease both towards the Equator and to a lesser extent towards the poles.[3] However, ozone levels in the polar areas are now abnormally low, especially in the Antarctic, as a result of anthropogenic pollution.[4] UVB radiation at the ground is much stronger near the Equator than at middle latitudes, since the average passage length for the UV radiation through the atmosphere is shorter simultaneously as the ozone concentrations in the air masses in the stratosphere also are lower, comparing near-equatorial latitudes to the middle latitudes. There is normally less change in the levels of UVB radiation reaching the ground when one compares middle and high latitudes. This is because the enhancement of the average passage length for the sun’s rays through the atmosphere as one goes from middle to high latitudes is partly compensated by a simultaneous reduction in the ozone concentrations of air masses in the stratosphere. But vitamin D synthesis in the skin of humans is decreased from middle to high latitudes (as well as from low to middle latitudes) also for another reason, viz. the reduction of ground temperatures making it necessary to use more clothes even during the summer months.[5] The area of skin which is directly exposed to UVB radiation will then be correspondingly reduced. Local temperatures depend, of course, not only on latitude but also on other factors such as oceanic currents, distance from the nearest coast and altitude, as well as on global changes of climate, especially when we compare the Ice Ages with the situation today. How much clothes are needed depends also on other meteorological factors such as wind velocities and rainfall, as well as on the level of physical activity. The temperature differences, comparing the situation in the same geographical areas during cold phases of the Ice Age and now, are so large that there can be no doubt that people who were living in Europe or in the Asian inland during cold phases of the Ice Age must have needed more clothes than people who are living in the same areas today. The Oceanic Polar Front in the North Atlantic Ocean, corresponding with the southern limit (2oC) of cold Arctic surface water, went much further south than now.[6] Arctic surface waters with drifting sea ice were found as far south as outside the present Atlantic coasts of France and northern Spain,[7] and wild reindeer were living as far south as in southwestern France and northern Spain.[8] It has been estimated that the average summer temperature in these areas may have been about 15oC.[9] But this estimate is most probably too high, since it is probable that the amount of cooling must have been considerably larger in southwestern France – at a time when there was drifting ice in the Biscayan Gulf – than in the Oman desert at the same time. And the average annual temperature in the Oman desert was about 6.5 degrees centigrade colder than now during the Last Glacial Maximum.[10] An important reason why the global climate was much colder than now was a much lower concentration of CO2 in the atmosphere.[11] Measurements of CO2 concentrations in ice-cores (from the icesheets in Antarctica and on Greenland) indicate that atmospheric CO2 concentrations were consistently about 80 parts per million lower during glacial periods compared with interglacial periods.[12] There may have beeen more than one reason for this, but it is possible that one of the most important causes was more sea-ice cover in the Antarctic, which resulted in reduced discharge of CO2 into the atmosphere from deepwaters upwelling in the Antarctic (because the sea-ice was functioning as a lid hindering CO2 exchange between the surface seawater and the air).[13] It might be noted that enhanced anthropogenic global warming must be expected to lead even more reduction of the sea-ice cover in the Antarctic (compared with the situation today), which might lead to further enhancement of the flux of CO2 from deepwaters upwelling in the Antarctic into the atmosphere (with this effect – being analogous to screwing off the lid of a bottle of mineral water - coming on top of the direct anthropogenic contribution to enhancement of atmospheric CO2). Another possible contributory cause that might help to explain the depression of atmospheric CO2 during cold intervals during the Ice Age may have been larger air-borne iron supply than now to the Southern Ocean.[14] Iron is today a growth-limiting plant nutrient in this region; i.e. the growth of planktonic algae can be stopped by iron deficiency before it is stopped by deficiency of other plant nutrients such as phosphate, nitrogen or silicon.[15] Enhancement of the supply of iron may therefore have given a fertilization effect; i.e. it may have caused enhanced algal growth (compared with the situation today) and hence enhanced CO2 binding by photosynthesis, which would lead to reduction of the CO2 partial pressure in the surface waters in areas of open sea without ice cover.[16] It has been shown from studies of glacier ice cores that not only CO2, but also methane (CH4) concentrations in the atmosphere were depressed at the time of the Last Glacial Maximum compared to the warm interval that followed.[17] The same happened also with N2O.[18] Methane and N2O are also important atmospheric greenhouse gases.[19] Both can be produced by biological processes in oxygen-deficient environments,[20] even though N2O can also be produced biologically when ammonium is oxidized by bacteria to nitrite and nitrate. After water vapour and CO2, methane is now the most abundant greenhouse gas in the troposphere.[21] On a per molecule basis, methane has a much greater climate warming potential than CO2.[22] It is produced in oxygen-deficient wetland habitats such as swamps, lakes, rice paddies, tundra, boreal marshes, etc., and also in the rumen of cattle and other ruminants, as well as in the digestive tracts of termites and perhaps other insects.[23] The rate of methane production is highest in tropical wetlands,[24] which may perhaps reflect the influence of temperature on rates of biochemical processes not only in higher organisms, but most probably in anaerobic archaebacteria including the methanogens as well. Tropical soils are probably also the most important natural source of N2O for the atmosphere today.[25] The total contribution from the oceans as sources of N2O is comparable to the total contribution from tropical soils.[26] It is probable that the total release of methane and N2O from land areas into the atmosphere must have been reduced during cold phases of the Ice Age not only because there was practically no methane and N2O release from areas covered by glaciers, but also because of greater all-over aridity over land as a result of the reduction of sea-surface temperatures causing reduction of the total rate of water evaporation from the sea. Changes in the temperature conditions over land may also have played some role, but was probably less important than the changes of precipitation causing enhancement of the total land area covered by deserts, at the same time as the total area covered by tropical rainforests was substantially less than during post-glacial times.[27] The total emission of methane and N2O from tropical wetlands was therefore most probably much reduced, compared with the situation during postglacial times. The direction and possible magnitude of changes of total methane and N2O fluxes from the sea into the atmosphere, comparing cold phases during the Ice Age with the situation today, is more difficult to estimate. The total flux of methane from the oceans into the atmosphere may today represent less than 10% of the total methane flux from terrestrial and freshwater ecosystems,[28] may be only some few percent of the latter.[29] The oceans, however, make a very significant contribution to the global atmospheric budget for N2O.[30] Local fluxes of these gases from the sea into the atmosphere may during the Ice Age have been enhanced in some parts of the world and decreased in other places (compared with the situation today), depending in part on whether there was more or less upwelling in the region concerned than now, but also on changes in the extension of sea ice cover. It may be possible that total rates of upwelling near the Equator may have been higher during cold phases of the Ice Age than now. This may have happened i.a. as a consequence of changes in global sea-surface topography (because of the Coriolis effect acting transversely to the direction of oceanic currents) resulting from the shutting-down of large-scale sinking processes in the North Atlantic Ocean during cold phases of the Ice Age,[31] at the same time as larger meridional temperature gradients than now (because Ice Age cooling was substantially greater at high latitudes than near the Equator) must be expected to have caused an over-all intensification of zonal winds, including the passat winds, in the atmosphere, which may in turn have led to a corresponding enhancement of the rates of many (but not all) of the corresponding oceanic currents, including the equatorial current systems both in the Atlantic and Pacific oceans. If the global rate of equatorial upwelling was enhanced, this must be expected to have caused some drop of average sea surface temperatures (SSTs) near the equator (with the effect of enhanced upwelling on local SSTs coming in addition to that of less greenhouse gases in the atmosphere), but most probably also enhancement of total rates of evaporation of biologically produced dimethylsulfide, dimethylselenide, methylbromide, methyliodide and N2O from the regions of equatorial upwelling.[32] On the other hand, it must be expected that a greater total extension of the sea ice cover must have led to considerable reduction of total fluxes of these gases into the atmosphere from the sea at higher latitudes, since the sea ice would not only cause some degree of inhibition of primary production below because of its shadow effect, but also must have acted directly as a lid effectively preventing all processes of gas exchange between surface seawaters and the atmosphere. What may have been especially important was the larger extension of the sea ice cover in the Antarctic, since all the region concerned is today part of an enormous upwelling region characterized today by high biological productivity (with large production of diatoms which are eaten by krill – with part of the krill next being eaten by whales). The Antarctic seas do represent a significant source of N2O to the atmosphere today,[33] most probably mainly as a consequence of N2O production during nitrification (ammonium oxidation) rather than during denitrification (nitrate or nitrite reduction). This is because the free water masses in the region may contain too much oxygen for denitrification to occur except within the sediments at the ocean floor. Water vapour is the most important one of all atmospheric greenhouse gases today. But the H2O/N2 mixing ratio is not constant, but depends strongly on the temperature of the air. When the temperature of the troposphere is reduced because of reduction of the concentrations of other greenhouse gases, this will lead to reduction of the H2O vapor concentration which leads to reduction of the greenhouse effect from H2O as well, which means in turn that there will be an amplification of the effect from the primary signal (e.g. a reduction of the concentration of CO2 in the air). Stratospheric ozone is also an important greenhouse gas. It may be possible that stratospheric ozone levels had a tendency to go up during cold phases of the Ice Age at the same time as levels of other greenhouse gases went down. But even if there should have been more ozone in the stratosphere than now (because of higher stratospheric temperature with less CO2, and also because of reduced supply of N2O to the stratosphere), this would not have been enough to compensate for the climatic effect of much lower concentrations of CO2 in the atmosphere than now at the same time as there was also substantially less methane, N2O and water vapour. The lower concentration of CO2 and other greenhouse gases in the air during the cold intervals during the Ice Age must have caused a corresponding reduction of the atmospheric ‘greenhouse effect’ (which is a consequence of back radiation of infrared light from air masses higher up towards the ground).[34] The rate of ground heating during the day would thus be decreased (because less infrared light would have come from the atmosphere above, even if the total energy flux coming directly from the sun should have been the same), and the rate of cooling of the ground during clear, cloud-less nights would be increased. These factors must have had an important impact on the local climate even in inland areas distant from the nearest coast (so that changes of sea surface temperatures e.g. in the North Atlantic Ocean would have little direct effect on temperatures over the land area concerned) – e.g. in places like present Mongolia, western China or Tibet. And they would also have affected places where there was no glacier cover because of too small annual precipitation (which was the case in much of present Siberia and Alaska). Ground temperatures were reduced not only at high middle to high latitudes, but probably all over the world as a result of the reduction of atmospheric CO2 concentrations as well as of some of the other greenhouse gases during Pleistocene glaciations. As an example may be mentioned the situation in Oman during a cold interval 15 000 to 24 000 before present.[35] The solubility of atmospheric noble gases (Ne, Ar, Kr and Xe) in water is temperature-dependent, which means that the concentrations of these gases in water can be used to calculate the temperature when the water was last in equilibrium with the atmosphere.[36] The average noble gas temperature (NGT) calculated for three Holocene (post-glacial) water samples from the upper Al Khwas Fan aquifer is 33.5 +/- 1.7 oC.[37] These estimated infiltration temperatures closely agree with measured groundwater temperature and the average annual ground temperature at the water table, i.e. 33 +/- 0.3 oC. [38] But three Pleistocene (Ice Age) groundwater samples were found to yield consistent NGTs between 26o and 27oC, with an average of 26.6o +/- 0.6oC, which is about 6.5o +/- 0.6oC less than the average annual ground temperature at the water table today.[39] The average annual ground temperature in Oman 15 000 to 24 000 years ago appears therefore to have been about 6.5oC lower than in the same region today. It is reasonable to believe that this mainly may reflect a change of the temperature corresponding to local radiation equilibrium (because of the reduction of the atmospheric greenhouse effect) rather than a change of wind temperatures (for air masses coming in from somewhere outside the area under consideration). This is because the clear skies found in desert areas are associated with so high rates of direct solar energy absorbtion during the day and so high rates of cooling as a result of infrared radiation from the ground during the night that these processes will dominate the local energy budget, making heat gains and losses by advection (i.e. heat transport by the winds) relatively less important. It is not probable, for instance, that those ice-sheets that covered much of North America and northwest Europe during the same period would have any significant influence on temperatures in the desert in Oman. Another kind of evidence showing that Ice Age temperatures must have been lower than today, even near the Equator, is the substantial depression of the snowline that took place on the high mountains of East Africa, such as Kilimandjaro and Mount Kenya. The position of the snowline is not uniquely a function of the mean annual temperatures, but depends also on the distribution of precipitation between different parts of the year. However, this latter factor must be less important near the Equator than at higher latitudes, where there are much more pronounced winter and summer seasons. It is estimated that the temperature 20 000-18 000 years ago was lower than today in most of Africa, in the order of 7 degrees centigrade colder in parts of East Africa.[40] This can be seen to be close to the change of temperature (using an entirely different method) that was found in Oman. Sea surface paleotemperatures can be estimated from 18O/16O isotopic ratios of siliceous or calcareous tests of fossil planktonic organisms,[41] but must be corrected for changes in salinity (which will change the 18O/16O isotopic ratio of the seawater itself). An independent method of estimating paleosalinity is therefore needed, if this method shall give answers that are precise enough to be useful for geophysicists studying world climates during the Ice Age. A depression of the annual average temperature from 33oC to 26.6oC in Oman would not have caused people who were living on the Arabian Peninsula during the Ice Age to freeze, at least not during the day, while a similar reduction of the annual average temperature must have been strongly felt by people living in what is now Denmark, Germany, Poland, Russia or Mongolia (and it may be possible that the reduction of average annual temperature may have been even larger in many of these areas than it was in the desert of Oman). Actually, there is good reason to suspect that the drop of average annual temperature must have been even larger at higher latitudes than it was in Oman, since the relative contribution of water vapour to the total atmospheric greenhouse effect decreases as one goes from lower to higher latitudes (with lower temperature and therefore lower H2O vapour concentration in the air). A drop of atmospheric CO2 concentration from about 300 ppm (by volume) to about 200 ppm would presumably have a greater effect on ground temperatures corresponding to local radiation equilibrium in regions where the air is very dry than in regions near the Equator where H2O concentrations in the lower troposphere are much higher. The same argument might also suggest that winter temperatures may have been even more strongly affected than summer temperatures by a substantial drop of the atmospheric CO2 concentration. Direct measurements of the temperature in drillcore samples from the Greenland ice-sheet have shown that the temperature at the top of the glacier was about 23 degrees Kelvin less than now during the Last Glacial Maximum.[42] The impact of less atmospheric greenhouse gases than now on the local radiation balance and ground temperature may therefore have been more than three times larger on top of the Greenland ice-sheet compared to desert in Oman. The amount of Ice Age cooling in Siberia (comparing the situations during the Last Glacial Maximum and now) was presumably in a range intermediate between those values that have been found, respectively, on the surface of the Greenland ice-sheet and in Oman, but may most likely (taking into consideration the effect of local temperature on concentrations of water vapour in the troposphere) have been closer to the amount of cooling observed in Greenland than to the amount of cooling observed in Oman. There can be no doubt, however, that people who were living in central and perhaps northern parts of Eurasia during the Ice Age must have known how to keep themselves warm, similarly as we know that for instance Inuits or Saami people have done during historically more recent times. But it can not have been very easy to do so, if the average annual temperatures in much of the interior of Eurasia were depressed by more than 14 degrees centigrade, compared with the average annual temperatures in the same places today. Even better clothes might have been needed – as protection against extreme cold - than are needed in order to keep warm by Inuits today. Such drastic depression of the average annual temperature could imply not only substantially lower winter temperatures than in the same regions today, but also substantially lower summer temperatures making it much more difficult e.g. for small children to go with much of the skin exposed to the sun’s rays even during the summer months. It may be possible that it was not temperature per se which was the most important factor determining where it was possible or not for Ice Age hunters to survive, but rather the availability of enough food resources. The extreme temperature conditions encountered in much of Siberia during the Ice Age must, however, have represented a substantial challenge not only to humans, but to other mammalian species as well. It may be possible that very large species such as the mammoth may have tolerated very low winter temperatures better than not quite so big ones such as the reindeer (because the ratio body surface/body mass and hence the cooling rate for a warm-blooded animal goes down as a function of increasing body mass). But even if the largest mammalian species such as the mammoth may have been even better adapted for extreme cold compared e.g. with the reindeer, they must also have been more vulnerable to hunting because of their slow reproduction. It may thus be possible that they may have managed to survive as long as the population density for humans was very low (because of some limiting factor other than the number of mammoths), or when the climate was so harsh as to keep the humans effectively out from substantial stretches of the Siberian territory. Global warming during the Bølling/Allerød interstadial and/or after the end of the Younger Dryas[43] may, however, have been accompanied by substantial migration both of reindeer populations and of reindeer hunters to the north, which again may have led to so much enhancement of the hunting pressure on the mammoths even in the coldest parts of Siberia that the latter had no geographical refugium left any more where it might have been possible for them to survive. It may not be unreasonable that a similar process also could help to explain the extinction of various large mammalian species in North America at more or less the same time. In spite of very harsh climate, there can be little doubt that there must have been humans throughout much of Central Asia and possibly also further north throughout much of the last Ice Age. While only archaeological evidence can give us direct proof that there were humans within a given geographical region at one particular time interval, it is also possible to draw some important conclusions from more indirect evidence pertaining to the genetic diversity among human populations now living within some of the territories concerned. Studies of human Y chromosomes have shown that total Y chromosome diversity is high among native Siberian populations.[44] In a study of Y-chromosome diverity in 50 different populations from different parts of the world, the highest level of Y-chromosome heterozygocity was found in populations from Central Asia, while African populations exhibited a higher level of mean pairwise differences among haplotypes.[45] Central Asia is revealed to be an important reservoir of genetic diversity and the source of at least three major waves of migration leading into Europe, the Americas and India.[46] The high total level of Y-chromosome diversity that has been observed among native Siberian populations as well as in Central Asia can most easily be explained assuming that the present human population in the region concerned has descended from populations that have had a very long prehistory within more or less the same territory (or neighbour territories, allowing for the possibility of substantial north-south migrations in response to changes in global climate), thus giving ample time for evolutionary diversification of the Y chromosomes, at the same time as many of the tribes concerned also have been living so hostile territories that they for that very reason may have been spared for massacres caused by foreign invaders that otherwise might have led to substantial reduction of Y chromosome diversity. Thus, it may be possible that essentially modern humans may have inhabited these territories at a time when Neanderthalers still were dominating (to the exclusion of modern humans?) in much or all of Western Europe. There can be little doubt that vitamin D deficiency must have been a widespread and serious problem in the colder parts of Eurasia during the Ice Age (because people needed to cover themselves with even more clothes than is needed in the same geographical regions today), unless people were able to find foods that were good sources for this vitamin. This would not have been difficult for coastal tribes who were eating much sea mammals and/or fish (since the livers both of cod and seal are excellent sources of this vitamin, and the liver of ice bear contains so much vitamin D and vitamin A that it is toxic and dangerous to eat). But it would have been more difficult for tribes living in the inland without access to seafoods rich in this vitamin – which may be illustrated by the persistence in places like Mongolia of vitamin D deficiency as a major public health problem even today, or at least until very recently.[47] It is well documented that vitamin D is up-concentrated upwards in marine food-chains, so that the vitamin D/lipid ratio is higher in cod liver than in whole capelin (Mallotus villosus) or whole herring, even higher in the livers of seal eating cod, and even higher than in seal liver in the liver of ice-bear eating seals. It is not unreasonable that something similar also may happen in food chains on land, so that livers from carnivores (e.g. wolf) or omnivores (e.g. bear) may contain more vitamin D than livers from herbivores (e.g. mammoth). The question might thus be raised if some of those populations of inland hunters who were living in regions with extremely harsh climate e.g. in parts of Siberia during the Ice Age may have depended on bear liver as a source of vitamin D. If this was the case, it may be possible that it was the availability of good dietary sources of vitamin D rather than the availability of food energy or dietary protein which was the most important factor limiting human population density in inland regions with especially harsh climate – thus keeping the human population density so low that it would have been possible for mammoths to survive even with scattered hunter populations dwelling permanently within the same territories. The bear liver/vitamin D hypothesis might also help to explain the close etymological connection between words meaning the animal bear and words meaning ‘to give birth’ (such as the verb ‘bear’ in English, being identical with the noun used as name for the animal), as well as words such as Norwegian ‘barn’ (meaning child) derived from words meaning ‘to give birth’.[48] Other explanations have also been given for this etymological connection, as well as for the bear cult which apparently must have been very widespread in Europe during the Stone Age.[49] However, it might be an even more direct and more satisfactory explanation for the etymological connection between words for the animal and for giving birth, as well as for the bear cult, if there had been a widespread understanding that girl children and/or their lactating mothers (while still breast-feeding their youngest girl child) should eat bear liver in order that the girls should be able to give birth without too serious complications (because of malformation of the pelvis) after they had grown up to become adult women. It should be emphasized that the problem of inadequate synthesis of vitamin D in the skin may have gone much further south in the Eurasian inland than it does today – when the inland climate gives high average summer temperatures e.g. in southern parts of Siberia or in Mongolia, even if the winter temperatures are low. It should, moreover, also be taken into consideration that the summers, as now, may have been associated with another problem for many of the populations concerned, even when temperatures were high enough that children well might have gone naked – viz. mosquitoes and other insects. There may thus have been many places where not only adults but also children may have been well-covered by clothes for protection against insects, even when day temperatures were high enough that they well might have gone completely naked without shivering. There may, furthermore, also have been social and psychological reasons why people may have used more clothes than was needed for temperature regulation during the summer - being connected with the sexual arousal a man may feel when seeing such parts of a woman’s body that normally would be covered by clothes. What is important here is that the psychological reactions may depend strongly on what he is normally accustomed to see. Seeing a woman’s naked breast will not normally produce any strong sexual arousal or attraction among men living in a warm country where all women go with their breasts uncovered throughout the year, while it may be completely different in a cold country where all women normally go with their breasts covered (for reasons of temperature regulation) most of the year. An analogy might be seen to the phenomenon of pharmacological tolerance development for opiate drugs. A drug addict who takes heroin every day will need to enhance the dose in order to obtain the desired effect. Then he comes into a prison where heroin is not available, or he goes voluntarily to an institution for treatment of his drug addiction problem. Everything is now good and well until that day when he is released from the prison or leaves the treatment institution. He meets some of his old friend, believes himself that he is careful when taking considerably less than the dose he used to take before – but he underestimates the magnitude of the drug tolerance effect (which has now disappeared during the long period he has been completely without opiate drugs), and dies therefore soon after from what is now a serious overdose. Such considerations would presumably not affect the amount of clothes used by small children during the summer. But it could have been of some importance for the amount of clothes used during summer times by pre-puberty and early puberty girls – at an age where vitamin D status is still very important for ensuring normal development of the pelvis (especially during the growth spurt of puberty). As far as the small children are concerned, it may be understandable if their mothers did not want the small one to be ‘eaten up’ by mosquitoes. Perhaps they may also have been thinking about the risk of snake bites. While a European viper’s bite is not normally much dangerous for an adult person (the fatality rate without treatment is low), it is quite different with a child only 2 or 3 years old. Serious vitamin D deficiency will cause rachitis in children and osteomalacia in adults.[50] One of the most serious consequences of this disease is malformation (flattening) of the pelvis in girl children, which increases the risk of maternal and infant morbidity and mortality during.[51] Rachitis can also cause skeletal deformities in the lower limbs and severe muscle weakness making it impossible for children to walk without support.[52] This must, of course, also have been a very severe handicap for nomadic hunter-gatherer peoples. It might be speculated if this problem might have played some role in the earliest domestication of animals used for riding (e.g. horses) or as draught animals pulling sledges or pulks during the winter – i.e. that live animals may have been captured for the purpose of helping somebody who could not walk on his own legs and also was a bit too heavy to be carried by other family members over great distances. It may be possible that the problem of vitamin D deficiency among hunter-gatherer tribes living in northern and central parts of the Eurasian inland during the Ice Age may have been compounded by the effects of very high dietary animal food/plant food ratios on urinary pH and urinary calcium excretion. Low urinary pH is associated with enhanced urinary calcium excretion.[53] It is possible that this may be due to a combination of more than one mechanism acting both at the levels of bone tissue,[54] endocrine glands,[55] and more directly in the kidneys. The net diurnal urinary excretion of acids or alkalies is normally governed (if we leave out of consideration clearly pathological situations such as diabetic ketosis) by the balance between so-called alkali-ash foods and acid-ash foods in the diet.[56] Alkali-ash foods contain a surplus of metallic cations (such as potassium, magnesium, sodium and calcium) over the acid-forming elements chlorine, sulfur and phosphorus, while acid-ash foods contain a surplus of acid-forming elements over the metals, calculated as equivalents of the corresponding acids and bases.[57] Much of the dietary intake of sulfur is in form of the sulfur amino acids cysteine and methionine. However, when these are metabolically degraded, sulfuric acid is formed as the quantitatively most important metabolic end product. For magnesium and even more for calcium, it must be taken into consideration that intestinal absorbtion is limited – and it is only the amount absorbed by the intestine which is important for the body’s acid-base budget (and hence for urinary pH). Most of the organic acids found in ordinary foods (e.g. in various fruits) with exception of oxalic acid and ascorbic acid (vitamin C) are almost completely metabolically degraded; they will therefore not affect the over-all acid-base balance. Most animal foods (such as meat, fish, offal and eggs) contain a large surplus of acid-forming over base-forming elements; they are therefore typical acid-ash foods.[58] Fruits, vegetables and plant tubers contain a surplus of alkali-forming elements, especially potassium but also magnesium, and are therefore alkali-ash foods.[59] Cereals and other seeds have much lower K/energy and K/protein ratios compared with most fruits, berries, vegetables and tubers, and the (total metals)/protein and (total metals)/food energy ratios are even smaller in refined than in unrefined cereals.[60] Polished rice is an acid-ash food.[61] The effects of 159 different retrojected preagricultural (hunter-gatherer) diets have been calculated.[62] The calculations show that most of these hypothetical Paleolithic diets gave a net surplus of bases (alkali-ash) and therefore would have produced a neutral or alkaline urine, in spite of protein intakes that were much higher than is common today - in the range 135-259 g protein/day.[63] The explanation for the surplus of base in most of the retrojected Paleolithic diets was a much higher total consumption of alkali ash – mostly in form of potassium - from plant foods than is common today.[64] The average net endogenous acid production for all 159 retrojected diets was –88 +/- 82 mEq/day - as against 48 mEq/day for the average American diet today.[65] The effect of mild metabolic acidosis and low urinary pH on urinary calcium excretion is very substantial, as illustrated by an experiment where a group of 18 postmenopausal women were given a constant diet containing 625 mg of calcium and 96 g of protein per 60 kg of body weight.[66] The effect of potassium bicarbonate supplementation nearly enough to completely neutralize the endogenous acid (60 to 120 mmol per day) was then tested. During the administration of potassium bicarbonate, the calcium and phosphorus balances were found to become less negative or more positive.[67] The average change in calcium balance was 56 +/- 76 mg per day per 60 kg body weight, while the average change in phosphorus balance was 47 +/- 64 mg per day per 60 kg body weight.[68] It should be noted that one must eat much extra calcium (given the limited intestinal calcium absorbtion) in order to compensate for an enhancement of the urinary calcium excretion by 50 mg per day. It may therefore be reasonable to conclude that mild metabolic acidosis caused by a surplus of acid ash over alkaline ash in the diet very plausibly might be regarded as the single most important cause of osteoporosis in the western world today (even though there may be also other important causal factors acting in the same direction, such as a high dietary intake of sodium, which is something which we shall return to below). The agricultural revolution was attended by a large enhancement of the consumption of cereals at the expense of many of those foods that had been consumed in greater quantity by Paleolithic hunter-gatherer populations.[69] Even if the total protein intake and the consumption of animal protein foods was reduced, the total consumption of potassium-rich plant foods was reduced even more, leading to enhancement of the net endogenous acid production. Today, it is also common over large parts of the world that people eat mainly refined cereal products (such as white wheat flour in North America, Great Britain and France, and polished rice in the countries of East Asia and Southeast Asia), as well as much sugar and edible fats and oils. These diets rich in energy-rich and refined foods will commonly give a surplus of endogenous acid production, even when the total protein consumption and the consumption of animal protein both are much lower than was common for Paleolithic hunter-gatherer populations.[70] The result of this will be a mild metabolic acidosis (i.e. the average pH of blood plasma will be slightly lower than was common during the Paleolithic) and acidic urine, which will not be associated with enhanced risk of osteoporosis, but also may have other adverse health consequences including an enhanced tendency for tissue protein loss which may lead to reduction of the skeletal muscle mass, and enhanced risk of kidney stone formation.[71] Furthermore, it may also be speculated that even a mild metabolic acidosis may be enough to contribute to enhanced activation of pain-conducting nerve fibers because of activation of so-called vanilloid receptors (also called capsaicin receptors); these receptors are sensitive i.a. to low pH,[72] noxious heat,[73] the endogenous cannabinoids anandamide (N-arachidonoyl-ethanolamine) and 2-arachidonoylglycerol (2-AG)[74] and fatty acid hydroperoxides and hydroxides produced by the 12-lipoxygenase and 15-lipoxygenase pathways,[75] as well as by leukotriene B4.[76] They are also sensitive to capsaicin,[77] which is the ‘burning’ substance found in red pepper.[78] It has been found that the degree of acidosis in modern, ‘westernised’ populations also has a tendency to increase with age.[79] It may be possible that this is not only a consequence of changes in total food intake or average diet composition as a function of age, but also may happen as a result of loss of mitochondrial capacity, partly as a result of normal mitochondrial aging[80] and partly because of reduction of the level of physical activity. The reduction of mitochondrial capacity might be associated with a tendency for enhanced metabolic lactic acid production even under resting conditions (and also at any level of physical activity) which in turn might be associated with enhancement of the average concentration of lactic acid in blood plasma (i.e. mild lactic acidosis) and enhanced urinary excretion of lactic acid. It may theoretically be expected that this problem may be enhanced by any toxic agent (e.g. carbon monoxide, various toxic heavy metals) and any dietary deficiency condition (e.g. thiamine deficiency, copper deficiency) that may contribute to inhibition of mitochondrial function. The risk of such deficiencies (especially subclinical ones) will, of course, be enhanced when people eat much “empty calories”, i.e. food which contain little or no water-soluble vitamins, essential trace elements, potassium and magnesium, as western populations commonly do. It should be noted that impairment of mitochondrial function e.g. in skeletal muscle also must be expected to enhance the risk of local acidosis that in turn may contribute to activation of vanilloid receptors and hence to the occurrence of chronic or intermittent muscular pain. It may be expected that a more carbohydrate-rich diet will enhance the net metabolic lactic acid production, other factors being equal. A diet rich in refined carbohydrates may thus have a double detrimental action because it enhances the risk of dietary deficiency conditions that cause inhibition of mitochondrial function (e.g. copper deficiency, thiamine deficiency) at the same time as it also enhances the substrate load for metabolic conversion of glucose (blood sugar) to lactic acid. This may, for reasons already explained (enhanced vanilloid receptor activation), very likely also contribute to enhancement of chronic pain problems e.g. localized to parts of the skeletal muscles. It might be added that adipose tissue is reported to have a high capacity for lactic acid production, which is enhanced in patients with type 2 diabetes and some of their first-degree relatives.[81] It may therefore be possible that obesity also may be an important factor tending to enhance the total level of lactic acid production (for a given diet composition and a given level of physical activity). Blood plasma levels of lactic acid are, furthermore, also enhanced by alcohol (which happens as a consequence of the effect of alcohol degradation on the liver cell [NADH]/[NAD+] concentration ratio, causing enhancement of the lactate/pyruvate ratio in the liver);[82] this may in turn help to explain the connection between alcohol consumption and gout (caused by deposition of crystals of uric acid in some of the joints)[83] since high concentrations of lactate in serum will inhibit the urinary excretion of uric acid.[84] While modern man has much lower average potassium consumption than was common among Paleolithic hunter-gatherer populations,[85] he has on the other hand much higher average sodium consumption, mainly from table salt (NaCl), but also from sodium bicarbonate used in many bakery products. A high intake of sodium will lead to corresponding enhancement of the urinary excretion of sodium (since sodium is very well absorbed in the intestine). This, however, will also lead to enhancement of the urinary excretion of calcium.[86] This is most probably because high levels of urinary sodium cause inhibition of the tubular reabsorbtion of calcium. For people who live on typical modern diets, it must therefore be expected that high intakes of sodium and a surplus of acid-ash over alkaline-ash foods both will interact with each other in an additive or synergistic factor, leading to enhancement of the urinary excretion of calcium. The limited absorbtion of calcium in the intestine can make it difficult to compensate for this enhancement of urinary calcium excretion, even at huge dietary calcium intakes. But it will, of course, be even more difficult to compensate for high urinary calcium losses if vitamin D status is marginal or if vitamin D conversion to ‘vitamin D hormone’ (1,25-dihydroxycholecalciferol) is inhibited e.g. because of high burdens of toxic heavy metals, such as cadmium, lead and most probably also mercury. It has been shown both in animal experiments and epidemiologic studies that toxic heavy metals such as cadmium and lead affect the conversion of vitamin D to 1,25-dihydroxycholecalciferol.[87] Cadmium, mercury and lead may, moreover, also inhibit active membrane transport of calcium,[88] which is one of the processes stimulated by 1,25-dihydroxycholecalciferol when this hormones promotes the intestinal absorbtion of calcium.[89] High-level lead exposure has also been reported to to block the stimulating effect of 1,25-dihydroxycholecalciferol on intestinal calcium absorbtion in experimental animals.[90] And mercury[91] and cadmium[92] have both been reported to enhance the urinary excretion of calcium, presumably by inhibiting calcium reabsorbtion in the renal tubuli. It is on this background not much surprising that high environmental cadmium exposure has been reported to be associated with enhanced incidence of osteporosis,[93] or that postmenopausal osteoporosis is more common among smoking women than among non-smokers,[94] given the importance of tobacco smoke as a source of cadmium[95] How mercury affects the conversion of vitamin D to 1,25-dihydroxycholecalciferol appears not to have been much studied, if at all, either experimentally or epidemiologically, but given the important chemical similarities between these three elements, it would be very surprising if mercury should not have a similar effect as has been earlier demonstrated both for cadmium and lead. Nor seems there to have been much research interest for the question, how mercury loads e.g. from dental amalgam fillings may affect the long-term calcium balance and risk of osteoporosis. It has been reported from a study in Japan, however, that the mercury concentrations in hair were considerably higher in patients suffering from osteoporosis, compared to normal controls.[96] The same was also found in patients suffering from several other ordinary diseases, such as atopic dermatitis, dementia, cerebral infarct, hypertension and diabetes.[97] This could perhaps be taken as an indication that mercury and also other toxic heavy metals such as cadmium and lead may play a much more important role as etiological factors (contributory causes) in several non-infectious ordinary diseases than hitherto has been realized. From what has been explained above, it must be expected that toxic heavy metals and a surplus of acid-ash foods over alkaline-ash foods in the diet most likely may interact with each other in strongly synergistic fashion as causes of osteoporosis. Both factors are likely to play a more than negligible role, even when acting alone, but the total effect must be expected to be larger than for a simple additive interaction when both are present simultaneously – which they could be for more than 50% of the total population in a country such as Norway. There may perhaps not be so much reason to wonder, after all, why there should be so much osteoporosis in Oslo, causing the city to lie near the top of the international statistical ranking list, as regards the (age-corrected) incidence of femoral fracture among the elderly.[98] Even if most of the retrojected diets of Sebastian et al.[99] had a surplus of alkali ash, which would be expected to lead to low rates of urinary calcium excretion, it may be possible that many hunter-gatherer peoples living under conditions of Arctic or sub-Arctic climate may have subsisted on diets even more extreme than the most extreme cases studied by Sebastian et al.[100] This is because potassium-rich plant foods tend to become progressively less abundant and less availability, compared to the abundance and availability of animal foods, as climatic conditions become more extreme. One of the most important reasons for this is that most of the plant foods concerned can be gathered only during the summer half of the year, and sometimes only during a short part of the summer or autumn seasons (e.g. lingonberries). There is much qualitative information available about the diets of several sub-Arctic and Arctic peoples (in northern Europe, northern Asia, northern America and Greenland) over the last few centuries, but for many of them not so much quantitative data.[101] It is evident that all of them have subsisted not only on animal foods, but also on several kinds of plant foods including berries of various kinds, green leafy vegetables (e.g. Angelica archangelica), and edible root tubers (e.g. from Polygonum species, so-called ‘Esquimo potatoes’).[102] In areas with forest (e.g. in Swedish Lapland), people have also been eating the cambium from certain trees (in form of so-called bark bread) not only as emergency food, but also as normal food.[103] Stomach contents from reindeer and intestinal contents from grouses have also been eaten (even among peoples who had a taboo against eating grouse meat because its taste was said to be too similar to that of meat from humans),[104] and in some of the most extreme climatic situations even faeces from grouses.[105] These (for us) unusual foods may not only have functioned as good sources of alkali ash, but also as sources of mineral nutrients such as manganese and boron which are found only in very low concentrations in practically all animal foods.[106] The possibility can on this background not be excluded that even some of those peoples who were living under sub-Arctic conditions may have eaten enough plant foods to give a neutral or alkaline urine. However, it is more reasonable to believe that most of them must have had acidic urines throughout most of the year - with exception of those seasons when berries etc. were most abundantly available. But two or three months (perhaps) with alkaline urine and low urinary calcium excretion would not be enough to compensate for the effect of 9 or 10 months with acidic urine and correspondingly high urinary calcium excretion (which, however, might be mitigated by much lower salt consumption than is common in modern populations). For many of the hunter-gatherer peoples who were living under conditions of Arctic or sub-Arctic climate in Europe and Asia during the Ice Age, it may thus be possible that the problem of marginal vitamin D supply or outright deficiency may have been compounded by a surplus of acid-ash foods over alkaline-ash foods leading to enhancement of the urinary excretion of calcium. The development of the pelvis in girl children may be especially vulnerable to deficiency of vitamin D during the growth spurt of puberty. If the opening of the pelvis became much too narrow because of childhood rachitis, it is probable that this may during the Stone Age often have made it impossible for young women to give birth to live children and also survive themselves without Caesarean delivery. Caesarean delivery, however, was rarely practised even as late as in Europe during the early nineteenth century and was then considered highly dangerous, being both technically and morally controversial.[107] In spite of this, it is not unreasonable to think that Stone Age people who were living in areas with much pelvic deformities because of rickets often may have tried to perform Caesarean section. This is because they may have understood this was the only possible way if they should try to save both the mother and the child, and the possibility that the child would survive may have been pretty good even if the death risk for the mother was probably often very high. It is reasonable to expect that mortality following this procedure often would have been high i.a. because very low human population densities on the tundra may have prevented rapid horizontal diffusion of knowledge about the best procedure helping to prevent the mother dying from hemorrhage (and sometimes from infection) shortly afterwards; there was probably nothing comparable to a modern medical school those days and no ‘tundra medical academy’. It is not difficult to understand that this problem must have constituted a strong evolutionary force; the evolutionary consequences will, of course, be the same if mother and child die during childbirth or if a woman understands that she must never have children, if she shall have any hope of reaching high age herself. Anything that may help to reduce this problem will thus be selected for; this may not only be the case in the classic evolutionary sense with genetic properties (such as alleles for light skin colour), but may also apply to cultural practices or habits because groups that had started with practices that increased the survival chances for their women during childbirth (e.g. coastal peoples eating cod liver, tundra hunting peoples consuming reindeer milk, learning how to perform Caesarean section as safely as possible) would also have more surviving offspring compared to groups that did not have the same positive-survival-value customs. Among possible dietary sources of vitamin D, one might wonder if liver from bears or other omnivore or carnivore species possibly might have played a role and if this may be one of the reasons for the common etymologies of words having to do with childbirth and human reproduction and the name of the animal species bear on the other side. Was bear liver something that was eaten by girl children in order that they should be able to give birth the normal way and not die during childbirth as soon as they became adult young women? Dark skin colour can be regarded as an evolutionary adaptation helping to protect people living at lower latitudes against damage resulting from too much ultraviolet radiation, such as acceleration of degenerative aging processes in the skin,[108] skin cancer,[109] and – perhaps most important during the Stone Age – immunodepression which is caused by a combination of different mechanisms.[110] Sunlight is responsible for wrinkling, blotching, drying, and leathering of skin, and it is estimated that 90% of all skin cancers result from long-term exposure to ultraviolet radiation.[111] Skin cancer is the most common malignancy in man, with an incidence of 1 million new cases diagnosed in the United States in 1999.[112] Solar radiation is a well documented risk factor both in melanoma and non melanocytic skin cancer, i.e. basal cell and squamous cell carcinoma.[113] UV light may also cause photochemical degradation of folate,[114] which may in turn lead to folate deficiency, especially when the dietary intake of this vitamin is marginal (which is very common today, but may not have been so common among Paleolithic hunter/gatherer populations as long as their total intake of food was adequate). It has been found that exposure of human blood plasma in vitro to simulated strong sunlight caused 30 to 50 percent loss of folate within 60 minutes.[115] Furthermore, light-skinned patients exposed to ultraviolet light for dermatologic disorders have abnormally low serum folate concentrations (if they do not take folate supplements at an adequate dosage level), suggesting that photolysis may also occur in vivo.[116] Folate deficiency, which occurs in many marginally nourished populations, may cause severe anemia, neural tube defects and other congenital malformations, frank infertility, and maternal mortality.[117] It has been proposed that prevention of ultraviolet photolysis of folate and other light sensitive nutrients by dark skin could be sufficient explanation for the maintenance of this characteristic in groups of humans living in regions with intense solar radiation.[118] An objection against this hypothesis is that the diets of Paleolithic hunter/gatherer populations may typically have been of much better quality than diets common today both in developing and industrial countries;[119] this may also have been the case with the diets of some of the Stone Age farmers or horticulturalists, as exemplified by the diet on the island of Kitava, which is one of the Trobriand Islands in Papua New Guinea.[120] Paleolithic man may typically have ingested much more micronutrients including folate than is common among impoverished populations living in regions with intense solar radiation today.[121] This may in turn have helped to reduce his vulnerability to deficiency disorders caused by photochemical degradation of folate and other UV-sensitive nutrients in the skin. It may be possible that the decrease of folate intakes, comparing Paleolithic diets with diets today, may be one of those dietary changes which most critically have affected the health of large groups of people both in industrial and poor countries. There may be reason to look closer at some of the consequences in relation to current health problems and explain why it is not only the health of our generation, but also the health of future generations that here may be at stake. Folate deficiency is a common cause, or contributory cause (in combination with genetic disturbances), of hyperhomocysteinemia, which in turn is strongly associated with enhanced risk of cardiovascular disease and enhanced cardiovascular mortality.[122] Moreover, folate deficiency may also cause impairment of immunological functions.[123] Cell-mediated immunity is especially affected by folate deficiency: the blastogenic response of T lymphocytes to certain mitogens is decreased in folate-deficient humans and animals, and the thymus is altered.[124] Folate deficiency must therefore be expected to contribute to enhanced morbidity and mortality from infectious diseases, especially when also the dietary intake of DNA simultaneously is low, as it usually will be in patients with a low total intake of dietary protein. This is because a good immunological response depends on a rapid proliferative response in various types of leukocytes or their precursors, which is not possible without correspondingly high rates of DNA synthesis in the proliferating cells. The effects of folic acid deficiency upon humoral immunity have been more thoroughly investigated in animals than in humans, and the antibody responses to several antigens have been shown to decrease.[125] For DNA synthesis to occur, it is necessary that there is an adequate supply of all of those four nucleotides (in form of the corresponding triphosphates) that are found in the DNA molecule. The genetic message is written in the DNA molecule in form of long ‘words’ (corresponding to different genes) that are written with four ‘letters’, corresponding to four different nucleotide bases.[126] During transcription, parts of the DNA molecules are copied to form corresponding RNA molecules.[127] These contain three of the same bases as the DNA molecules, while bases number four are different in the DNA and RNA molecules, being uracil in RNA and thymine in DNA.[128] RNA and DNA also contain two different sugars, with RNA containing ribose while DNA contains deoxyribose.[129] During synthesis of DNA and RNA, it is necessary that the nucleotide bases are available in form of the corresponding nucleotides which, furthermore, must be transformed into the corresponding energy-rich triphosphates before they can be incorporated into DNA or RNA molecules.[130] Nucleotides used during DNA and RNA biosynthesis can be made in two different ways, either by de novo pathways from precursor molecules that do not contain nucleotide bases, or by so-called salvage pathways from degradation products of DNA and RNA (which may come from dead human cells, from the diet, or from bacteria and other microorganisms e.g. in the intestine), so that purine and pyrimidine bases from degraded DNA and RNA molecules can be used once more to form new DNA or RNA.[131] Folate participates in the de novo biosynthetic pathways for three of the four different nucleotides found in DNA molecules, viz. the purine base-containing nucleotides deoxyadenylate and deoxyguanylate and the pyrimidine base-containing nucleotide thymidylate.[132] It also participates in the de novo biosynthetic pathways for the purine base-containing nucleotides adenylate and guanylate which are used during RNA biosynthesis.[133] During de novo thymidylate biosynthesis, folate participates as an essential component of the enzyme thymidylate synthase, which makes thymidylate from deoxyuridylate.[134] During de novo biosynthesis of the purine nucleotides (adenylate, guanylate, deoxyadenylate and deoxyguanylate), folate participates as an essential component of two different enzymes catalyzing two consecutive steps in the same pathway, viz. GAR transformylase (also abbreviated GART) and AICAR transformylase.[135] These folate-dependent steps in de novo pathways for biosynthesis of nucleotides needed for DNA and RNA biosynthesis are inhibited by the anti-cancer drug methotrexate, which functions as a folate antagonist.[136] This may at least in part help to explain the anti-cancer action of this drug. It should be noted, however, that the same nucleotides that are needed for DNA biosynthesis are also needed during DNA repair. It must therefore be expected that methotrexate will inhibit DNA repair in the tumor cells, which may in turn enhance the probability of severe DNA damage triggering apoptosis (cellular suicide) in the tumor cell population. It should also be noted that nucleotides are needed during cell growth not only because they are needed as precursors for making DNA and RNA, but also because they participate in biosynthetic pathways for various membrane lipids (e.g. for making phosphatidylcholine from free choline) and carbohydrate molecules.[137] Adenylate, furthermore, is also needed for making ATP, which is the chief ‘energy currency’ molecule used by the cells to drive a large number of different non-spontaneous chemical reactions including DNA and RNA synthesis.[138] It is therefore easy to understand why cell growth processes will be slowed down or stop altogether if they contain too little of one or more of those nucleotides that are needed for energy metabolic and biosynthetic pathways essential for cell growth. This may not only apply to cellular division, but also other forms of cellular growth as it may be observed in non-dividing muscle cells or nerve cells, e.g. during the growth of the infant brain, during regeneration processes following brain trauma or stroke, and quite generally during learning processes (which may depend on micro-anatomical remodelling processes improving the synaptic contact between particular pairs of neurons while perhaps also decreasing the synaptic contact between other pairs of neurons). However, it may be expected that processes depending on rapid cellular growth – which includes various immunological functions and also the regeneration of the intestinal mucosa - may be especially sensitive to nucleotide depletion. The functional disturbances that may occur as a consequence of folate deficiency will, however, not depend only of the degree of folate deficiency. They will also depend on the dietary intake of nucleotides and other nutrients which can be made endogenously by de novo pathways dependent on folate. For the same degree of folate deficiency, it must be expected that DNA and RNA biosynthesis will be more severely affected if the dietary intakes of DNA and RNA are low than if they are high. The same may presumably also be the case with processes of DNA repair. This is because more nucleotides can be produced by salvage pathways when the dietary intakes of DNA and RNA are high than if when are low. DNA and RNA will always follow protein in the diet (with the probable exception of some highly refined protein-rich food products such as surimi). A general positive correlation will thus exist between the dietary intake of protein and the dietary intakes of DNA and RNA. It must therefore be expected that poor people in developing countries who have low total intakes of dietary protein most commonly will have low dietary intakes of DNA and RNA as well. This may in turn be expected to make them much more vulnerable to folate and also vitamin B12 deficiency, compared to more affluent people living in the industrial countries (who can afford to buy more protein-rich foods, especially in form of animal products, and therefore will ingest more DNA and RNA as well). But the average protein intakes may be much lower, even in many of the affluent industrial countries, compared to the diets of many of other Paleolithic hunter-gatherer ancestors.[139] Model calculations on the compositions of a large numbers of Paleolithic model diets in order to estimate their effects on the acid-base balance showed a range of protein intakes from about 135 g protein/day to 259 g protein/day[140] - and it is possible that the daily protein intake may have been even higher for some of the hunter/gatherer peoples who were living in sub-Arctic or Arctic environments (e.g. inland Inuits in Alaska until some 50-60 years ago, to mention a recent example). It may thus be expected that also the daily intakes of DNA and RNA typically may have been much higher with Paleolithic diets than is common today, even for populations living in affluent western industrial societies. The DNA/protein and RNA/protein ratios are not the same in all types of food. The DNA/protein ratio depends on the density of cell nuclei, mitochondria and chloroplasts in the tissue or organ concerned, while the RNA/protein ratio presumably will depend on the rate of protein turnover, being therefore higher in organs with high capacity for protein biosynthesis such as for instance the pancreas, the liver and the testes. It may be expected that plant foods rich in storage protein (e.g. cereal grains) most probably will have lower DNA/protein and RNA/protein ratios compared with green leaves, which are functionally much more active, and also compared with most animal foods. Many refined, energy-rich foods (e.g. refined sugar, margarine) are virtually empty both of DNA and RNA. It is therefore probable that the proportionate decline of nucleic acid intakes must have been greater than for protein, comparing typical Paleolithic diets with diets typical of the western industrial countries today. The decline of DNA and RNA intakes may probably have started already with the Stone Age agricultural revolution, but may have been greatly accentuated by dietary changes that have occurred over the last 100-200 years with greatly enhanced consumption of various refined carbohydrate foods and edible fats and oils simultaneously as the average per capita food energy consumption has decreased as a result of decreased physical activity. Another factor that may possibly also have acted in the same direction, especially as far as the intake of DNA is concerned, is reduced consumption of various visceral organs such as heart, liver, lungs, brain, etc. At the same time, it may also be possible that poverty – as it occurs in many developing countries – often may be accompanied by proportionate reductions of the intakes of RNA and DNA which may be even larger than the relative reductions of protein intake, compared to diets typical of the affluent countries and also compared to diets typical of the more affluent socio-economic groups in the developing countries themselves. It follows that the deleterious effect of a certain degree of folate deficiency in relation to processes dependent on rapid cellular proliferation (including immunological functions and also regeneration of the intestinal mucosa) must be expected to be more serious when it affects people who because of poverty have low dietary intakes of nucleic acids than when a similar degree of folate deficiency affects people who are more affluent and therefore can afford to eat more of such foods that are good sources both of protein and nucleic acids. The same may also be the case with dietary deficiency of vitamin B12 (because of the close biochemical collaboration between folate and vitamin B12). On the other hand, it must also be expected that the functional consequences of a given degree of folate deficiency (e.g. because of rapid photochemical degradation of folate in the skin) would have been smaller for people who were living on Paleolithic diets than for most people subsisting on modern diets. It must be expected that the combination of folate (or vitamin B12) deficiency and low dietary intakes of DNA and RNA must lead to impairment of immunological defense against virtually any kind of infectious disease (even though it may be possible that the replication of the infectious agent sometimes also might be inhibited as a result of nucleotide deficiencies, especially perhaps in the case of various viral infections). At the same time, it may also be possible that it commonly may lead to (or contribute to) degeneration of the intestinal mucosa (villus atrophy), with the combination of intestinal mucosal damage and impaired immunological functions in the intestine both contributing to increased morbidity and mortality from gastrointestinal infections. Another important question is what may be the possible consequences of nucleotide deficiencies (because of the combination of low intakes of folate and/or vitamin B12 on one side and low dietary intakes of DNA and RNA on the other) for DNA repair processes – and what consequences inefficient DNA repair in turn might have both for the incidence of cancer and for biological aging. One might wonder how much inhibition of DNA repair (because of a poor diet) could mean e.g. for the problem of liver cancer in many developing countries. And is it possible that smoking and alcohol abuse both might be even more dangerous – as a consequence of less efficient DNA repair – for poor people living in developing countries than they are for affluent people living in North America or Western Europe? It may be mentioned that one of the enzymes needed by the salvage pathway of thymidylate biosynthesis, viz. thymidine kinase, is inhibited by the drug zidovudine (also called AZT). Zidovudine was the first drug that was used at a large scale for treatment of HIV disease.[141] It is still much used for treatment of AIDS, but now most commonly in combination with other anti-HIV drugs, which helps to inhibit viral replication more effectively than is possible with one drug alone and therefore also helps to counteract (or delay) the evolution of drug resistance in the virus.[142] After entering the host cell, zidovudine is phosphorylated by thymidine kinase to zidovudine monophosphate, and finally by nucleoside diphosphate kinase to active zidovudine 5-triphosphate.[143] High concentrations of the monophosphate may accumulate in the cell, and the intracellular half-life of zidovudine 5-triphosphate is approximately 3 hours.[144] Zidovudine 5-triphosphate terminates viral DNA chain elongation by competing with thymidine triphosphate for incorporation into viral DNA.[145] Zidovudine 5-triphosphate also weakly inhibits cellular DNA polymerase-alpha and mitochondrial polymerase-gamma, and the monophosphate competitively inhibits cellular thymidine kinase, an effect that reduces levels of thymidine triphosphate.[146] These latter effects may contribute to the drug’s cytotoxicity and adverse effects.[147] It may thus be theoretically expected that the combination of folate deficiency and zidovudine may by itself be enough to cause immunodeficiency, even when HIV viral replication is efficiently suppressed. This is because the proliferation of leukocytes or their precursors will now be hindered by a shortage of thymidylate, which will lead to corresponding reduction of the rate of DNA biosynthesis in the proliferating cell population. Since zidovudine is acting as a competitive inhibitor of the enzyme concerned, it must be expected that this effect of zidovudine will be more serious in a situation where the dietary intake of DNA is low, while a high dietary intake of DNA possibly may help to overcome the suppression of thymidylate biosynthesis caused by zidovudine at a therapeutic dosage level. This might potentially be very important not only for the proliferation of leukocytes of various kinds (or their precursor cells), but also for the proliferation of intestinal epithelial cells (enterocytes and colonocytes). Suppression of intestinal epithelial cell proliferation may cause development of villus atrophy (“flat intestine”), which may in turn lead to malabsorbtion not only of important nutrients (which may in turn enhance the risk of diarrhoeas caused not only by the reduction of the area of absorbtive surface, but also by associated brush border oligosaccharidase deficiencies leading e.g. to lactose intolerance or sucrose intolerance), but presumably also malabsorbtion of drugs used either for treatment of the HIV disease itself or for treatment of other infections, such as tuberculosis or malaria. The effective dosage level of the drug concerned may thus become too low, which will not only reduce the effect of the therapy, but also must be expected to increase the risk of drug resistance development in the pathogenic organism concerned - which might be the HIV virus itself, but also Mycobacterium tuberculosis or some Plasmodium species, e.g. P. falciparum, or any among several other disease-causing organisms.[148] The putative public health consequences if this should occur at a mass scale because of the liberation of cheap zidovudine for treatment of millions of poor HIV patients in developing countries are indeed appalling - and not only for the populations most directly concerned; it will, for instance, also make it much more difficult for foreign medical personnel or other aid workers to go to the countries concerned if there is no drug available for treatment of malaria any more because the disease-causing organism as evolved multiresistance against absolutely all drugs previously available for treatment of this dangerous disease. It may also be expected that some of the multiresistant pathogens concerned (e.g. multiresistant plasmodia) may spread rather easily from one part of the world to another (especially when patients who have been infected with some multiresistant organism while travelling abroad finally return to their homeland). Not a very nice prospect for a future ‘greenhouse world’ - where insects responsible for the transmission of malaria and other tropical diseases may thrive also in several countries which are now too cold for them! Finally, and perhaps most seriously, folate deficiency is mutagenic i.a. because of faulty incorporation of uracil instead of thymine into the DNA molecule during DNA synthesis or repair.[149] This form of DNA damage can be repaired, but faulty repair is common, which will lead to permanent mutations in the cells concerned, often in the form of chromosomal damage (following chromosome breaks).[150] During repair of uracil in DNA, transient nicks are formed; two opposing nicks could lead to chromosome breaks.[151] A level of folate deficiency causing chromosome breaks was found in approximately 10% of the population in U.S.A., and in a much higher percentage of the American poor.[152] Again, it must be expected that effect of a given degree of folate deficiency must depend on the dietary intake of DNA: folate deficiency must be expected to be more strongly mutagenic when the dietary intake of DNA is low than when it is high. It must also be expected that the mutagenic effect of folate deficiency (because of misincorporation of uracil in the DNA molecule instead of thymine) must be enhanced by zidovudine with the combination of zidovudine with low dietary intakes both of folate (and/or vitamin B12) and DNA being especially dangerous. There may thus be good reason to fear what may be the possible consequences in terms of DNA damage if zidovudine shall be used at a mass scale for treatment of millions of HIV-infected patients (most of which are still in their fertile age) in poor countries. The most important reason for concern is here not what it could mean for the incidence of cancer or for biological aging processes among the patients (because of more rapid accumulation of DNA damage in the mitochondria), but what could be the possible consequences for future generations. Enhancement of the rate of mutations in somatic cells will increase the risk of cancer when it occurs in nuclear chromosomes | ||