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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 pho�to�che�mical synthesis of vitamin D (by solar ultraviolet radiation) in the skin among peop�le who were li�ving at higher la�ti�tu�des and/or under cold climatic conditions at the same time as their dietary intake of vi�ta�min 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 mo�le�cu�le, 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 atmo�sphe�re be�fo�re it reaches the ground (be�ing shortest when the sun is in zenith) and on the con�cen�tra�tions of ozone in the air, especially in the stra�tosphere.[2] The amounts of ozo�ne in the stra�tosphere are highest at middle la�ti�tu�des, from where they decrease both to�wards the Equa��tor and to a lesser extent to�wards the poles.[3] However, ozone levels in the polar areas are now abnormally low, es�pe�ci�ally in the Antarctic, as a result of anth�ro�po�ge�nic pol�lu�tion.[4] UVB radiation at the ground is much stronger near the Equator than at middle la�ti�tudes, since the ave�rage passage length for the UV radiation through the atmosphere is shorter simul�ta�ne�ously as the ozone concentrations in the air masses in the stra�to�sphe�re also are lower, com�paring near-equa�torial 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 com�pensated by a si�mul�ta�neous reduction in the ozone concentrations of air masses in the stra�to�sphere. But vitamin D synthesis in the skin of humans is decreased from middle to high la�ti�tu�des (as well as from low to middle latitudes) also for another reason, viz. the reduction of ground tem�pe�ratures ma�king it necessary to use more clothes even during the summer months.[5] The area of skin which is di�rect�ly exposed to UVB radiation will then be cor�res�pon�ding�ly reduced. Lo�cal tem�pe�ratures depend, of course, not only on la�ti�tu�de but also on other factors such as ocea�nic currents, distance from the nearest coast and altitude, as well as on global changes of climate, espe�ci�ally when we compare the Ice Ages with the situation today. How much clothes are needed depends also on other meteo�ro�lo�gical factors such as wind velo�cities and rainfall, as well as on the level of physical activity. The temperature differences, comparing the situation in the same geographical areas during cold pha�ses 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 li�ving 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 rein�deer were living as far south as in southwestern France and northern Spain.[8] It has been estimated that the average summer tem�pe�rature 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 con�si�de�rably larger in southwestern France � at a time when there was drifting ice in the Bis�cayan Gulf � than in the Oman desert at the same time. And the average annual tem�pe�rature in the Oman desert was about 6.5 degrees centigrade colder than now during the Last Glacial Ma�xi�mum.[10] An important reason why the global climate was much colder than now was a much lower con�cen�tra�tion of CO2 in the atmosphere.[11] Measurements of CO2 concentrations in ice-cores (from the icesheets in Antarctica and on Greenland) indicate that atmo�sphe�ric CO2 concentrations were consistently about 80 parts per million lower during glacial periods com��pared 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 Ant�arc�tic, which resulted in reduced discharge of CO2 into the atmosphere from deep�wa�ters 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 anth�ropogenic 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 fur�ther enhancement of the flux of CO2 from deep�waters up�welling in the Antarctic into the atmo�sphe�re (with this effect � being analogous to scre�wing off the lid of a bottle of mineral water - coming on top of the direct anth�ro�po�genic con�tri�bu�tion to en�han�cement of atmo�sphe�ric CO2). Another possible contributory cause that might help to explain the depression of at�mospheric 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] En�han��cement 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 pho�to�syn�the�sis, which would lead to reduction of the CO2 partial pressure in the surface wa�ters in areas of open sea with�out ice co�ver.[16] It has been shown from studies of glacier ice cores that not only CO2, but also me�tha�ne (CH4) con�cen��tra�tions in the atmosphere were depressed at the time of the Last Glacial Maximum compared to the warm in�ter�val that followed.[17] The same happened also with N2O.[18] Methane and N2O are also important atmospheric greenhouse gases.[19] Both can be pro�du�ced by bio�logical processes in oxygen-deficient environments,[20] even though N2O can also be produced bio�lo�gi�cally when ammonium is oxi�di�zed by bacteria to nitrite and nitrate. After water vapour and CO2, methane is now the most abundant greenhouse gas in the tropo�sphe�re.[21] On a per molecule basis, methane has a much greater climate warming potential than CO2.[22] It is pro�du�ced 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 in�sects.[23] The rate of methane production is highest in tro�pical wetlands,[24] which may perhaps reflect the in�flu�en�ce of temperature on rates of biochemical processes not only in higher organisms, but most pro�bab�ly in an�ae��ro�bic archaebacteria including the metha�no�gens as well. Tropical soils are probably also the most important natural source of N2O for the atmosphere today.[25] The total con�tribution from the oceans as sources of N2O is comparable to the total contribution from tro�pi�cal soils.[26] It is probable that the total re�lea�se of methane and N2O from land areas into the at�mo�sphere 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 be�cau�se of greater all-over aridity over land as a result of the reduction of sea-surface tem�pe�ra�tu�res causing reduction of the total rate of water evaporation from the sea. Changes in the tem��perature conditions over land may also have played some role, but was pro�bably less important than the changes of precipitation causing enhancement of the total land area co�ve�red by deserts, at the same time as the total area covered by tropical rainforests was sub�stan��tially less than during post-glacial times.[27] The total emission of methane and N2O from tropical wetlands was therefore most probably much re�du�ced, 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 situa�tion today, is more difficult to esti�mate. 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, how�ever, make a very significant contribution to the global atmo�sphe�ric budget for N2O.[30] Lo�cal fluxes of the�se gases from the sea into the at�mo�sphere may during the Ice Age have been en�han�ced in some parts of the world and de�creased in other pla�ces (compared with the si�tua�tion today), depending in part on whether there was more or less upwelling in the re�gion con���cer���ned 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 con�sequence of changes in global sea-sur�face topography (because of the Coriolis effect acting transversely to the direction of oceanic currents) re�sul�ting from the shutting-down of large-scale sin�king 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 (be�cau�se Ice Age cooling was substantially greater at high latitudes than near the Equa�tor) must be ex�pec�ted to have caused an over-all intensification of zonal winds, in�clu�ding the passat winds, in the atmo�sphe�re, which may in turn have led to a corres�pon�ding en�han�cement of the rates of many (but not all) of the corres�ponding oceanic cur�rents, in�clu�ding the equatorial current systems both in the Atlantic and Pacific oceans. If the global rate of equa�torial upwel�ling was en�han�ced, this must be expected to have caused some drop of ave�rage sea surface tem�pe�ra�tu�res (SSTs) near the equator (with the effect of en�han�ced up�wel�ling on local SSTs coming in addition to that of less greenhouse gases in the atmo�sphere), but most probably also enhan�ce�ment of total rates of eva�poration of bio�lo�gically produced dimethylsulfide, dime�thyl�se�lenide, methyl�bro�mide, methyl�iodide and N2O from the regions of equatorial up�wel�ling.[32] On the other hand, it must be expected that a greater total extension of the sea ice cover must have led to consi�de�rab�le reduction of total fluxes of these gases into the atmo�sphere 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 sea�waters and the atmosphere. What may have been especially important was the larger ex�tension of the sea ice cover in the Antarctic, since all the region concerned is today part of an enormous up�wel�ling 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 sig�ni�fi�cant source of N2O to the at�mo�sphere today,[33] most probably mainly as a consequence of N2O production during nit�ri�fi�ca�tion (ammonium oxidation) rather than during denitrification (nitrate or nitrite re�duc�tion). This is because the free water masses in the region may contain too much oxy�gen for de�nit�rification to occur except within the sedi�ments at the ocean floor. Water vapour is the most important one of all atmospheric greenhouse gases today. But the H2O/N2 mi�xing 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 con�cen�trations of other greenhouse gases, this will lead to reduction of the H2O vapor con�cen�tra�tion 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 re�duc�tion 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 green�hou�se 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 strato�sphe�re), 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 me�tha�ne, 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 cor�res�ponding reduction of the atmo�spheric �greenhouse effect� (which is a consequence of back radiation of inf�ra�red light from air masses higher up towards the ground).[34] The rate of ground hea�ting during the day would thus be decreased (because less inf�rared light would have come from the at�mo�sphe�re 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 in�crea�sed. 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 At�lan�tic Ocean would have little direct effect on temperatures over the land area con�cerned) � e.g. in pla�ces like present Mongolia, western China or Tibet. And they would also have af�fec�ted places where there was no glacier co�ver be�cau�se of too small annual pre�ci�pitation (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 green�hou�se gases during Pleistocene glaciations. As an ex�amp��le may be mentioned the situation in Oman during a cold interval 15 000 to 24 000 be�fo�re present.[35] The solubility of atmospheric nob�le gases (Ne, Ar, Kr and Xe) in water is tem�perature-dependent, which means that the concentrations of these gases in water can be used to calculate the tem�pe�ra�ture when the water was last in equilibrium with the atmo�sphe�re.[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 tem�pe�rature and the ave�rage annual ground tem�pe�ra�tu�re at the water table, i.e. 33 +/- 0.3 oC. [38] But three Pleis�to�ce�ne (Ice Age) ground�wa�ter 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 ave�rage annual ground tem�pe�ra�ture at the water table today.[39] The average an�nu�al ground tem�perature 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 cor�responding to local radiation equilibrium (because of the reduction of the atmospheric green�house effect) rather than a chan�ge 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 los�ses by ad�vec�tion (i.e. heat transport by the winds) relatively less important. It is not pro�bab�le, for instance, that those ice-sheets that covered much of North America and north�west Europe during the same period would have any significant influence on tem�pe�ra�tures 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. How�ever, 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 me�thod) that was found in Oman. Sea surface paleotemperatures can be estimated from 18O/16O isotopic ratios of siliceous or cal�ca�reous tests of fossil planktonic orga�nisms,[41] but must be corrected for changes in salinity (which will chan�ge the 18O/16O isotopic ratio of the sea�wa�ter itself). An independent method of estimating pa�leosalinity is therefore nee�ded, if this method shall give answers that are precise enough to be useful for geo�phy�si�cists stu�dying 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 tem�pe�ra�ture must have been strongly felt by people living in what is now Den�mark, 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 tem�pe�ra�ture 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 va�pour 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 Equa��tor 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 green�house gases than now on the local radiation ba�lan�ce and ground tempe�ra�ture may therefore have been more than three times larger on top of the Green�land ice-sheet compared to desert in Oman. The amount of Ice Age cooling in Siberia (comparing the situations during the Last Glacial Maxi�mum and now) was presumably in a range intermediate between those values that have been found, respec�ti�vely, on the surface of the Greenland ice-sheet and in Oman, but may most likely (taking into consideration the effect of local temperature on concen�tra�tions of water vapour in the troposphere) have been closer to the amount of cooling ob�ser��ved 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 his�to�rically more recent times. But it can not have been very easy to do so, if the ave�rage an�nual temperatures in much of the interior of Eurasia were depressed by more than 14 degrees cen�tigrade, compared with the ave�rage 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 ave�ra�ge annual tempe�rature could imply not only sub�stan�tially lower winter temperatures than in the same regions today, but also sub�stan�tially lower summer tempera�tures 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 de�ter�mi�ning where it was possible or not for Ice Age hunters to survive, but rather the availability of enough food re�sources. The extreme temperature conditions encountered in much of Siberia during the Ice Age must, how�ever, have represented a substantial chal�lenge 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 tem�pe�ra�tu�res bet�ter than not quite so big ones such as the reindeer (because the ratio body surfa�ce/body mass and hence the cooling rate for a warm-blooded animal goes down as a func�tion 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 be�cau��se of their slow re�pro�duc�tion. It may thus be possible that they may have managed to survive as long as the popu�la�tion density for humans was very low (because of some limiting factor other than the number of mam�moths), or when the climate was so harsh as to keep the hu�mans ef�fec�ti�vely out from sub�stan�tial stretches of the Siberian territory. Global warming during the B�l�ling/Al�ler�d inter�stadial and/or after the end of the Youn��ger Dryas[43] may, however, have been accompanied by substantial mig�ration both of rein�deer populations and of rein�deer hunters to the north, which again may have led to so much en�han�cement of the hunting pres�su�re on the mammoths even in the coldest parts of Si�be�ria that the latter had no geo�gra�phi�cal refugium left any more where it might have been possible for them to survive. It may not be un�rea�sonable that a similar process also could help to explain the extinction of va�ri�ous large mammalian spe�cies in North Ame�rica 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 ar�chaeo��logical 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 evi�den�ce pertaining to the genetic diversity among human populations now living within some of the territories con�cerned. Studies of human Y chromosomes have shown that total Y chromosome diversity is high among na�ti�ve Siberian populations.[44] In a study of Y-chromosome diverity in 50 dif�fe�rent populations from different parts of the world, the highest level of Y-chromosome hete�rozygocity was found in populations from Central Asia, while African populations exhibited a higher level of mean pairwise differences among haplotypes.[45] Cen�tral 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 po�pu�lations as well as in Central Asia can most easily be ex�plained assuming that the present human popu�la�tion in the region concerned has des�cen�ded from popu�la�tions that have had a very long prehistory within more or less the same terri�tory (or neigh�bour ter�ri�to�ries, allowing for the possibility of substantial north-south mig�ra�tions in response to changes in global climate), thus giving ample time for evolutionary diversification of the Y chro�mo�somes, at the same time as many of the tribes concerned also have been living so hostile ter�ri�to�ries that they for that very reason may have been spared for massacres caused by foreign invaders that other�wise might have led to substantial reduc�tion of Y chromosome diversity. Thus, it may be possible that es�sen�tially modern humans may have inhabited these terri�to�ries at a time when Neanderthalers still were domi�na�ting (to the ex�clu�sion of modern hu�mans?) 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 sea�foods rich in this vitamin � which may be illustrated by the persistence in places like Mon�golia 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 (Mal�lo�tus 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 car�ni�vo�res (e.g. wolf) or omnivores (e.g. bear) may contain more vitamin D than livers from herbivores (e.g. mam���moth). 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 vi�ta�min D rather than the availability of food energy or dietary protein which was the most important factor li�mi�ting human population density in inland regions with especially harsh climate � thus keeping the human popu�la�tion density so low that it would have been possible for mammoths to survive even with scattered hunter po�pu�la�tions dwelling permanently within the same territories. The bear liver/vitamin D hypothesis might also help to explain the close etymolo�gi�cal connection between words meaning the animal bear and words meaning �to give birth� (such as the verb �bear� in Eng�lish, 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 wide�spread in Europe during the Stone Age.[49] However, it might be an even more direct and more satis�factory 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 under�stan�ding that girl children and/or their lactating mothers (while still breast-feeding their youn�gest girl child) should eat bear liver in order that the girls should be able to give birth without too serious com�pli�ca�tions (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 ave�rage 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 as�so�ciated with an�other prob�lem for many of the populations concerned, even when tem�pe�ratures were high enough that child�ren 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 pro�tec�tion against insects, even when day tem�pe�ra�tures were high enough that they well might have gone completely naked with�out shi�ve�ring. There may, furthermore, also have been social and psy�cho�lo�gi�cal 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 clo�thes. 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 at�trac�tion among men living in a warm country where all women go with their breasts un�co�vered 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 regu�lation) most of the year. An analogy might be seen to the phenomenon of phar�ma�co�lo�gical tolerance de�velopment for opiate drugs. A drug addict who takes heroin every day will need to en�hance the dose in order to obtain the desired effect. Then he comes into a prison where he�roin is not avail�able, or he goes voluntarily to an institution for treatment of his drug ad�dic�tion prob��lem. Everything is now good and well until that day when he is released from the pri�son or leaves the treat�ment institution. He meets some of his old friend, believes him�self that he is careful when taking con�si�derably less than the dose he used to take before � but he underestimates the magnitude of the drug tolerance effect (which has now dis�ap�pea�red during the long period he has been completely without opiate drugs), and dies the�re�fore 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 de�ve�lop�ment of the pelvis (es�pe�cially 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 mos�qui�toes. Perhaps they may also have been thinking about the risk of sna�ke bites. While a European viper�s bite is not normally much dangerous for an adult person (the fa�ta�lity rate without treatment is low), it is quite dif�fe�rent with a child only 2 or 3 years old. Se�ri�ous vitamin D deficiency will cause rachitis in children and osteomalacia in adults.[50] One of the most serious con�se�quences of this disease is mal�formation (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 cour�se, 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 cap�tu�red for the purpose of helping some�body 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 ef�fects 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 com�bination of more than one me�cha�nism acting both at the levels of bone tissue,[54] endocrine glands,[55] and more di�rect�ly in the kidneys. The net di�ur�nal urinary excretion of acids or alkalies is normally governed (if we leave out of con�sideration clearly pa�tho�logical 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 me�tal�lic cations (such as potassium, magnesium, sodium and calcium) over the acid-forming elements chlo�rine, sul�fur and phosphorus, while acid-ash foods con�tain a surplus of acid-forming elements over the me�tals, cal�cu�la�ted as equivalents of the cor�responding 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 me�ta�bo�lically degraded, sulfuric acid is formed as the quantitatively most important metabolic end pro�duct. For mag�nesium and even more for calcium, it must be taken into consideration that intestinal ab�sorb�tion 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 ex�cep�tion of oxalic acid and ascorbic acid (vi�tamin C) are almost completely metabolically de�gra�ded; they will the�re�fore 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, ve�ge�tables and plant tubers contain a surplus of alkali-forming elements, especially potassium but also mag�nesium, and are therefore alkali-ash foods.[59] Cereals and other seeds have much lower K/energy and K/pro�tein ratios compared with most fruits, berries, vege�tab�les and tubers, and the (total me�tals)/protein and (total metals)/food energy ratios are even smaller in refined than in unre�fined cereals.[60] Po�li�shed 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 neut��ral or al�ka�line urine, in spite of protein intakes that were much higher than is common today - in the ran�ge 135-259 g protein/day.[63] The explanation for the surplus of base in most of the ret�ro�jec�ted Paleolithic diets was a much higher total consumption of alkali ash � mostly in form of po�tas�sium - from plant foods than is common today.[64] The average net endogenous acid production for all 159 ret�ro�jec�ted diets was �88 +/- 82 mEq/day - as against 48 mEq/day for the ave�ra�ge American diet today.[65] The effect of mild metabolic acidosis and low urinary pH on urinary calcium ex�cre�tion is very sub�stan�tial, 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 com�pletely neutralize the endogenous acid (60 to 120 mmol per day) was then tested. Du�ring the ad�mi�nis�tra�tion of potassium bicarbonate, the calcium and phosphorus balances were found to become less negative or more positive.[67] The average change in calcium ba�lance was 56 +/- 76 mg per day per 60 kg body weight, while the average change in phos�phorus 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 con�clu�de 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 im�por�tant cause of osteoporosis in the western world today (even though there may be also other im�por�tant causal factors acting in the same direction, such as a high dietary intake of so�di�um, which is so�me�thing 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 po�pu�lations.[69] Even if the total protein intake and the con�sump�tion of animal pro�tein foods was reduced, the total consumption of potassium-rich plant foods was reduced even more, lea�ding to enhancement of the net en�do�genous acid pro�duction. Today, it is also common over large parts of the world that people eat mainly refi�ned 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 com�mon�ly give a surplus of endo�ge�nous acid production, even when the total protein con�sump�tion and the consumption of ani�mal protein both are much lower than was com�mon for Paleo�lithic hunter-gatherer popu�la�tions.[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 asso�cia�ted with en�han�ced risk of osteo�po�ro�sis, but also may have other adverse health con�se�quences inclu�ding an enhanced tendency for tissue protein loss which may lead to reduc�tion of the ske�le�tal muscle mass, and en�han�ced risk of kidney stone for�ma�tion.[71] Furthermore, it may also be spe�cu�la�ted 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 re�cep�tors are sensitive i.a. to low pH,[72] noxious heat,[73] the endogenous cannabinoids anan�da�mide (N-arachidonoyl-ethanolamine) and 2-ara�chi�do�no�ylglycerol (2-AG)[74] and fatty acid hyd�ro�per�oxi�des and hydroxides pro�du�ced by the 12-lipoxygenase and 15-lip�oxy�ge�na�se path�ways,[75] as well as by leukotriene B4.[76] They are also sen�si�ti�ve to capsaicin,[77] which is the �burning� sub�stan�ce 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 con�se�quence of changes in total food intake or average diet compo�si�tion 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 re�duc�tion of the level of physical activity. The re�duction of mitochondrial capacity might be associated with a ten�den�cy for enhanced me�tabolic lactic acid production even under resting conditions (and also at any level of physical activity) which in turn might be associated with en�han�cement of the ave�rage con�cen�tration of lactic acid in blood plasma (i.e. mild lactic acidosis) and en�han�ced urinary excretion of lactic acid. It may theo�re�tically be expected that this problem may be enhanced by any toxic agent (e.g. carbon monoxide, various toxic heavy metals) and any dietary deficiency con�dition (e.g. thia�mine deficiency, copper deficiency) that may con�tri�bute to inhibition of mi�to�chondrial function. The risk of such deficiencies (especially sub�cli�nical 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 ele�ments, potassium and mag�ne�si�um, as wes�tern populations com�monly do. It should be noted that impairment of mito�chond�rial func�tion e.g. in skeletal muscle also must be expected to enhance the risk of local aci�dosis that in turn may con�tri�bu�te to activation of vanilloid receptors and hence to the oc�cur�rence of chro�nic or in�ter�mittent muscular pain. It may be expected that a more carbohydrate-rich diet will enhance the net metabolic lactic acid pro�duction, 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 con�ditions that cause inhibition of mitochondrial func�tion (e.g. copper deficiency, thiamine de�fi��ciency) 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 (en�han�ced va�nilloid receptor activation), very likely also contribute to enhancement of chronic pain prob�lems e.g. localized to parts of the skeletal muscles. It might be added that adipose tissue is reported to have a high ca�pa�city for lactic acid production, which is enhanced in patients with type 2 diabetes and some of their first-deg�ree relatives.[81] It may therefore be possible that obe�si�ty also may be an important factor tending to enhance the total level of lactic acid pro�duc�tion (for a given diet composition and a given level of phy�si�cal 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, cau�sing enhancement of the lactate/pyruvate ratio in the liver);[82] this may in turn help to explain the connection between alcohol con�sumption 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 ex�cre�tion of uric acid.[84] While modern man has much lower average potassium consumption than was com�mon among Pa�leo���lithic hunter-gatherer populations,[85] he has on the other hand much higher average sodium consumption, mainly from table salt (NaCl), but also from sodium bicar�bo�na�te used in many bakery products. A high intake of sodium will lead to cor�res�pon�ding enhancement of the urinary ex�cre�tion of sodium (since sodium is very well ab�sor�bed in the intestine). This, however, will also lead to enhan�cement of the urinary excretion of cal�cium.[86] This is most probably because high levels of urinary sodium cause inhibition of the tubular reabsorbtion of cal�cium. For people who live on typical modern diets, it must the�re�fo�re be expected that high intakes of so�di�um and a surplus of acid-ash over alkaline-ash foods both will interact with each other in an additive or syn�ergistic factor, leading to enhancement of the urinary ex�cre�tion of cal�ci�um. The limited absorbtion of calcium in the intestine can make it difficult to compensate for this en�han�ce�ment of urinary calcium excretion, even at huge dietary calcium intakes. But it will, of course, be even more difficult to compensate for high urinary cal�ci�um losses if vitamin D status is marginal or if vitamin D con�ver�sion to �vitamin D hor�mo�ne� (1,25-di�hyd�ro�xycholecalciferol) 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 expe�ri�ments and epidemiologic studies that to�xic heavy metals such as cadmium and lead affect the con�ver�sion of vitamin D to 1,25-di��hyd�ro�xy�cho�le�cal�ci�fe�rol.[87] Cadmium, mercury and lead may, moreover, also inhibit active membrane transport of calcium,[88] which is one of the pro�ces�ses stimulated by 1,25-di�hyd�ro�xy�cho�le�cal�ciferol when this hor�mones promotes the intes�ti�nal ab�sorb�tion of calcium.[89] High-level lead expo�su�re has also been re�por�ted to to block the stimu�la�ting effect of 1,25-dihyd�ro�xy�cho�le�cal�ci�fe�rol on intes�tinal calcium ab�sorb�tion in ex�pe�rimental animals.[90] And mercury[91] and cadmium[92] have both been reported to en�hance the urinary excretion of calcium, presumably by in�hi�bi�ting calcium reabsorbtion in the renal tubuli. It is on this background not much surprising that high en�vi�ron�men�tal cadmium ex�po�sure has been re�por�ted to be asso�cia�ted with enhanced incidence of osteporosis,[93] or that post��me�no�pau�sal os�teo�po�rosis is more common among smo�king women than among non-smo�kers,[94] given the im�por�tance of tobacco smoke as a source of cadmium[95] How mer�cu�ry affects the con�ver�sion of vi�ta�min D to 1,25-di�hyd�ro�xy�cho�lecalciferol appears not to have been much studied, if at all, either expe�ri�men�tal�ly or epi�de�mio�logically, but gi�ven the im�por�tant chemi�cal simi�la�rities between these three elements, it would be very sur�pri�sing if mer�cury should not have a similar effect as has been earlier de�mon�strated both for cadmium and lead. Nor seems there to have been much re�search interest for the ques�tion, 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 os�teo��porosis, 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 (con�tri�bu�tory causes) in several non-infec�ti�ous 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 syn�ergistic 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 simul�ta�neously � 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 inter�na�tional sta�tis�tical 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 pos�sible that many hunter-gatherer peop�les living under conditions of Arctic or sub-Arctic climate may have subsisted on diets even more ex�tre�me than the most extreme cases studied by Sebastian et al.[100] This is because po�tas�sium-rich plant foods tend to become pro�gres�si�ve�ly less abundant and less availability, compared to the abundance and availability of ani�mal 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. lin�gon�ber�ries). There is much qualitative information available about the diets of several sub-Arctic and Arctic peop�les (in northern Europe, northern Asia, northern America and Greenland) over the last few centuries, but for many of them not so much quan�titative data.[101] It is evi�dent that all of them have sub�sis�ted not only on animal foods, but also on several kinds of plant foods including berries of various kinds, green leafy vegetables (e.g. Angelica arch�an�gelica), and edible root tubers (e.g. from Polygonum species, so-called �Esquimo po�ta�toes�).[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 grou���ses have also been eaten (even among peop�les 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 situa�tions even faeces from grouses.[105] These (for us) unusual foods may not only have func�tioned as good sources of alkali ash, but also as sour�ces 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 peop�les 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 through�out most of the year - with exception of those seasons when berries etc. were most abundantly avail�able. 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 ex�cre�tion (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 Eu��ro�pe 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 defi�ci�ency of vitamin D during the growth spurt of puberty. If the opening of the pelvis became much too narrow because of child�hood ra�chitis, it is probable that this may during the Stone Age often have made it impossible for young wo�men to give birth to live children and also survive them�selves without Caesarean delivery. Caesarean delivery, however, was rarely practised even as late as in Europe during the early nineteenth century and was then con�si�dered 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 de�for�mities because of rickets often may have tried to perform Cae��sarean sec�tion. 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 mor�ta�li�ty fol�lowing this procedure often would have been high i.a. be�cau�se very low human po�pu�lation den�si�ties on the tundra may have prevented rapid horizontal diffusion of know�ledge about the best pro�cedure helping to pre��vent the mo�ther dying from hemorrhage (and sometimes from infection) shortly after�wards; there was pro�bably no�thing comparable to a mo�dern me�di�cal school those days and no �tundra medical aca�de�my�. It is not difficult to understand that this problem must have constituted a strong evo�lutionary 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 her�self. Anything that may help to reduce this problem will thus be selected for; this may not only be the case in the classic evolu�tio�nary 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 sur�vi�val chances for their women during childbirth (e.g. coastal peoples eating cod liver, tundra hunting peoples consuming rein�deer milk, lear�ning how to perform Caesarean sec�tion as safely as possible) would also have more sur�vi�ving offspring com�pa�red to groups that did not have the same positive-survival-value customs. Among pos�sib�le 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 li�ving at lo�wer latitudes against damage resulting from too much ultraviolet radia�tion, such as acceleration of de�ge�ne�ra�tive aging processes in the skin,[108] skin cancer,[109] and � perhaps most important during the Stone Age � immu�no�de�pression which is caused by a combination of different mechanisms.[110] Sunlight is res�pon�sible for wrinkling, blotching, drying, and lea�the�ring of skin, and it is es�ti�ma�ted that 90% of all skin cancers result from long-term exposure to ult�ra�vio�let radiation.[111] Skin cancer is the most common malignancy in man, with an in�ci�dence of 1 million new cases diagnosed in the United States in 1999.[112] So�lar 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 de�fi�ciency, especially when the dietary intake of this vitamin is marginal (which is very common today, but may not have been so common among Paleolithic hun�ter/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] Fur�ther�mo�re, light-skinned patients ex�po�sed to ultraviolet light for derma�to�logic disorders have ab�normally low serum folate con�cen�trations (if they do not take folate supplements at an ade�quate dosage level), sug�ges�ting that photolysis may also occur in vivo.[116] Folate deficiency, which oc�curs in many marginally nourished populations, may cau�se severe ane�mia, neural tube defects and other con�ge�nital malformations, frank infer�ti�li�ty, and maternal mortality.[117] It has been proposed that prevention of ult�ra�vio�let pho�to�ly�sis 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 ob�jec�tion against this hypothesis is that the diets of Paleo�lithic hun�ter/gatherer populations may typically have been of much better quality than diets common today both in de�ve�loping and industrial coun�tries;[119] this may also have been the case with the diets of some of the Stone Age far�mers or horticulturalists, as exemplified by the diet on the island of Ki�ta�va, which is one of the Trobriand Islands in Papua New Guinea.[120] Pa�leo�li�thic man may ty�pi�cal�ly have ingested much more mic�ro�nutrients in�cluding folate than is common among im�po�ve�rished popu�la�tions living in regions with intense solar radiation today.[121] This may in turn have helped to reduce his vulnerability to deficiency dis�or�ders caused by pho�to�che�mical de�gra�dation 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 gene�ra�tions that here may be at stake. Folate deficiency is a common cause, or contributory cause (in combination with ge�ne�tic dis�tur�ban�ces), of hyperhomocysteinemia, which in turn is strongly associated with en�hanced risk of cardiovascular dis�ease and enhanced cardiovascular mor�ta�lity.[122] Moreover, folate deficiency may also cause im�pair�ment of im�mu�nological func�tions.[123] Cell-mediated immunity is especially affected by folate deficiency: the blastogenic response of T lymphocytes to cer�tain mitogens is decreased in folate-deficient humans and animals, and the thymus is al�te�red.[124] Folate deficiency must therefore be ex�pected to con���tri�bu�te to enhanced morbidity and mortality from infectious diseases, es�pe�cially 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 be�cau�se a good immunological response depends on a ra�pid proliferative response in various types of leukocytes or their precursors, which is not possible without correspondingly high rates of DNA synthesis in the pro�li�fe�ra�ting cells. The effects of folic acid deficiency upon hu�mo�ral immunity have been more thoroughly in�ves�ti�ga�ted 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 nuc�leotides (in form of the corresponding triphosphates) that are found in the DNA molecule. The genetic mes�sa�ge 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 co�pied to form corresponding RNA molecules.[127] These contain three of the same ba�ses as the DNA molecules, while bases number four are different in the DNA and RNA mo�le�cu�les, 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 avail�able in form of the corresponding nucleotides which, furthermore, must be trans�for�med into the corresponding energy-rich triphosphates before they can be incor�porated into DNA or RNA molecules.[130] Nuc�leotides used during DNA and RNA biosynthesis can be made in two different ways, either by de novo path�ways from precursor molecules that do not con�tain nucleotide bases, or by so-cal�led salvage pathways from de�gradation products of DNA and RNA (which may come from dead human cells, from the diet, or from bac�teria and other microorganisms e.g. in the intestine), so that purine and pyrimidine bases from de�graded 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 dif�fe�rent nucleotides found in DNA molecules, viz. the purine base-containing nucleotides de�oxy�adenylate and deoxyguanylate and the pyrimidine base-containing nucleotide thy�mi�dy�late.[132] It also participates in the de novo bio�synthetic pathways for the purine base-con�tai�ning nucleotides adenylate and guanylate which are used during RNA biosynthesis.[133] Du�ring de novo thymidylate biosynthesis, folate par�ti�cipates as an essential component of the enzyme thy�mi�dylate synthase, which makes thy�mi�dylate from deoxyuridylate.[134] During de novo biosynthesis of the purine nucleotides (adenylate, gua�ny�late, deoxyadenylate and de�oxy��gua�ny�la�te), folate participates as an essential com�po�nent of two different en�zy�mes ca�ta�ly�zing two consecutive steps in the same pathway, viz. GAR transformylase (also ab�bre�via�ted GART) and AICAR transformylase.[135] These folate-de�pen�dent steps in de novo pathways for biosynthesis of nuc�leo�tides nee�ded for DNA and RNA biosynthesis are in�hi�bited by the an�ti-cancer drug me�thotrexate, 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 bio�syn�the�sis are also needed during DNA repair. It must therefore be expected that metho�trexate will inhibit DNA repair in the tumor cells, which may in turn enhance the pro�ba�bi�li�ty of severe DNA damage triggering apoptosis (cel�lular suicide) in the tumor cell po�pu�la�tion. It should also be noted that nucleotides are needed during cell growth not only becau�se they are nee�ded as precursors for making DNA and RNA, but also because they par�ti�ci�pate in biosynthetic pathways for various mem�bra�ne lipids (e.g. for making phos�pha�ti�dyl�choline from free choline) and carbohydrate molecules.[137] Adenylate, furthermore, is also needed for making ATP, which is the chief �ener�gy cur�ren�cy� molecule used by the cells to drive a large number of different non-spontaneous che�mi�cal reac�tions 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 nuc�leotides that are needed for energy metabolic and biosynthetic pathways essential for cell growth. This may not only apply to cellular di�vi�sion, but also other forms of cellular growth as it may be observed in non-dividing musc�le cells or nerve cells, e.g. during the growth of the infant brain, during regeneration pro�ces�ses following brain trauma or stroke, and quite generally during learning processes (which may depend on micro-anatomical re�mo�delling processes improving the synaptic con�tact between particular pairs of neurons while perhaps also decreasing the synaptic con�tact between other pairs of neurons). How�ever, it may be expected that processes de�pen�ding on rapid cellular growth � which includes various immunological functions and also the re�ge�neration of the intestinal mucosa - may be es�pe�ci�al�ly sensitive to nucleotide de�ple�tion. 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 af�fec�ted 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 nuc�leo�tides can be produced by salvage path�ways 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 cor�re�lation 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 in�dus�trial 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 com�po�si�tions 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 pro�te�in/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 hun�ter/ga�therer peoples who were living in sub-Arctic or Arctic en�vi�ronments (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 com�mon today, even for popu�la�tions 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 lea�ves, which are functionally much more active, and also compared with most animal foods. Many refined, ener�gy-rich foods (e.g. refined sugar, margarine) are virtually empty both of DNA and RNA. It is the�refore 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 indus�trial countries today. The decline of DNA and RNA intakes may probably have started al�rea�dy 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 con�sumption of various refined car�bo�hyd�rate 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 direc�tion, 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 deve�lo�ping 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 al�so compared to diets typical of the more affluent socio-economic groups in the developing countries them�sel�ves. It follows that the deleterious effect of a certain degree of folate deficiency in rela�tion to processes dependent on rapid cellular proliferation (including immunological func�tions 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 there�fore 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 de�gra�dation 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 im�mu�nological defense against virtually any kind of infectious disease (even though it may be possible that the replication of the in�fec�tious agent sometimes also might be inhibited as a result of nucleotide defici�en�cies, es�pe�cially perhaps in the case of various viral infections). At the same time, it may also be possible that it com�mon�ly may lead to (or contribute to) degeneration of the intes�ti�nal mucosa (villus atrophy), with the com�bi�na�tion of intestinal mucosal damage and im�pai�red immunological functions in the intestine both con�tri�bu�ting to increased mor�bi�dity 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 pro�ces�ses � and what consequences inefficient DNA repair in turn might have both for the incidence of can�cer and for biological aging. One might wonder how much in�hi�bition of DNA repair (because of a poor diet) could mean e.g. for the problem of liver cancer in many de�ve�lo�ping countries. And is it possible that smoking and alcohol abuse both might be even more dan�ge�rous � as a consequence of less efficient DNA repair � for poor people living in deve�lo�ping 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 thy�mi�dylate bio�syn�the�sis, 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 com�bi�na�tion with other anti-HIV drugs, which helps to inhibit viral replication more ef�fec�tively than is possible with one drug alone and therefore also helps to counteract (or delay) the evo�lu�tion of drug resistance in the virus.[142] After entering the host cell, zidovudine is phos�pho�ry�lated by thymidine kinase to zidovudine monophosphate, and finally by nucleoside di�phos�pha�te kinase to active zido�vudine 5-triphosphate.[143] High concentrations of the mono�phos�pha�te may accumulate in the cell, and the intracellular half-life of zidovudine 5-triphosphate is ap�pro�ximately 3 hours.[144] Zidovudine 5-triphosphate terminates viral DNA chain elon�ga�tion by competing with thymidine tri�phos�pha�te for incorporation into viral DNA.[145] Zi�do�vu�di�ne 5-triphosphate also weakly in�hi�bits cellular DNA polymerase-alpha and mitochondrial polymerase-gamma, and the monophosphate com�pe�titively inhibits cel�lular thymidine ki�na�se, an effect that reduces levels of thymidine triphosphate.[146] These latter effects may con�tri�bute to the drug�s cytotoxicity and adverse effects.[147] It may thus be theoretically expected that the combination of folate de�fi�ci�ency and zidovudine may by itself be enough to cause immunodeficiency, even when HIV viral re�plication is ef�fi�ci�ently suppressed. This is because the proliferation of leukocytes or their precursors will now be hindered by a shor�ta�ge of thymidylate, which will lead to corres�pon�ding reduction of the rate of DNA biosynthesis in the pro�li�fe�ra�ting cell popu�la�tion. 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 sup�pression of thymidylate biosynthesis caused by zidovudine at a therapeutic dosage level. This might po�ten�tially be very important not only for the pro�li�fe�ra�tion of leukocytes of va�ri�ous kinds (or their precursor cells), but also for the proliferation of intestinal epi�the��lial cells (enterocytes and colonocytes). Suppression of intes�tinal 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 en�han�ce the risk of diarrhoeas caused not only by the reduction of the area of absorbtive surface, but also by associated brush border oligosaccharidase de�fi�ciencies leading e.g. to lactose intolerance or sucrose in�to�le�ran�ce), but presumably also mal�absorbtion of drugs used either for treat�ment of the HIV disease itself or for treat�ment of other infections, such as tu�ber�culosis or malaria. The effective dosage level of the drug con�cerned may thus become too low, which will not only reduce the effect of the the�rapy, but also must be ex�pec�ted to increase the risk of drug resistance development in the pathogenic organism con�cerned - which might be the HIV virus itself, but also Myco�bac�terium tuberculosis or some Plasmodium spe�cies, e.g. P. fal�ci�parum, or any among several other disease-causing organisms.[148] The putative public health con�se�quen�ces 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 di�rect�ly concerned; it will, for instance, also make it much more dif�fi�cult for foreign medical personnel or other aid workers to go to the countries con�cer�ned if there is no drug available for treatment of malaria any more because the disease-cau�sing organism as evol�ved mul�ti�re�sistance against absolutely all drugs previously avail�able for treatment of this dangerous dis�ea�se. It may also be ex�pec�ted that some of the multiresistant pathogens concerned (e.g. mul�ti�re�sistant plasmodia) may spread rather easi�ly from one part of the world to another (especially when patients who have been in�fec�ted with some multi�re�sistant organism while travelling abroad finally return to their ho�me�land). Not a very nice pros�pect for a futu�re �greenhouse world� - where insects res�pon�sible for the trans�mission of malaria and other tropical dis�ea�ses may thrive also in several countries which are now too cold for them! Finally, and per�haps most se�rious�ly, folate deficiency is mutagenic i.a. because of faulty in�cor�po�ration of uracil instead of thy�mi�ne into the DNA molecule during DNA syn�thesis or repair.[149] This form of DNA damage can be repaired, but faulty repair is common, which will lead to per�ma�nent mutations in the cells concerned, often in the form of chro�mo�somal damage (following chromosome breaks).[150] During repair of uracil in DNA, transient nicks are for�med; two op�po�sing nicks could lead to chromosome breaks.[151] A level of folate deficiency cau�sing chromosome breaks was found in approximately 10% of the po�pu�lation 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 die�tary intake of DNA: folate deficiency must be expected to be more strong�ly 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 defi�ci�ency (be�cause of misincorporation of uracil in the DNA molecule instead of thymine) must be enhanced by zi�do�vu�dine with the com�bi�na�tion 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 pos�sible 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 pos�sible 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[153] and en�han�ce the rate of biological aging when it occurs in mito�chondrial DNA. A typical cell contains many mito�chondria, and each mito�chond�rion con�tains many chromosomes, which may bring the total number of mito�chondrial chro�mo�so�mes per cell to typically about 1000 (as against only 2 per cell for each of the nuc�lear chro�mo�so�mes with exception of the sex chromosomes in men). In a newborn child, there are there�fore typically about 1000 copies of each mitochondrial gene per cell. But the mutation rate is much higher for mitochondrial DNA than for nuclear DNA, which means that more and more of the mitochondrial gene copies per cell will be lost as an individual becomes older.[154] This will sooner or later lead to a situation where the synthesis rate for critical mitochond�rial proteins will be decreased. This will first lead to some degree of impairment of mito�chond�rial function (causing reduction of the cellular capacity for ATP production and en�hanced oxidative stress), but sooner or later (when the inhibition of mito�chondrial function becomes more severe) to the death of the cells concerned. This may in turn lead to organ failure which will in turn lead to the death of the orga�nism if some very critical organ (e.g. the heart) is affected. No person can survive his own mitochondria! There is strong reason to believe that the process of progressive accumulation of DNA lesions in the mitochondria (much of it in form of deletions) must be one of the most fundamental mechanisms of aging, if not the most fundamental one, in multicellular animal organisms.[155] It must be ex�pec�ted that the rate of mitochondrial DNA mutation can be en�han�ced both as a result of factors that may enhance the rate of production of primary mito�chondrial DNA lesions (before DNA repair has taken place) and factors that may interfere with DNA repair. It may therefore be expected that folate deficiency may be an important contributory cause of accelerated mitochondrial aging.[156] If the rate of mutation is enhanced also in the germ cells (e.g. in the mitochondrial DNA of resting female germ cells), this will enhance the burden of deleterious mutations in fu�tu��re generations. Enhancement of the mutagenic burden for future generations is also what should be considered by far the most serious me�di�cal consequence of to�bac��co smo��king, worse than the enhanced risk of dying from cancer or heart disease for the smoker himself. But while girls at the age of puberty (when many of them will start smoking) are warned against the risks of lung cancer and heart disease if they start smoking, how many of them are warned that it can also damage their egg cells � and that they should avoid intercourse with a boy who is a tobacco smoker if they want to minimize the risk of getting genetically unhealthy children, grandchildren or grandchildren�s grandchildren? And how many of them are asked the question, what may be worst for themselves and for society as a whole, either dying at a much too young age from an overdose or heroin or morphine, making themselves a life-long psychiatric casus through misuse of drugs (such as ecstacy) that kill serotonin-producing and/or dopamine-producing nerve cells in their brain � or misusing substances (such as tobacco and most probably also alcohol) that may damage the DNA molecules of their children, grandchildren and grand�child�ren�s grandchildren? Enhancement of the mutagenic burden for future generations must also be considered the most se�ri�ous putative consequence of inadequate control of direct or indirect geno��to�xi�ci�ty of substances used as drugs by mil�lions of people. This could be a potentially much underestimated problem because the net now used in order to discover geno�to�xic sub�stances (including drugs new and old) is not fine-mas�ked enough; i.e. those tests that are routinely used for mutagenicity scree�ning, such as the Ames test, will not reveal all re�le�vant forms of direct or indirect ge�no����to�xi�city, as in such cases where a substance which is inert by itself (as far as genotoxicity is concerned) is metabolized by mammalian cells into one or more substances that function as generators of reactive oxy�gen species through a redox cyc�ling mechanism. And it is also much too common that no ap�propriate re�gu��la�to�ry action is ta�ken, even when there is very good do�cu�mentation for the di�rect or indirect genotoxicity and/or car�ci�no�ge�ni�city of sub�stances used as drugs (e.g. zidovudine, also called AZT),[157] as food or feedstuff ad�di�ti�ves (e.g. BHT and BHA)[158] or for other such pur�po�ses that may lead to exposu�re of lar�ge num�bers of peop��le. It appears as if very short-sighted economic inte�rests too often may have prio�ri�ty over the question of protection of our own genes. What use (except for a short time of momentaneous pleasure) is there in the transfer of DNA mole�cules from man to woman if the DNA molecules in the germ cells both of the donor and recipient partner already are destroyed? Another example of the same type of problem is the continued large-scale use of dental amal�gam fillings for several years after the toxicological hazards of mer�cu�ry (simi�larly as for various other toxic heavy metals) had be�co�me over-abun�dantly docu�men�tated in the inter�na�tional scien�ti�fic literature. Mercury can exert an im�por�tant indirect ge�no�toxic effect because it may cause inhibition of H2O2-sca�ven�ging selenium-de�pen�dent enzyme sys�tems vital for the protection of the DNA mo�le�cules against H2O2-in�du�ced oxidative da�ma�ge. H2O2 damages DNA mole�cules.[159] This hap�pens mainly in reactions which are catalyzed by iron and other redox-active metals.[160] The resulting damage is similar to that caused by ionizing radiation.[161] Mercury inhibition of the thioredoxin re�duc�ta�se/thi�o�re�do�xin/2-Cys per�oxi�redoxin sys�tem of H2O2 sca�venging is probably especially important here. 2-Cys per�oxi�re�do�xins scavenge H2O2 with reduced thio�re�do�xin as reducing cofactor.[162] This cofactor is next re�ge�nerated in its reduced form by thioredoxin re�ductase, which is at the same time both a fla�voprotein, a dithiol-enzyme and a seleno�pro�tein using NADPH as its reducing cofactor.[163] Thio�re�do�xin re�duc�tase has a very unusual structure with sele�no�cys�teyl and cysteyl groups in neighbour po�si�tion, making this enzyme un�usua�lly sen�sitive to in�hi�bi�tion by toxic heavy metals.[164] As an ex�ample, it may be men�tio�ned that the sen�si�ti�vity of this enzyme to the organic gold compound auranofin (which is used for treatment of rheu��matoid arth�ritis) is more than 1000-fold higher than the sen�si�ti�vi�ties of glu�ta�thio�ne per�oxi�dase (which is an�other sele�no�pro�tein) and of the dithiol en�zy�me glu�ta�thio�ne re�duc�ta�se to auranofin.[165] This indirect genotoxic effect of mercury (be�cau�se it inhibits se�le�ni�um-de�pen�dent enzyme systems important for protection of the DNA molecules against H2O2-induced damage) must be expected to dependent on the level of selenium intake, so that it may be en�han�ced when the selenium intake is low and reduced when the selenium intake is high. However, the ave�ra�ge se�le�nium intake is dan�ge�rous�ly low in several European countries including the United Kingdom,[166] while no re�gu�la�tory action is by the health authorities in the countries concerned (including Norway, Den�mark and Sweden) in order to correct this problem � with the only ex�cep�tion of Finland among European countries. There seems also to be very little interest among the regulatory agencies and inter�national or�ga�ni�za�tions con�cerned about the mu�ta�ge�nic effects of dietary deficiency con�di�tions (such as suboptimal intakes � which may or may not lead to cli�ni�cal defi�ci�en�cy symptoms � of folate, vitamin B12, selenium or sulfur ami�no acids) and the con�se�quen�ces such diet-in�du�ced mutations may have for the health of future generations. Man is not only the cause of widespread de�fo�res�ta�tion causing acce�lerated soil erosion all over the world;[167] we are also damaging our genes and ero�ding our own genetic heritage in a way and at a tempo which po�ten�tially might threaten our future survival as a spe�cies.
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