Metabolic Pathways and The Demographic Dividend Edward Hugh Barcelona July 2006

Second Draft Only, Not For Quoting Without The Explicit Permission Of The Author Introductory note: at the end of the paper I have appended a short conceptual glossary appendix. This is not intended for incorporation in any final published version, but may prove helpful for any economist wishing to evaluate the claims made herein who is unfamiliar with the conceptual terrain involved.

Abstract

It has long been recognised that a process known as the demographic dividend is operative during the early take-off of newly developing economies. The principal motors behind this demographic dividend have been assumed to be either compositional (labour force participation, dependency ratios), or behavioural ( savings and investment, prime-age worker productivity) in character. However, an increasing body of work has recently drawn attention to the role of health in economic performance, and in particular to the relationships between health, life expectancy and economic growth. Drawing on recent epidemiological research and analytic work in the field of Life History Theory this paper asks whether there may not be additional mechanisms in the demographic dividend process - the so called 'metabolic pathways' -which are yet to be identified and formally specified. In particular Life History Theory has drawn our attention to the way in which many of the factors which influence our life histories, like age-specific mortality schedules and age at menarche, may in fact be endogenous to the economic development process. In drawing this conclusion this approach is substantially in harmony with recent work by Robert Fogel and Dora Costa, and in particular with their technophysio evolution hypothesis. In addition recent work in the epidemiology of the great mortality decline has shown the extent to which both Body Mass Indexes and final heights may be associated via the operation of a combined influence from nutritional environment and disease load in early life. Key to interpreting this relation is the 'fetal programming' hypothesis advanced by Barker and his colleagues. Applying this hypothesis to major life history trade-offs between maintenance and growth (especially in the context of the immunological, endocrinological and cognitive systems) the conclusion is tentatively drawn that an important component in the lagged output and productivity growth spurts which characterise the development process may, in fact, be masquerades

associated with the cohort-based impact of the arrival of a generation (or waves of generations) with comparatively lighter early allostatic loads (vis-avis preceding generations) in terms of maintenance costs, a change which leads to a more orderly and complete development of immune, endochrine and cognitive systems. In a nutshell this means the 'wave like' arrival of longer-living, healthier and more productive adults. In terms of future directions for research the paper tentatively advances five areas which might prove fruitful: i) the development of adequate quantitative techniques for testing the hypothesis herein advanced; ii) increasing evidence which suggests that there may be a kind of metabolic syndrome associated with the combination of early-life nutritional constraints subsequently relaxed and the evolution of a sedentary lifestyle constitutes a warning signal that the rapid economic growth now taking place in many developing societies may contain a negative health kick-back which has yet to be adequately understood. iii) a re-examination of earlier work by Nick Crafts (on the industrial revolution in the UK) and Alwyn Young (on the Asian tigers) may be called for in order to explore the hypothesis that the inability to identify significant TFP elements in early economic growth may be associated with the kind of mechanisms herein identified; iv) historical time series for developed economies have long been known to contain data trends which have been hard to account for (the so-called long-wave effects). It is proposed that it might prove fruitful to re-examine this issue in the light of the processes herein identified; v) the existence of an early demographic dividend associated with the age specific mortality decline at the younger ages implicity raises the question of whether or not there may be a subsequent 'demographic penalty' correlate to investigate in the context of the second stage of the mortality decline and continuously ageing socities. This issue is not considered in any depth here, but it is suggested that they key to this may be addressed via a consideration of whether Jones's early observation that the physiological age of each new generation is remaining more youthful at the same chronological age remains a valid one in the context of the second stage mortality decline or whether the economic processes we are now seeing in the most elderly of the ageing societies (Japan, Germany, Italy) represent a deferred payment for an earlier allocatively-driven benefit.

The Demographic Dividend Economics is a branch of biology broadly interpreted (Alfred Marshall, 1920, p. 637) "the Mecca of the economist lies in economic biology rather than in economic dynamics" (Alfred Marshall, 1920, p. xiv).

What has become known as the demographic dividend occurs when the decline in birth rates which normally follows the initial mortality decline associated with the onset of the demographic transition leads to changes in

the age distribution of a population. These changes mean that the youngestyoung gradually become an ever smaller percentage of the total population, an age transition which implies that slowly but steadily less collective expenditure is required to meet the needs of the youngest age groups - there is a constant reduction in downward intergenerational wealth flows to use the terminology of John Caldwell or Ronald Lee (Caldwell, 1982, Lee, 2006) . Essentially a falling birth rate makes for a smaller share of the population in the younger, dependent, ages and for relatively larger share in the adult working age groups who comprise the productive labor force. Thus the ratio of productive workers to child dependents in the population is improved, and with this the potential per capita income. In principal this should make for faster economic growth and fewer burdens on individual families and collective welfare systems. According to Bloom and Williamson (Bloom and Williamson, 1998) the 'demographic dividend' leads to opportunities for growth in output per capita for two principal reasons. Firstly, there is a 'pure' age-structure impact on total GDP due to a simple 'factor availability' or 'growth accounting' effect in that having a rising share of the total population in the working-age group increases the ratio of producers to consumers. Obviously this situation is extremely favourable to the growth of output per capita. This 'composition effect' may be also be enhanced by positive feedback processes associated with the ongoing fertility decline which, for example, release more women from childrearing activities and enable them to enter the labour market. A second changing age-distribution impact is identified by Bloom and Williamson, and they group this impact together under the heading 'behavioural effects'. These behavioural effects take a variety of forms. On the one hand there are a growing number of prime-age workers in the work force and this enhances overall per capia income due to the well-know prime-ageworker productivity effect. On the other hand there are changes in aggregate saving and consumption following some sort of life cycle pattern. This increase in saving can, in principal, make capital more available, and hence make it relatively cheaper. There may also be human capital impacts from gender related issues associated with the fertility decline as changing attitudes to female emancipation lead to an increase in female participation in the education system, and hence to a more educated female labour force. The sum total impact of all of these factors combined is a further substantial increase in potential growth in output per capita.

Clearly this demographic dividend is far from permanent. There is a limited window of opportunity. In time, the age distribution changes again, as the large adult population moves into the older, less-productive age-brackets and is followed in its turn by the smaller cohorts that were born during the fertility decline. When this occurs, the dependency ratio rises again, as does the level

of intergenerational transfers, but in this case 'dependency' means the care and support needs of the elderly, rather than the the costs of supporting a large young population. Also, as the transition evolves, fertility continues its downward course, gradually leading to the arrival of below replacement fertility, and eventually the phenomenon which has become known as lowestlow fertility in a growing number of developed and developing countries (Kohler et al 2002, Hugh, 2006a). The entire course of this trajectory may perhaps best be followed through what Bo Malmberg calls the Four Phases of the Demographic Transition schema (Malmberg and Sommestad, 2000, Hugh, 2006b). It sould be noted that this entire process seems to involve a series of complex and intricate trade-offs and feedback mechanisms, where fetal growth, adult health, longevity, initiation of reproductive age and fertility all seem to be interconnected in ways which have yet to be adequately specified. The dividend is also, of course, far from automatic. While demographic pressures are eased as fertility falls, some countries will be better able to take advantage of this easing than others. Institutional structures matter. Some countries will act to capitalize on resources released and will use them effectively, while others will not. From an examination of median ages (see Hugh, 2005) it can be observed that countries like Russia, Cuba and North Korea have passed through their demographic dividend epoch without gaining anything like the growth boost they might have expected. Iran seems to be about to add its name to this list. The Eastern European transition countries also have special characteristics in this regard, since while inclusion in the European Union now means that many of their economies are passing through a 'catch-up' growth process, they are doing this long after the initial impact of declining child and infant mortality has past, and they are now about to enter a process of rapid ageing with uncertain consequences. There may however be other mechanisms at work in the dividend process. In a certain sense Bloom and Williamson's examination of the compositional and behavioural impacts remains purely descriptive (Bloom et al, 2002). Essentially the changes they describe simply happen, although of course they do have consequences. But the possibility remains that these compositional and behavioural components may be associated with and driven by a much more fundamental set of interconnections which underlie the whole process. Since most of the effects identified relate to the age structure of any given population, then simple intuitions should tell us that they must at some level be associated with fertility and longevity, and with the relative co-movements of these two parameters. Of course the key problem here is to identify canditates for mechanism, and canditates for the indicators whose movement might help us see where the interconnections lie, and what exactly the interconnections are. Among potential candidates one of the most important and promising is undoubtedly health. It is long been known that the process of economic development is associated with an improvement in the general level of health of the population. Conventionally health improvements have been thought to

be associated with an improvement in the general nutritional environment of a population and with a reduction of the disease load on young children. (McKeown, 1976, Fogel, 1996). More recently a number of authors have taken a look at this health impact on growth (Bloom et al, 2004, Bloom and Canning, 2005, 2003, Weil, 2005, Schultz, 2005). As we shall see below there are now good reasons for considering the possibility that these two elements nutrition and susceptibility to disease - may in fact be inter-related. Health impacts on economic performance may be thought of in a number of ways. In particular, health conditions affect child mortality and adult longevity, both of which may be considered to be major determinants which enter into long run fertility decisions. The inuence of health on adult longevity clearly influences the horizon over which important economic decisions, decisions affecting for example both savings and investment behaviour, are taken, and thus will interact with levels and rates of both physical and human capital formation. In particular the overall health status of an individual influences the effective time the individual needs to acquire human capital or to perform a certain task, i.e. his or her productivity, as well as the quantity of time which he or she needs to invest in obtaining this capital, and thus could be thought to influence, indirectly, the timing of reproductive decisions. One way of looking at these health issues has traditionally been to consider the way health influences the quantity and quality of human capital. Health can either be considered to enhance productivity by increasing physical capacities, such as strength and endurance, or it can improve cognitive functioning and reasoning ability. Improvements in health should thus lead to higher productivity for both skilled and unskilled workers. There have been a number of studies which have indicated how this process may work at the microeconomic level (Savedoff and Schultz 2000; Schultz 1999, 2002, 2005; Schultz and Tansel 1992; Strauss and Thomas 1998). Higher incomes also clearly facilitate access to many goods and services which may be beneficial to health and longevity, such as a better nutrition, safe water and sanitation, and improved health care, so there may well be interesting feedback mechanisms at work here too, and in recent years awareness of the possible existence of such feedback processes has lead researchers to investigate the possibility that the income-health correlation may also involve a causal link running in the 'reverse direction' from health to income. Now it has long been known that a number of plausible pathways exist through which health improvements may influence the pace of income growth - via, as has been said, impacts on labor market participation, worker productivity, investments in human capital, savings, fertility, and population age structure - and many of these avenues are already well-explored (Bleakley, 2003, Bloom and Canning 2000, Bloom et al, 2003, Easterlin 1999, Gallup and Sachs, 2000, Hamoudi and Sachs 1999, Kremer and Miguel, 2004).

One common approach to the study of these health-income-economic growth correlates has been to focus on cross-sectional data for a variety of countries and to regress the rate of growth of income per capita on the initial level of health (typically measured by life expectancy), with controls for the initial level of income and other likely relevant factors. Such factors might include, for example, policy variables like openness to trade, institutional quality, educational attainment, the rate of population growth and geographic characteristics. However, as argued in Dasgupta (Dasgupta,2004, see also Azariadis et al, 2006), the linkages may be more subtle than these approaches envisage and poor health may also be thought of as having the potential for generating a kind of poverty trap through the mechanism of poor health making workers unproductive, with the resulting low incomes then reinforcing poor health. Dasgupta uses the very suggestive term 'metabolic pathways' to describe the "physiological links connecting nutritional status and work capacity among adults, and those connecting nutritional status and physical and mental development among children" (Dasgupta, 2004). This idea of the metabolic pathway is one which we will return to in detail below. Another way of thinking about all this is to examine the role of mortality and life expectancy in the context of the fertility transition (Heer and Smith, 1968, Cassen, 1978, Kirk, 1996, Mason , 1997 and Macunovich, 2000), since life expectancy, and in particular adult longevity, seems to be a key determinant of human capital acquisition and income differences across countries (Soares, 2005, Shastry and Weil, 2003). This kind of approach is also consistent with the ndings of Lorentzen et al (2005) who provide evidence that life expectancy may have a causal impact on economic development, in addition to investigating the reasons why changes in longevity tend to precede changes in fertility behavior. The theoretical role played by these different dimensions of human development has, however, not been widely investigated. One exception would be the work of Rodrigo Soares, who, for example, in a recent study (Soares, 2005) found that passing cross country panel data for the years 1960 to 1990 through his 'estimated model' suggested a 10 year gain in adult longevity produced a reduction in fertility of the order of 1.7 points, increased average schooling in the population by 1 year, and increase in the growth rate by some 5%, while a reduction of 100 per 1,000 in child mortality implied a 1.5 point decrease in the total fertility rate. Now the magnitude of these finding may be open to question (according to the specification of the model used), but the existence of such relationships, and the direction of the co-movements, is certainly not without interest. In similar fashion Lorentzen et al (2005) advance the hypothesis that mortality affects growth by altering the timescale over which decisions are taken. Essentially they argue that people who expect to die young fail to take actions which entail short-term costs and but do have associated long-term benefits. As we will see later this could be termed the live now-pay later trade-

off. They suggest, for example, that a high death rate from exogenous causes (a climatically related susceptibility to malaria, for example) could lead to behaviour which is associated with a high death rate from endogenous causes (specifically they consider the cases of smoking and AIDS). In this way a number of the proximate determinants of growth, such as the accumulation of physical and human capital, as well as the rate of fertility, may all be affected by the mortality rate. The problem that is presented in the context of all this literature is that such macro-level aggregates for 'big indicators' like fertility and longevity, need to be comprehensible at the micro level, and need an explanatory mechanism which can demonstrate just how such processes might work. Now it has long been known that life events in-utero and during early childhood have significant impacts on individual health throughout the whole life course (Barker, 1992), and that as well as nutrition, the disease environment encountered during the early years of life plays a critical role in the subsequent evolution of health (Fridlizius, 1984). In order to see exactly what may be involded in such processes it is analytically convenient to classify early life health impacts on two different levels. In the first place it is postulated that there is an early environment impact on mortality, which is then followed by a subsequent 'cohort based' impact on the lifetime health of the individual. From an economic point of view these two components (mortality, and lifetime health) both need to be accounted for in terms of economic growth theory. In the second place the mortality decline can itself be conveniently subdivided into two separate components, an initial decline in infant and child mortality, and a subsequent decline in mortality rates in later life (Cutler and Meara, 2001). As Cutler and Meara suggest (in their case in a US context) aggregate mortality trends conceal as much as they reveal. There have been relatively continuous declines in mortality in the US over the course of the 20th century, but the age distribution of this mortality decline has not been at all uniform. In the first four decades of the 20th century 80 percent of life expectancy improvements resulted from reduced mortality for people under 45, with the majority of this reduction being explained by a decline in mortality for infants and children. During the next two decades life expectancy improvements showed no discernable age specific pattern. Since 1960 however the pattern has once more demonstrated a clear trend, with two-thirds of life expectancy improvements coming from mortality reductions for persons over age 45. A change has also also occured in the epidemiological characteristics associated with the mortality decline. During the first half of the 20th century, infectious diseases were the leading cause of death. Changes in the ability to avoid and withstand infection were the prime factors in reduced mortality. The disease-fighting ability reflected in this was not predominantly a medically-based one. Nutrition (Fogel, 1994), and public health measures (Preston, 1996) are considered to have been much more important in achieving the reduced mortality than medical interventions were. Since 1960,

however, the substantial decrease in U.S. adult mortality has been associated to some extent with continued improvements in living standards, but it has been health behaviour, and in particular the availability of medical care, which has shown the closest association with the lowered mortality from chronic diseases which characterises the decline, especially in the cases of heart disease and stroke. One additional possibility is that this improvement represents in part a cohort-relative footprint of earlier environmental impacts produced via the fetal-programming mechanism (see below), but at this level it is often difficult to separate one causal factor from another. One convenient framework for thinking about mortality and reproductive schedules comes from a branch of evolutionary anthropology known as Life History Theory (LHT). Essentially LHT is concerned with evolved human life history characteristics like mortality schedules, age at puberty and menopause, relations between body size and growth etc. Initially LHT postulated that such characteristics were essentially 'extrinsic' (Charnov, 1993, Kozlowski & Wiegert, 1986) and not subject to endogenous processes. However - as Hillard Kaplan suggests - this approach is theoretically unsatisfying, as there is evidence that higher organisms exert control over virtually all causes of mortality (e.g., by altering patterns of travel to avoid predators, by investing in immune function etc) and these endogenous processes can also be seen at work in the varyiance in ages of menarche and menopause (Kaplan and Robson, 2002, Kaplan et al, 2003). This argument has some resonance with recent economic approaches, notably Robert Fogel and Dora Costas idea of technophysio evolution (Fogel and Costa, 1997, Fogel, 2001). Technophysio evolution is defined by Fogel as follows: "Technophysio evolution is the result of a synergism between technological and physiological improvements that has produced a form of human evolution that is biological but not genetic, rapid, culturally transmitted, and not necessarily stable. This process is still ongoing in both rich and developing countries. Unlike the genetic theory of evolution through natural selection, which applies to the whole history of life on earth, technophysio evolution applies only to the last 300 years of human history, and particularly to the last century." (Fogel, 2001, p4) again according to Fogel: "The process has been synergistic.....with improvement in nutrition and physiology contributing significantly to the process of economic growth and technological progress.......... Technophysio evolution appears to account for about half of the economic growth in Europe over the past two centuries. Much of this gain was due to the improvement in human thermodynamic efficiency. The rate of converting human energy input into work output appears to have increased by about 50 percent since 1790." (Fogel, 2001, p4) The traditional LHT framework has also been thought to be analytically

limited, in that it does not provide a complete explanation of how mortality rates evolve. In reality what varies as a function of ecological factors are not set mortality rates, but rather functional relationships between mortality and the efforts allocated to reducing it. Exogenous variation can be thought of in terms of varying 'assault' types and rates (Kaplan et al, 2003). The essential features of the human life history are normally considered to be those concerned with growth, mortality and fertility (Mace, 2000). A fundamental assumption of LHT is that trade-offs exist between energy expended on growth and factors influencing mortality on the one hand and reproduction on the other (Williams 1957; Roff 1992; Stearns 1992). Historically the costs of reproduction may be paid in terms of energy being diverted away from body repair and maintenance (Kirkwood & Rose 1991) and reduced investment in immunological competence. According to LHT, at any point in time, an organism faces a key decision. Its energy can be converted into offspring or into life sustaining activities (e.g., additional energy harvesting, growth, predator reduction, repair, etc.), in any proportion. Put on a more general level, resources need to be allocated between three domains: growth, reproduction, and maintenance. The level of energy intake less the costs of staying alive (maintenance) determines the quantity of resources available for growth and reproduction (productivity). Allocation of resources to one domain meets some goals (e.g., increased maintenance to increase longevity) at the expense of the ability to invest in other competing demands (e.g., increased growth to enhance adult size and competitive advantage or reproductive capacity, Allal et al., 2004). It is also important to be aware that costs and benefits may accrue on different time schedules (Metcalfe and Monaghan, 2001). For instance, maintenance may be economised earlier in the life course in order to handle a period of calorie restriction, but this may then carry the deferred cost of later mortality risk. Mortality schedules determine the probability that an organism will survive to realize a time-delayed cost or benefit. A second major life history trade-off, first discussed by Lack (1954, 1968), concerns the allocation of reproductive resources. LHT conceptualizes specific reproductive trade-offs in terms of three broad, fundamental decisions: the present-future reproduction trade-off (or reproduce now/reproduce later), the quantity-quality of offspring trade-off, and the trade-off between mating effort and parenting effort. The first trade-off should be a familar one to any economist who has thought about the phenomenon of below replacement fertility, since its operation in a modern context is easily recogniseable in the form of the 'birth postponement process'. The second is also readily familiar as is has shown up in economics under the guise of Gary Becker's 'home economics' (Becker 1981, 1975, Becker and Lewis, 1973). These two trade-offs working together really produce the quantum-tempo dilema which is at the heart of much recent demographic debate and head scratching (Bongaarts and Feeney, 1998). The third trade-off might be conceptualised as follows: essentially it is a well known phenomenon that couple stability has declined steadily in developed societies over the last

half century. Now in terms of expectations theory this has obvious consequences, as both parties to a union now need to factor into decison making the rising possibility that any relationship may terminate before reaching contractual term (even if the contract in question here may increasingly be considered as an implicit one). Couple participants wouldn't really be be 'fully rational' if they didn't do this in some way or another. The consequence of this change for parental investment theory, given that the investment of each parent in any ensuing union offspring is not equal, would seem to be important. Essentially women still bear a disproportionate part of the 'reproductive burden' whether this be thought of in terms of corporeal energetics, time invested, or earnings and career opportunities foregone. Now in a world which is becoming increasingly gender-equal some kind of response to this imbalance was only to be expected, and it is possibly there, in terms of increasing 'choosiness' on the part of females about the ultimate father of their children. The sociological and anthropological literature has undoubtedly addressed this issue with more vigour than the economic literature has (Oppenheimer, 1988, Mills, 2004, Lesthaeghe and Moors, 2000, Goldscheider and Kaufman, 1996, Kaplan and Lancaster, 2003, Gangestad and Simpson, 2000), although there is a tradition in the economic literature which clearly relates to this process even if it tends to conceptualise the growing disconnect between union formation and reproduction almost exclusively in union stability terms (Lehrer, 2006, Becker et al, 1977, Weiss, 1997, Popenoe and Whitehead 1999,Raley and Bumpass 2003, McLanahan 2004). This then would be the modern interpretation of LHTs standard trade-off between mating effort and parenting effort, and it has one evident consequence: more birth postponement. In order to adress such issues analytically the evolutionary anthropologist Hillard Kaplan and the economist Arthur Robson have proposed a model based on the concept of 'embodied capital' (Robson and Kaplan, 2003, Kaplan et al, 2003, Kaplan et al, 2001). What Kaplan and Robson propose is that (a) the present/future reproduction trade-off may perhaps be best understood in terms of optimal investments in own- versus offspring embodied capital (as reflected in the timing of reproduction), and (b) the quantity-quality trade-off can be understood in terms the size of investments in the embodied capital of each offspring vs. the number of offspring produced. Kaplan and Robson argue that embodied capital theory allows us to address problems which standard life history models had previously been unable to handle. In the first place, the exclusive focus of classic LHT on physical growth offered only a partial understanding of human development. The large human brain, for example, embodies a stock of capital which includes a great deal of skill and knowledge acquired during both the juvenile and the adult periods. In this sense growth in the form of knowledge (intensive, rather than extensive growth) may be just as important as growth in body and brain size when considered with respect to the provision of benefits through time.

In the second place, parental investment not only affects the survival to adulthood of offspring, it also influences the adult income (or productivity) of the offspring produced. This is just as true of humans in modern societies as it was amongst our ancestors the hunter-gatherers. Economic theory suggests that there are four possible sources of productivity growth: better trained or better educated workers, better ways of organizing production, more investment in capital (equipment, buildings, and so forth), and lastly, improved quality of capital, that is, equipment that works faster or better in some way. It is this last source which has become known in the literature as the embodied technological change component of growth. During the internet boom of the late 90s, for example, many observers attributed much of the productivity surge to embodied technical change. Solow himself acknowledges (in his Nobel Prize lecture for example, see Solow, 1987) that his original version of the neo-classical growth model omitted the embodiment mechanism, and that this absence would clearly lead to a bias away from investment process effects in the growth accounting exercises which were carried out using his initial model. Solow later modified his early growth model (Solow, 1957 Solow, 1960), and in the revised version of his model the effectiveness of innovation in increasing output is reflected in the rate of gross investment. A change which leads to increased investment could thus be thought to lead naturally not only to higher capital intensity, which may or may not be an important factor in improved productivity, but also to the faster transfer of new technology into current production, and this obviously should be. The intriguing point here is that there may well be a parallel to be found between investment and embodiment in fixed capital and investment and embodiment in the human capital variant, since brain growth also embodies improved human brain quality through cultural transmission and the learning and environmental interaction process. One of the consequences of looking at things this way might be, for example, that one is then able to ask the following question: what proportion of the increase in human performance over that of other higher primates is due to the increases in human brain size (or greater energetic investment in and of itself) and what proportion comes from increased quality where the improvements are driven by continuing interaction with an external environment? In the latter case an increasingreturns learning-by-doing element enters the calculations, since the same quantities of energy-throughput are recycled to achieve a higher brain-output advantage, and this learning-by-doing both implicitly alters the most favourable fertility trade-off path as well as the end state ultimately achieved. In fact the whole process becomes state dependent. Taking this idea one step further, it might be noted that one very thought provoking set of models which Kaplan and his co-workers have produced tries to argue something which implies just this: that investments in embodied capital affecting adult-income, or rates of energy-capture, should be

considered to co-evolve with investments affecting mortality and longevity (Kaplan et al., 2003; Kaplan et al, 2001. Kaplan and Robson, 2002). In pre-modern societies the energy-balance between maintenance, growth and reproduction is often extraordinarily finely balanced. Ronald Lee offers the following example which may prove useful in order to focus on some of the issues involved: "Turning to juvenile mortality when there is parental investment, contrast the death of a baby bird just after hatching with a death just before a baby fledges. The classic theory predicts equal selection against mortality at the two ages. However, the later death would be a total loss, whereas the early death would free up parental resources for greater investment in the surviving chicks, boosting their survival, size, and reproductive fitness, thus offsetting the direct effect and perhaps even increasing the survivors to maturity." (Lee, 2003, p 2637) Now imagine an environmental change which means that the young chick instead of dying, survives, and survives for a lot more years to boot. This simple alteration changes the entire energetic balance. Much of the reproductive energy consumed is now not a simple energy drain, but is rather conserved and enhanced, since the rate of return on energy investment suddenly increases. At the same time the maintenance cost of caring for the increased number of surviving chicks also goes up, leading to increased competition between offspring for available resources. With time evolution may lead to less chicks being born so that (in evolutionary biology terms) more can survive to reproductive age. Of course, the important point here is 'with time', since time, and generations, is exactly what evolution needs to do its work. Essentially the mechanism outlined above offers a simple structural description of the demographic transition. For reasons which needn't concern us at this point the transition starts when an environmental change occurs and the number of surviving offspring increases (this could be, for example, thought of as being produced by an external shock, Galloway, 1986, Boucekkine et al, 2003). Viewed in this light transition 'break-out' should occur when each individual offspring, benefiting from improved in-utero and early life conditions, also starts to live to ever higher ages. Now since what humans do isn't maximise fitness in the biological sense, but possibly "maximise the wealth stream of a dynasty or lineage" (let's not get hung up on what goes in between the "" at this stage, since nothing particularly hangs on this. Other interpretations can be offered), then it obviously pays to increase the maintenance input into each individual to recover the now potentially enhanced return on each initial investment. This is why at some stage, after the start of the mortality decline which characterises the transition, there is a lagged decline in fertility. (The reasons why this lag is longer or shorter again need not concern us here, just the fact that it exists). This fertility decline then unleases an increasing returns type feedback process where growth in per capita incomes, and increases in life expectancy, increase the potential return

on each individual child. Hence we get both the the quantity/quality trade-off and the reproduce now/reproduce later one. The idea that improvements in mortality schedules may not be due to medical intervention but may be due to factors endogenous to the economic development process itself is not a new one. Thomas McKeown (McKeown 1976, 1979) was perhaps the first to address issue this explicity when he made the seemingly valid point that medical influence on one of the key 'killer diseases', smallpox, could hardly be attributed to the intervention of modern medicine since vaccination (despite being available from the end of the eighteenth century) was not widely used in England until after 1840. Gunnar Fridlizius later drew similar conclusions regarding the evolution of the mortality decline in Sweden (Fridlizius 1984). This approach was subsequently developed by Robert Fogel. In support of his thesis that nutrition plays a decisive role in the process of long term improvement in life expectancy Fogel used final heights as a proxy measure of net nutrition and health during childhood. Height is seen by Fogel as a cohort-related measure of health, while weight and the body mass index are seen as life-period measures (Fogel, 1996). On the Fogel account, individuals who, as a consequence of having had well-nourished and healthy mothers, were well-nourished during the foetal stage experience lower death-risk during infancy. If they are well-nourished and healthy their cells and organs develop better, they attain a greater height and tend to have a longer life. Demonstrating correlates for health and improved economic conditions is one thing, however, and identifying the mechanisms through which the process works is another. To move an interpretation up from the hypothesis level to the theory one it is essential to have both empirical correlates and explanatory mechanism.The body of theory which may now make this kind of upgrading possible for a hypothesis of the Fogel type has its origins in a line of investigation pursued by the epidemiologist David Barker and the biologist Nick Hales (Barker 1994, 1992). The 'Barker hypothesis' - which is sometimes referred to as the womb with a view hypothesis (Deaton, 2005) - essentially revolves around the idea that events in the womb have long-lasting effects on health throughout the entire lifespan, and especially effects on health outcomes that only become apparent later in the life course. In the language of the original hypothesis nutritional insults in utero, which prevent the foetus developing to its full potential, or which produce an adaptation which is illsuited to the external environment which the individual will ultimately encounter, may cause a selective abandonment of function, an abandonment which disfavors or disables precisely those features in the organism whose primary function is to prevent disease in late life beyond the normal reproductive span (this is, of course, one version of the LHT 'live now pay later' trade-off, Metcalfe and Monaghan, 2001). In it's original formulation the theory cleary embodied an insult/pathology conceptualisation which may in fact not provide a completely satisfactory account of the complex relationships now thought to inter-connect the maternal environment with lifelong health , and to this we will return later.

On Barker's account, poor gestation conditions in utero result in impaired fetal growth and prompt an adaptive energy-sparing response on the part of the fetus which at the same time impairs pancreatic development and increases insulin resistance. Postnatally, the resultant energy-efficient adjustments in metabolic regulation foster rapid growth and promote weight gain. These adjustments have an adaptational logic in the context of a harsh nutritional environment but they also mean the system becomes rapidly overburdened when confronted with adequate-to-overnutrition, a carbohydrate-rich diet, and sedentism. The fetal origins hypothesis was in fact the outcome of extensive epidemiologic research by Barker and his co-workers who found, on examining British public health records, significant correlations between low birthweight and subsequent cardiovascular disease (Barker et al, 1989). These initial associations between small body size at birth and during infancy and later cardiovascular disease have subsequently been widely confirmed (Frankel et al, 1996, Rich-Edwards et al 1997, Leon et al, 1998), and followingup on their early lead Barker and his co-workers soon came to the conclusion that the antecedents of this subsequent heart disease were to be found in an insulin-resistance syndrome (dyslipidemia, glucose intolerance, elevated blood pressure - Barker, 1990, 1991, Hales et al, 1991, Law et al, 1991, Phillips et al, 1993a,1993b, 1994) 1. In order to account for these correlations an additional hypothesis - the fetal programming one - was also advanced (Lucas, 1991). Programming is thought to involve the setting of the physiological system by an early stimulus or insult operating during a sensitive period, and resulting in long-term consequences for function. Programming occurs through the induction, deletion or impaired development of a permanent somatic structure as a result of a stimulus or insult (Davies and Norman, 2002, p. 386). An accompanying mechanism was also advanced in an attempt to explain the operation of the programming: the thrifty phenotype hypothesis. The thrifty phenotype process is thought to operate via alteration in the glucose-insulin metabolism (Hales and Barker, 1992, 2001). Since Barker first demonstrated the existence of such relationships between birth weight and ischaemic heart disease mortality the role of prenatal programming as a determinant of subsequent adult disease has become increasingly clear. Programming is now considered to be an important underlying feature of many systemic adult diseases including coronary heart disease, hypertension, insulin resistance syndromes and osteoporosis. (Nathanielsz and Thornburg, 2003). The fetal origins hypothesis was later extended to include the idea of an 'appropriateness of fit' between the phenotype and its environment. This has resulted in attention being focused on problems which may occur if there is a mismatch between physiologic capacities established in early development and the environments in which they later function.

The fetal origins literature also directs our attention to the possibility of an intergenerational transmission of health via the translation of maternal experience, as mediated by environmental conditions, from one generation to the next. (Barker, 2001). Such environmental conditions may be physiological (maternal metabolic regulation), psychobehavioral (stress or smoking), or ecological (poverty or unstable food supply). In developing countries, and among economically deprived populations in developed ones, there is some evidence that fetal programming effects may not be limited to the first generation, but that the poor health of the mother may be transmitted to the child, and then from the chid to the grandchild. Indeed, intergenerational effects may 'masquerade' as a genetic predisposition to cardiovascular disease in subsequent generations. (Drake and Walker, 2004), Cohort Theory One clear implication of the Barker hypothesis is that the health of the adult in a nutritionally fluctuating environment may be a function of birth timing: the when of birth. This has given rise to what has come to be called cohort analysis in epidemiological research. Cohort analysis is a line of investigation which attempts to explore how disease incidence and life expectancy vary across cohorts in differing (and especially extreme) environmental settings. In the context of the 'great mortality decline' (which ocurred in Northern and Western Europe in the nineteenth century), when we talk about cohort-based health factors what we are normally talking about are factors which affect certain generational groups more than others, factors which may well have long-lasting effects on the lifetime health of the groups in question. In fact, in the context of the great mortality decline, 'cohort analysis' is essentially concerned with with two health related factors: improvements in nutrition and living conditions during the pre-birth foetal period and in early childhood, and the disease environment present during pregnancy and the early life years of a child. Both of these factors may, through their subsequent impact on health, be associated with longer term changes in life expectancy. Essentially, in the literature it is possible to identify two types of cohortrelated explanations for the mortality decline: (1) increased nutritional intake during the foetal stage and/or early years of life, and (2) decreased 'effort' during the foetal stage or early childhood being required to fight disease either on the part of the mother or of the child, or both. In both cases case the process operates not only through the impact on short term mortality but also through longer run impacts on the health of the individual. One mechanism which has been suggested for this process is via the imact of early life events on the rate of growth of the individual and the

effects of this growth period on long run health. (Mangel and Munch, 2005, Gluckman et al, 2005, Metcalfe and Monaghan, 2003). Ouside the human context laboratory studies on rodents have found that severe caloric restriction retards growth (resulting in a small bodied adult) but also lengthens lifespan, a finding which might well suggest that excessively fast early growth can have negative impacts on subsequent mortality and lifespan (Rollo, 2002; Metcalfe and Monaghan, 2003). Calorie restriction of rats at young ages has also been found to have a tendancy to slow down growth rates and to lead to short adult stature, even when food becomes abundant later in the juvenile period (Shanley and Kirkwood, 2000). Epidemiologists and demographers of an earlier generation, those who studied the great modern mortality decline from the vantage point of the 1920s and 30s, were already aware of this 'early life history' possibility (Derrick 1927, Kermack et al 1934). They noticed that mortality for children declined much earlier than mortality for adults, and that each succeeding generation seemed to carry with it the same relative mortality from childhood though to old age. Distinguishing here between period and cohort effects on mortality, if period effects (that is environmentally significant impacts on health like more clement weather, or better nutrition, or rising living standards, operating across a given time period) were the dominant factor in the mortality decline, then, in theory, it should be possible to see the health consequences of these effects being evenly distributed across both young and old segments of the population in relatively equal measure. If, on the other hand, cohort elements are dominant, then any change in health outcomes should be asymmetric, with each group (young and old) demonstrating a different pattern from the other. In this latter case there are arguably reasonable prima facie grounds for suspecting that cohort factors may be at work. Recent research seems to have increasingly confirmed this latter possibility and in so doing has begun to offer substantial justification for the initial conclusions of the early researchers. Sam Preston and Etienne van de Walle , for example, in their study of urban France, or Gunnar Fridlizius, who studied the Swedish data, found cohort effects to be significant (Preston and van de Walle, 1978, Fridlizius, 1989). Further evidence for the cohort effect can be found in the finding of Gabrielle Dobblhammer and James Vaupel (Dobblhammer and Vaupel 2001, Dobblhammer, 2002), that life expectancy at 50 varied historically on a seasonal basis - depending on the month of birth. They found that, in the northern hemisphere, 50 year olds in the studied cohorts who were born in the months of October and November (to mothers who it is hypothesised had had better access to cheap and plentiful fresh fruits, vegetables, eggs etc through most of their pregnancy) could expect to live about three-quarters of a year longer than those who had been born in the spring. They also found the same seasonal pattern in the southern hemisphere, only this time there was a six-month shift in the timing of the effect for those born in the South, with the interesting variant that those who had been born in the

North and who died in the South (European migrants in Australia, for example) continued to display the Northern pattern. Similar corroborative evidence comes from the Dutch famine of 1943, followup studies on which seem to support the claim that nutritional deficits in pregnancy have long-term impacts on, for example, obesity, with deficits in the first trimester of pregnancy predicting later adiposity, and deficits in the third trimester inhibiting it. There have even been findings which relate subsequent behavioural disorders and schizophrenia to early prenatal nutrition in this context.(Susser and Lin, 1992, Neugebauer et al, 1999, Ravelli et al, 1999, 1998, Rosebooma, 2000, van der Zee, 1998). In the realm of modern economic theory however, and in the interaction of this with economic history, there can be little doubt that if there has been one scholar who has done more than any other to advance our understanding of how the cohort hypothesis might play a central role not only in epidemiological research, but in getting to grips with the process of modern economic growth, it has been Robert Fogel (Fogel, 1994, 1996, 2001). While there is considerable evidence to back the Fogel view that life expectancy correlates with average height (Floud et al., 1990; Fogel, 1994), and that being taller correlates with a lower mortality rate (Marmot et al., 1984; Waaler, 1984), the situation may not be as straightforward as it appears at first sight, since there is also evidence that while the incidence of some causes of death, such as cardio-vascular and respiratory disease, are inversely related to height, others, such as reproductive cancers, increase in frequency with height (Leon et al., 1995; Smith et al., 2000; Song et al., 2003). There is even some debate as to whether being taller is as beneficial as it is sometimes thought to be (Samaras et al, 2003).

It is also not entirely clear either what the exact relationship is between measures of body condition and mortality. As in the case of height, there has been a good deal of research into how exactly the body mass index (BMI) interacts with mortality. Nowadays the relationship is normally thought to be a non-linear one (Wienpahl et al, 1990, Rissanen et al, 1991, Laara and Rantakallio, 1996, Yuan et al, 1998, Engeland et al, 2003, Kuriyama et al, 2004), with individuals with both low BMI and those with high BMI experiencing relatively higher mortality rates.

One evident problem with the kind of work Fogel and others have been doing in this area is that establishing correlations is one thing, and finding mechanisms (and especially micro-mechanisms) to explain these correlations is quite another. This need for mechanism has only been reinforced by more recent work in immunology and endocrinology (Mcdade, 2005, 2003, Worthman and Kazara, 2005, Ibaez et al, 2006) which suggests that subsequent BMIs may not simply be a period effect, but may, in fact, bear a

direct relationship with events experienced in-utero. Support for a modified variant of the Fogel hypothesis is, however, offered by recent work fom Caleb Finch and Eileen Crimmins (Finch and Cribbins, 2004, Crimmins and Finch, 2006). Finch and Crimmins develop a new concept - the 'cohort morbidity phenotype' - which they suggest may serve to represent the inflammatory processes (disease claims) that persist from early age into adult life. Specifically Finch and Crimmins propose the hypothesis that decreased inflammation experienced during early life, a decrease which is associated with improved infant and child health, leads directly to the subsequent decrease in morbidity and mortality resulting from chronic conditions found in old age. They point out, for example, that later life risk of heart attack and stroke is known to be correlated with serum levels of inflammatory proteins such as C-reactive protein (CRP). At the individual level, CRP levels are also correlated with the number of seropositivities to common pathogens, a relationship which tends to indicate a history of prior infections. Furthermore, drugs with anti-inflammatory properties (nonsteroidal anti-inflammatory drugs, statins etc) have been found to reduce the risk of vascular events and even possibly Alzheimer's disease. This kind of evidence may be read as implying the existence of links between levels of inflammation and major chronic conditions which are important in old age, and thus between exposure to infectious disease in early life and health in old age.

Using the longer data set now available for Sweden (infant mortality data was previously not available for cohorts which had been born before 1895) Finch and Crimmins have updated earlier work by Jones (Jones, 1956), by detailing age-specific mortality rates for five birth cohorts over the years between 1751 and 1940. They find that mortality at any given age across the lifespan drops steadily with each successive cohort. Cohorts with lower young-age mortality also have lower mortality at any given age in later life, and this is entirely consistent with an earlier (and very interesting) Jones hypothesis to the effect that the physiological age of each new generation is remaining more youthful at the same chronological age (Jones, 1956). As Finch and Crimmins emphasise, data on the historical demography of Sweden offers an unparralled possibility of deriving unique mortality profiles across the entire lifespan since it offers the possibility of initiating a study with cohorts born in the years immediately prior to the industrial revolution (when mortality was, of course, high) and then following the initial and subsequent cohorts across the entire life course from birth to old age. With this comprehensive data in their hands they proceed to examine age-specific mortality trajectories for Sweden from 1751 right through to 1940, and they find that the data offer support to the hypothesis that old-age mortality declined in a cohort and not a period fashion across all ages. In so doing they develop two points which were essentially already present in the earlier work of Kermack et al. and Jones: (i) that the historical mortality decline among the old and young begins in the same cohort, and

(ii) that infant mortality has a stronger relationship to later-life mortality than does mortality in subsequent childhood years. They also conclude that declines in mortality after age 70 tend to lag about 70 years behind those for infants. When they relate childhood mortality to laterage mortality for Swedish birth cohorts born in the 177-year period from 1751 to 1927, they find strong relationships between rates of childhood mortality and mortality for cohort survivors in old age, indeed they find that most of the identified variance in cohort mortality is explicable in terms of mortality before the age of 10. Moreover, they find that the annualized effect of each childhood year on old-age mortality is three times as great for infant mortality as it is for mortality in subsequent childhood years. Using this study of the Swedish data as primary evidence they then develop the argument that the inflammatory-infection and the Barker fetal-nutrition hypotheses need not be seen not as competing interpretations but rather they may form complementary, and mutually re-inforcing - hypotheses. The two hypotheses may, in fact, be seen as jointly linking the mechanisms of morbidity between early and later life. As they argue, even well-fed babies are vulnerable to rampant infections, and infections alone can cause malnutrition and later dietary deficiencies. Childhood diarrheas, for example, impair cardiac muscle synthesis, and this could be a factor which underlies the associations which have been found between infant diarrhea and later cardiovascular disease . As they suggest slowed infant growth under the Barker hypothesis could in part be understood as responses of the immune system to infections that have inflammatory consequences as well as being related to impaired nutrient absorption. It is important at this point to keep in mind the LHT trade-off between growth and maintenance. In similar vein Bengtsson and Lindstrom, using longitudinal data, and following individual cases rather than simply relying on grouped aggregate data - a limitation which had characterised the earlier work of Kermack, Fridlizius, and others - have studied historical Swedish cohorts to test both the nutritional and the inflammation hypotheses. They have done so by examining the effects of food prices and disease load at time of birth on subsequent old age mortality during the years 17661894. They conclude that the level of infection among infants was a stronger influence than food availability on later-life mortality and life expectancy. In particular they identify problems leading to the impairment of the respiratory mechanism as the principal source of this influence. (Bengtsson and Lindstrm, 2000, 2003) Barbi and Vaupel objected to the initial findings of Finch and Crimmins (Finch and Crimmins, 2004, Barbi and Vaupel, 2005) on the ground that the most recent analyses of mortality patterns over age and time have revealed that period effects are generally more important than cohort ones in explaining mortality decline at the older ages and that, in fact, contemporary demographic and epidemiological studies tend to suggest that the cohort effect is at best modest. In defence of their position they cite, for example, the Danish twin studies which indicate that less than 10% of the variation in life

expectancy for these twins is attributable to variation in shared health conditions early in life ( McGue et al, 1993, Herskind et al, 1996). In particular they point out that, in developed countries at least, progress in reducing old-age mortality accelerated around 1950 and accelerated even further around 1970, doing so simultaneously at all older ages. Finch and Cribbins (2005) responded by pointing out that since their analysis explicitly excludes modern birth cohorts, members of which have benefited from immunizations and the use of antibiotics, many of the points made by Barbi and Vaupel have limited validity in the context of their argument (it would also be pertinent at this point to bear in mind the twofold typology of mortality decline proposed by Cutler and Meara referred to above). Finch and Crimmins specifically hypothesize that inflammation associated with cardiovascular disease and cancer (the incidence of which is attenuated by modern drugs with anti-inflammatory activities) is the strongest connective link between early and later cohort mortality and that such cohort inflammatory mechanisms are most active when mortality from infections is high. As childhood infection has decreased due to immunization, public health advances, and the use of antibiotics early inflammatory exposure has had much less impact on cohort old-age mortality for the modern cohorts. What we seem to have here are two interrelated, but distinct phenomena, the pre-1950 cohort-related effect of decreased childhood inflammation on average life expectancies, and the post 1950 improvement in mortality rates at the older ages. At this level the arguments of Finch & Crimmins and Barbi & Vaupel are entirely compatible, with the former having a high degree of relevance to the pre-1950 situation (and its 'shadow' in older age mortality post 1950), and the latter to the post 1950 one tout court. Now analytically, as has been indicated, these processes are really quite distinct, as is the economic interpretation which can be given to each of them. Basically, following Finch and Crimmins, we might say that a predominance of cohort influences characterise the first stage, whilst (following Vaupel) period (or environmental and health care) influences dominate the second one. This analytical distinction also raises a rather interesting point about whether Jones, when he observed that "the physiological age of each new generation is remaining more youthful at the same chronological age" may not have been looking at cohorts which came from the first stage of mortality decline, and not cohorts which form part of the elderly expectancy improvement we are currently seeing. If this is so the implications will be important.

As indicated above the age-specific mortality trajectories from 1751 to 1940 used in the Finch and Cribbins work strongly suggest that old-age mortality declined in a cohort, and not a period, fashion from the time of the industrial revolution to the mid-twentieth century. The mortality trends at age 70 in any given calendar year, or the period mortality trend in old age, do not resemble the trend for the younger age groups. In fact they suggest that, following an initial rise after 1751, mortality declines first became significant in the Swedish 1791 cohort, and this at both the young and the older ages for that cohort.

Period mortality, on the other hand, first declined significantly among the old in the years from 1861 to 1870, years, of course, which correspond to the very cohort in which the onset of the decline was first observed. Again, generally speaking, child mortality trends correlate less with old-age mortality trends in the same year (period effect) than with mortality trends seven decades later (Finch and Crimmins, 2005). Barbi and Vaupel's critique has not, however, been completely barren as it has forced Finch and Crimmins to sharpen and clarify their argument considerably. Hence, in a second, subsequent, work on the same core topic (Crimmins and Finch, 2006) , where they extend their analysis to France, England and Switzerland, they are at pains to point out that they: "focus exclusively on cohorts born before the 20th century, when levels of infection were high, but before smoking, a major inflammatory stimulus, became popular. Most importantly, these cohorts entered adulthood before general childhood immunizations and before antibiotics." and: "The inflammatory mechanisms that we describe can only work when mortality from infection is high; once childhood infection is low, it can no longer be a factor in explaining old-age trends." (Crimmins and Finch, 2006, p 499) Now in their second paper Crimmins and Finch produce some really intriguing cohort-relative life-expectancy data. For the earliest cohorts they study (Sweden 1751, France 1806, England 1841, and Switzerland 1876) cohort life expectancy at birth was low: 34 in Sweden, 38 in France, 42 in England, and 45 in Switzerland. By the time we get to the 1899 cohort, however, life expectancy has jumped to 55 in Sweden, 56 in Switzerland, 53 in England, and 50 in France. In all cases the comparatively low life expectancies imply that all the cohorts (both the earlier and the later ones) were exposed to the then highly prevalent infection environment. It is at this point that the argument becomes truly interesting. Fogel himself (in the company of Dora Costa) has recently proposed the idea that a process he calls techno-physiological evolution may be at work by means of which increased energy which becomes available for growth and improved resistance to infection (see above) operates through a dual circular-causality mechanism wherby better technology means improved food production which leads to faster economic growth which in turn enables an ongoing revolution in technological innovation (Fogel, 2001). Now the Fogel hypothesis has been thought to present the difficulty that increases in height do not always follow increases in income and nutrition; and certainly not in the way his theory would anticipate. Height has even been found to have decreased during some periods of improving income in early industrial cities (Flood et al, 1990). However modifying (or blending) the Fogel hypothesis with the work of Crimmins and Finch it can reasonably be argued that a decrease in infections

and ensuing inflammation had the potential to increase height independently of improved food intake, thus making the joint hypothesis far more compatible with the observed evidence. Bengtsson and Brostrm develop a methodology to try to test whether or not events which occur during the subsequent life course may mediate the effects of early-life factors on later life mortality, and in particular whether changes in economic circumstances (proxied by the degree of access to land) in adult life plays any kind of health role (Bengtsson and Brostrm, 2006). They find no support for the null hypothesis that the influence of disease load in the first year of life is not permanent throughout life but is moderated by socioeconomic condition later in life (and more specifically at age 50 years). They find that those who (according to the land-wealth criteria they use) could be considered economically unsuccessful by the time they reached 50 did not suffer more from the damage caused by the first year of life disease load than those who had done relatively well (economically speaking) and who had attained or retained access to land. They also find that those who were exposed to a heavy disease load in the first year of life, and who survived to be 50, had an estimated remaining median life expectancy of about two years less than those who were born in years with low to moderately high infant mortality. Specifically,Bengtsson and Brostrm find that: "Children born in years with very high disease load face more than 90 percent higher mortality than the others after controlling for all the covariates included in the model" (Bengtsson and Brostrm, 2006, p9). Well let's think about this for a moment, and lets think about it in the context of the behavioural relationship between scarce means and conflicting demands, and in the context of Kaplans trichotomy between growth, reproduction and maintenance and in order to do so lets go back to Barbi and Vaupel's original objection to Finch and Crimmins. Which was that: "while Finch and Crimmins hypothesize that decreased inflammation during early life has led directly to a decrease in morbidity and mortality resulting from chronic conditions in old age.......demographic and epidemiological studies suggest that the effect is modest" (Barbi and Vaupel, 2005, p. 1743). As has already been noted, this leads Finch and Crimmins to respond to Vaupel with a much sharper version of their argument. In particular they qualify their argument by stating: "Our analysis excludes modern birth cohorts, individuals of which have benefited from immunizations and the use of antibiotics....(while)...The comment by Barbi and Vaupel incorrectly implies that death rates among the elderly in developed countries declined only after 1950.....As childhood infection decreases because of immunization, public health advances, and antibiotics, the early inflammatory exposure has much less impact on cohort old-age mortality." (Finch and Crimmins, 2005, p. 1743)

So what we have here are two interrelated, but distinct phenomena, the pre1950 cohort-related effects of decreased childhood inflammation on average life expectancies, and the post 1950 improvement in mortality levels in the older ages. Inflammation is largely a pre-1950 issue (in the Swedish case, but not of course, in the context of the current developing world) and this is where things get rather interesting, especially if we think about Bengsston's finding that children born in years with a low disease load experience around 10% of the mortality exposure of children born in the high disease load years. These (low disease load) children, not only survive in greater numbers, they also live longer, and healthier (and hence logically more productive) lives. Now lets think of this in terms of Kaplan's tripartite trade off. And in terms of economics. And in terms of his embodied capital model. Firstly the low disease-load years experienced in North Western Europe from the early nineteenth century mean that mothers need to invest less energy in reproduction, since more children survive. That immediately frees-off more energy for growth and maintenance. But, since the children are healthier there is less expenditure on maintenance, or, what amounts to the same thing, the investment in maintenance is more cost effective. Secondly after an initial disease and nutritional 'shock' a growth process ensues, growth in height, growth in life expectancy, and let's not forget, of course, economic growth, which at the end of the day this is what this essay is all about. Now according to Xavi Sala i Martin (and he, if anyone, should know, Sala-i-Martin, 1997a, 1997b): "The relation between most measures of human capital and economic growth is weak. Some measures of health, however, (such as life expectancy) are robustly correlated with growth" (Sala i Martin, 2002, p. 10) In fact Barro and Sala-i-Martin (1995) already drew attention to this growth/life expectancy correlation and nearly all the subsequent studies that have examined economic growth in this context have found evidence of a positive, significant, and sizable influence of life expectancy (or some related health indicator) on the pace of economic growth (see, for example, Barro 1991, 1996; Barro and Lee 1994; Barro and Sala-i-Martin 1995; Bhargava and others 2001; Bloom, Canning, and Sevilla 2004; Easterly and Levine 1997; Gallup and Sachs 2000; Sachs and Warner 1995). While results derived from empirical growth regressions are generally not considered to be sufficiently robust to draw definitive conclusions, it is interesting to note that both Levine and Renelt (1992) and Sala-i-Martin (1997a, 1997b) found that examination a total of more than 32,000 regressions, involving permutations of over 60 variables, showed initial life expectancy to be a positive, consistent and significant predictor of economic growth (over a 196092 time horizon) in more than 96 percent of the specifications. This would certainly seem to make initial health one of the

most robust predictors of subsequent economic growth. Now, with all of this in mind, if we go back to Kaplan it should not be too hard to see why this relation between growth and 'growth' (which was also to some extent evident to Fogel) should be so. Kaplan, on the basis of systematic research, estimates that male children in the foraging societies he studied only become fully self-sufficient around the age of 20. This age may vary somewhat from one foraging society to another according to the types of specialisation involved (Lee, 1979, Bird and Bliege Bird, 2002). For agricultural societies the self-sufficiency age may be somewhat lower: nutritional consumption is more constricted and children start to work from a comparitively early age. But let's take the relatively higher age of 20 as a benchmark. Following the initiation of the 19th century mortality decline and the consequent improvement in mortality and reduction in the disease-load, getting the individual child to 20, not only involves less maintenance energy, it also produces an individual who is bigger, stronger, and has better developed cognitive capacities. Whatsmore the resulting transformation sees the arrival at an increased rate of individuals who have, say, 35 productive years out in front of them instead of say, none, or at least considerably less than 35. (Think here also of Lee's reproductive trade-off point cited above) In addition there is a widely accepted rising productivity profile with age, a profile which is normally considered to peak at around the age of 55 in modern industrial societies, (interestingly this pattern is remarkably similar in foraging and industrial societies, as Lee has noted, Lee, 2006). So what we have are both more years, and more productive years, and all for the same initial investment. The economic impact of this is obviously considerable. Of course such an economic and productive impact can only be realised within a technological and institutional context that makes such realisation possible, but in the presence of this we seem to have here a huge increasing-returns type mechanism which can help explain why demographic and metabolic processes are much more important to economic development and growth than has been hitherto been recognised. This potential 'health effect' (or metabolic pathway) would also seem to have very important implications for those contemporary societies where infant mortality is still high, and where diahorrea and malaria etc are still responsible for the deaths of large numbers of people, and it might give us some indication of how societies which are still caught in this health trap will be able to grow once they break out (Alderman and Behrman, 2006). The finding is also important since it indicates that this kind of demographic 'dividend' is only possible in societies where child-health related nutritional deficiency and inflammation is still an issue, and thus it tells us relatively little about the economic outloook for those societies where the major increases in life expectancy are only expected to come from improving the health outlook in the older age groups (future comparisons between India and China should prove interesting in this context since the child mortality decline in China occured much earlier than it is doing in India, and to a certain extent before the most recent economic 'take-off' really got started).

Clearly investigating what actually happened to health in Europe back in the nineteenth century presents us with, if not insurmountable problems, then at least considerable difficulties. There are, however, contemporary situations which, although not offering exact parallels, at least offer the possibility of making some interesting comparisons. As has been suggested there are three classes of possible live-now/pay-later trade offs which would seem to have some importance for thinking about the specific pathways through which the metabolic level may intereact with and influence the economic growth one: the immune system, the endochrinal system and the cognitive system. Energetic allocation decisions often require the coordinated tuning of a variety of somatic systems, and in terms of phenotype growth the most important of these are undoubtedly the cognitive, endochrinal and the immunological ones. Increased load on the immune system, for example, requires increased effort devoted to immune function which may be allocated via a reduction in maintenance expenditure which may in turn impact the cognitive system. Now there is a good deal of research illustrating the ways in which poor fetal or early life nutrition may affect later economic performance, including cognitive performance (Bryan et al, 2004, Carpenter, 1994, Craviato et al, 1966, Glewwe et al, 2001, Holliday, 1978, Klein et al, 1977, Kretchmer et al, 1996, Liu et al, 2003, Moore, 1998, Morgane et al, 2003, Penland et al, 1997, Penland et al, 1999, Prentice and Goldberg, 2000, Tarleton et al, 2006). Specifically a good deal of recent research has identified iron, zinc and iodine deficiencies as a good indictors of later cognitive under-development (Black, 1998, Dallman, 1986, Dunn, 1992, Halpern, 1994, Hambridge, 2000, Kirksey et al, 1994, Levitsky and Strupp, 1995, Sandstead, 1996, Sandstead et al, 2000, Stanbury, 1994, Walter, 1990, Youdim, 1990). Studies in rats have also confirmed some of the potential importance of such processes (Dallman, 1975, Dallman, 1977, Taylor and Morgan, 1990). Also there is a growing body of work on the endochrine system and the effects of nutritional and disease insults (Beisel, 1984, Byrne, 2001, Matkovic, 1997, McDade and Kuzawa, 2004, Worthman and Kohrt, 2005). The factors responsible for linking accelerated growth and development with adult health and life expectancy are not well understood, but a growing literature certainly implicates shifts in endocrine regulation. The endocrine system regulates body composition, fat deposition, skeletal mass, muscle strength, metabolism, body weight and general physical well being, and is often thought be associated with many of the physiological manifestations of ageing which are related to the effects of declining hormone levels. One possible mechanism which has been proposed for lifetime health consequences of early fluctuations in the endochrinal system operates via the levels and lifespan trajectories of the adrenal androgen DHEAS and changing gonadal activity in women and men (Ellison et al, 1993, Worthman, 1999). DHEAS has been linked to cardiovascular risk in women and body fat patterning in both sexes (Worthman, 2002), and appears to serve as an index of lifetime allostatic load. Greater lifetime exposure to gonadal steroids as a result of early maturation and lifetime gonadal upregulation may lead to

increased risk for reproductive cancers in early maturing affluent populations (Eaton et al, 1994). Low birthweight is known to be associated with a whole range of metabolic changes, including variability in the pancreas (decreased pancreatic b-cell mass), kidney (decreased nephron numbers), the liver (altered zonation, increased capacity for gluconeogenesis), in body composition (increased fat, decreased muscle), in metabolic regulation (increased insulin resistance, decreased glucose tolerance), and in endocrine systems (reviewed in Barker et al., 2002; Byrne, 2001, Dodic et al., 1999, Hales and Barker, 2001, Holt, 2002, Matthews, 2002, Phillips, 2002, Seckl, 2004). Also the immune system is costly to maintain, and energy devoted to immune function may affect performance in other critical physiological and developmental systems. In protecting the body against infectious and neoplastic diseases, the immune system is central to survival. There are costs, as well as obvious benefits, associated with immune activity, and trade-offs are therefore inevitable (Lochmiller and Deerenberg, 2000, Mcdade et al, 2000, Sheldon, 1996, Sheldon & Verhulst, 1996). These trade offs may be genetically encoded, or they may be developmentally mediated as a result of facultative adaptation to environmental circumstances during an individuals lifetime. The latter process is generally invoked to explain biological variation across human populations, where limited phenotypic plasticity allows individuals to respond adaptively to a range of ecological conditions (Hill and Hurtado, 1996, Stearns and Koella, 1986). Conceptually, trade-offs may occur between major life history functions (e.g., investing resources in maintaining the soma versus investing in reproduction or growth), between physiological systems (e.g., investing in immune tissues at the expense of the musculoskeletal system), and/or between subsystems within the system itself. Key ecological factors will determine the intensity of these trade-offs and will make investment in certain physiological systems (or subsystems) more critical than others. As has been suggested, the original concept of fetal programming was framed primarily in terms of gestational insult and postnatal pathology. It is, however, possible to view this proces in another light, one in which fetal programming represents an inherent feature of fetal development. Insofar as fetal development relies on probabilistic epigenesis, fetal development is fetal programming because development itself involves the establishment of regulatory dynamics within and across physiologic systems (Worthman and Kuzrara, 2005) Fetal programming could then be viewed as implying that there is one optimal setpoint that all somatic systems will reach unless they are perturbed or programmed away from the presumed default setting. Fetal programming may be also thought of as incorporating a set of Predictive Adaptive Responses (PARs) which imply a form of probabilistic gamble on anticipated outcomes in terms of expectable environments, a gamble based on (imperfect) information received during gestation, rather than one which involves insult

and pathology (Gluckman et al, 2005, Bateson et al, 2004) . One class of models of stress response also suggest that the insult and pathology metaphor may be misleading, and that ontogenetic plasticity may well involve hierarchical and graded (or norm of reaction type) responses that integrate overall balances of sensory inputs with central processing, rather than a series of decision points on branching pathways (on/off, high/ low) (Pacak and Palkovits, 2001). In this case variation in fetal outcomes may be associated with continuous gradients in health responses across the entire range of birthweight. Fetal programming (or phenotype plasticity as Barker himself has subsequently termed the phenomenon, Barker, 2004) thus works to 'configure' the somatic system so that in conditions of good maternal health, low juvenile morbidity rates, and sustained normal nutrition the 'settings' work just so as to increase overall productivity and reduce the relative cost of maintenance (the meaning of 'good health', 'low juvenile morbity' and 'normal nutrition' should be understood in terms of the pre-historic foraging environment where our adaptive biology was effectively evolved). From this initial 'setting' any sustained increase in nutritional energy input (or reduction in the disease load on the immune system) tends towards increased growth and accelerated maturation (this incidentally may help understand those puzzling long-term fluctuations in population sizes and final heights which characterised the pre-industrial world, Hill and Hurtado, 1996). Such environmental circumstances may also be thought to operate indirectly on age at maturity since they may well act as a signal of resource availability and mortality risk. The norm of reaction for timing of maturation in humans is large with documented population median ages at menarche ranging from 12.318 years (Eveleth and Tanner, 1990), and mean age at menarche has been falling steadily in modern growth environments (Weil, 2005). The question still remains however as to whether the functional correlates of birthweight should be regarded as reflecting adaptive plasticicity or tolerable insult. The evident trade-offs could be interpreted as implying that the present health consequences of differential fetal outcomes represent the resurfacing of costs deferred in early trade-offs (Metcalfe and Monaghan, 2001). According to the fetal programming hypothesis permanent alterations in metabolic regulation under early conditions of adversity could be seen as adaptive in virtue the overarching need to produce an energy-sparing phenotype (Hales and Barker, 2001). The resulting conceptual problem has been to clarify why such permanent changes should be adaptive if they yield little in the way of future benefits, yet do exact a future cost. One solution which has been proposed involves the idea that a permanent advantage does not need to exist for a trade-off choice to be adaptive, it may be sufficient that there be an early benefit (survival) with little or no probability of paying a long-term fitness cost (Finch, 1990; Rose and Mueller, 1998). Thus it is quite possible that trade-offs conferring early advantage but

which incur subsequent delayed costs may have been selectively favoured by our adaptive biology. The pay-back for this may only come into play when survival improves and the debt has to be paid. In developed economies the predominant morbidities associated with fetal origins are normally chronic conditions of middle and later life, ones which would have had little significant impact on fitness during the epoch in which are adaptive biology was effectively formed. Initial deferred costs may now, to some extent, have resurfaced with the contemporary increase in life expectancy (Worthman and Kohrt, 2005). Also, as we can see in the context of the rapid economic and social changes which are taking place across the developing word, a problem may arise if the actual environment differs substantially from the anticipated one (Drewnowski and Popkin, 1997. Popkin, 2001, Prentice, 2005). The consequence of this is that low birthweight and restricted nutrition in early infancy is often now associated with rapid weight gain during early growth years and this then correlates with an elevated risk for adult coronary heart disease, diabetes, and hypertension, otherwise known as the metabolic syndrome (glucose intolerance, high blood pressure and dyslipidaemia: Gluckman and Hanson, 2004). This combination of low weight, short body length, and thinness at birth (when not a product of pre-term birth), and rapid subsequent catch-up growth in the immediate post-birth period accompanied by accelerated growth in height and weight during childhood has been shown by a variety of studies to be problematic, and in particular to be strongly associated with the development of type-two (non-insulin dependent) diabetes (Forsn et al, 2000, Hales et al, 1991, Lithell et al, 1996, Rich Edwards et al, 1999, Ibaez, 2006). Numerous epidemiological studies also suggest the existence of an inverse relationship between low birth weight (LBW) and hypertension, an observation now supported by numerous animal studies. The mechanisms linking LBW and hypertension appear to be multifactorial and involve alterations in the normal regulatory systems and renal functions involved in the long-term control of arterial pressure (Alexander, 2005, Hales, 2001). Since McCance and Widdowsons early work (McCance and Widdowson, 1964), it has been repeatedly demonstrated that minor alterations to the diets of pregnant animals can produce lasting changes in the offsprings physiology and metabolism (Desai and Hales, 1997, Kwong et al, 2000). The existence of phenotypic plasticity thus enables one single genotype to give rise to a range of different physiological or morphological states in response to different environmental conditions during development (West-Ebberhard, 1989). Such gene-environment interactions are ubiquitous in the development of all living beings. The benefit of developmental plasticity is that, in a changing environment, it enables the production of phenotypes that are better matched to their environment than would be possible by the production of the same phenotype in all environments. When undernutrition during early development is followed by improved nutrition many animals and plants stage accelerated or compensatory growth, thus giving rise to the life now/pay later trade off . Compensatory

growth has costs, however, which in animals include reduced life-span (Metcalfe and Monaghan, 2001). In the context of the fetal origins of lifelong health our adaptive biology may be conceptualised on two different levels, that of the phenotype, and that of the genotype. i) At the phenotype level we have the hypothesis of the 'thrifty phenotype', or the predictive adaptive response account. Such frameworks suggest the presence of some form of trade-off in each and every human foetus, with outcomes depending on the precise characteristics of the environment in-utero. The live-now/pay-later trade-off in this context is one based on the fetal anticipation of a range of early environment outcomes and the need to confront these. The 'thrify' option may be deployed to enable the young infant to survive harsh conditions. Implementing, for example, the thrifty option may then be thought of as being associated with the early onset of a range of adult diseases, and with a life expectancy which is comparatively shorter in relation to the norm. If the conditions are too harsh (as eg in the case of the Dutch famine winter) then a whole suite of lifetime health conditions may also come attached (diabetes metlitus, the metabolic syndrome, etc). This option also has the variant that such outcomes may also be provoked if the initial constraints are over-rapidly relaxed, and the encountered environment is significantly different from the anticipated one. ii) Another type of live-now/pay-later trade-off, however, may also exist at the genotype level. This trade-off may mean that we have a kind of evolved target life expectancy, and have, as a species, gained survival advantage, large brain weight, a sophistocated immune system, all in return for steadily deteriorating health after a certain age (Fries, 2000). If Fries is right then there are important economic implications which arise in the context of the second epidimiological revolution, since it is this age horizon whose envelope we are now pushing in the context of the second stage mortality decline (the first stage may in these terms be thought of as the attainment of the optimal fetal setting, without recourse to the 'thrifty phenotype' option) and the increasing medicalisation of health. Of course extended lifespans are here the product of increasingly costly medical and care interventions, with no apparent significant gain in productive outcomes via recovery of function (Fogel, 2oo1). If this scenario is at all realistic then perhaps this essay would have been more appropriately entitled metabolic upsides and downsides in the demographic transition. Conclusions

The possibility that there may be a strong underlying life expectancy and health process at work in economic development, and in particular in the phenomenon known as the demographic dividend has been explored in this article, with the possible mechanisms at work being loosely grouped together under the heading 'metabolic pathways'. It has been suggested that there is strong prima facie evidence for such effects, even if quantifying the actual extent of the impact lies beyond the scope of the present work. It has been argued that the trade-offs analysed by life history theory may provide a useful initial framework for addressing such issues, and that the key idea which we can avail ourselves of from LHT is its understanding that many of the life history events identified may well be endogenous. This view has been argued to be completely compatible with the technophysio framework advanced by Robert Fogel and Dora Costa. It has been suggested that the study of the epidemiological transition in 19th century Europe reveals significant evidence to support the idea that there was an increasing returns type economic growth-improved health-increased life expectancy process at work, and that the transmission mechanism for this is the existence of cohort level health effects underpinned by the presence of fetal programming. The application of this general methodology produces interesting conceptual insights as it allows for a resolution of the BMI/final heights connundrum, and also illustrates that disease environment and nutrition are not rival explanatory mechanisms, but may well form part of one common, integrated process.

Future Research Issues Quantitative testing. The most pressing concern is the development of adequate quantitative techniques for testing the hypothesis herein advanced. Nutrition and development in the third world. Poor fetal nutrition was initially advanced as a predictor of postnatal conditions in order to offer the 'thrifty metabolism' a survival advantage in a posterior environment. The eventuality that the phenotypic consequences of earlier trade-offs will have deleterious effects, even in the deferred terms of secondary chronic morbidities (diabetes, heart disease), clearly depends on subsequent environments. Existing evidence suggests that the widespread and sustained presence of a trio of contemporary conditions - dietary change with early under nutrition followed by chronic overnutrition, early and persistent sedentization, and reduced morbidity and pathogen/parasite load - is unique in human history (Eaton et al, 1997, Trevathan et al, 1999). A number of recent studies of cardiovascular risk factors among circumpolar groups, in both North America and Siberia, have documented a strong, positive association between the rapid adoption of modern lifestyles and a population burden of plasma lipids and other risk factors. Several authors

have identified a shift from traditional to carbohydrate rich market sources of food as an important element in the increased prevalence of cardiovascular disease found as these groups undergo dietary and lifestyle change (Rode and Shephard, 1995b, Young et al, 1995, Leonard et al, 2002, Sorensen et al, 2005). A possible pathology of excessively early menarche followed by obesity and diabetes is clearly evident. It should be noted that most of the societies currently exhibiting lowest-low menarche age (circa 12.3 in Spain, Italy, Portugal, Greece, Singapore, S Korea, Taiwan) are those whose economic development has been comparatively late, and especially rapid. They are also the societies where lowest-low fertility is particularly in evidence. It is not suggested here that these two phenomena are directly related, simply that they provide an interesting correlate, and raise the question as to why this should be. These are not the societies which currently enjoy the highest global percapita incomes, and thus this phenomenon cannot simply be taken as evidence of improved health from economic growth. More questions need to be asked, in particular given the existence of the metabolic syndrome (Grundy, 2004), and the possibility that other rapidly developing economies may now follow this pattern. It is hoped that the framework offered here could serve in facilitating the development of subsequent relevant research.

Puzzles about TFP and early economic development. It is suggested that the mechanisms identified herein may help clarify some questions which have long puzzled economists, in particular the role of total factor productivity (TFP) in economic take-off. Two cases immediately come to mind. In the first place Alwyn Young, in two papers in the early ninetees (Young, 1994, Young, 1995), caused a good deal of controversy when he suggested that while in the early Asian Tiger growth process he could identify very rapid factor accumulation, TFP growth was generally quite low, and perfectly in keeping with that being experienced across a range of countries at the same time. Additionally the work of Nick Crafts (Crafts, 1985, 2005, Crafts and Harley, 1992) in studying the industrial revolution process in the UK was also able to identify very rapid early factor accumulation with virtually no growth in TFP. It would therefore be interesting to explore the possibility that the intital absence and subsequent explosion of significant TFP elements in early economic growth may be associated with the kind of mechanisms herein identified. Long wave theory. Historical time series for developed economies have long been known to contain long-run data trends which have proved hard to account for (the so-called long-wave effects, Zarnowitz, 1999, 1992). One common approach has been to try to identify the presence of what have become know as Kondratieff Cycles. Kondratieff developed his idea of long terms cycles (or waves) based on a study of nineteenth century price behavior (Kondratieff, 1984). This theory has proved to be hugely controversial, and is largely technologically driven. Kondratieff was convinced that his studies of economic, social, and cultural life proved that a long-term wave-like process

existed and that incorporating the presence of such waves could be used as an analytic framework of modelling future economic development. A number of other, more mainstream, 20th century economists were also puzzled by the difficulties presented by the kind of data which Kondratieff seemed to have uncovered (Schumpeter, 1939, Kuznets, 1953, Abramovitz,1989). This approach has been widely criticised, but the data remains, and still 'a bouge'. One approach to the problem has been to interpret the data via the mechanism of general purpose technologies (GPT), and the wave-like impact on economic growth and productivity that the introduction of these may have (David, 1991, David and Wright, 2003, Helpman and Trajtenberg, 1998) . Another line of investigation could however be to examine the impact of changing health and increasing life expectancy. Given that such impacts have a cohort character, it could be expected that the consequences of any sustained improvment in health would make its presence felt over the entire course of a subsequent generation in a way which would be consistent with some form of modified version of the wave hypothesis.

The Jones hypothesis, and the possibility that there may be a demographic penalty. The existence of a phenomenon like the demographic dividend poses indirectly the question of whether or not there may be a 'demographic penalty' correlate to investigate in the context of continuously ageing societies. This issue has not been considered in any depth here, but it has been suggested that the core of the problem may be addressed via the concepts of fetal programming and the reaction norm and a consideration of whether Jones's early observation that the physiological age of each new generation is remaining more youthful at the same chronological age remains a valid one in the context of the second stage mortality decline or whether the older-age mortality process which is now unfolding may not represent the deferred payment for an earlier allocatively-driven benefit.

Footnote
1 The presence of long-term, systematic health effects arising from in-utero events may have appeared revolutionary when Barker first raised the idea back in 1992, and the possibility of selection bias was one of the first questions raised and effectively answered. As is indicated here numerous subsequent studies have been performed in a wide variety of countries and settings, and the overwhelming burden of evidence has only served to confirm the strength of the initially postulated association between low birthweight and adult chronic diseases. Other types of explanation have been proposed including, naturally, genetic factors (Smith et al, 2001). Studies on twins with discordant birthweight have been found to show a higher adult mortality in smaller twins as compared to larger ones (Vagero, 1994) , a finding which could be considered to favour the Barker hypothesis. A study by Christensen et al. (2001) on twins identified the presence of a contribution from genetic factors, though even in this case modulated by environmental circumstances. In fact most studies of twins are in agreement that the heritability of lifespan is less than 50% (Herskind et al, 1996) and an ongoing study of agieng in Swedish twins that includes a large group of adopted twins who were reared separately (Ljungquist et al, 1998) has concluded that a maximum of one-third of the variance in integrated mortality risk is attributable to genetic factors and that almost all of the remaining variance is due to nonshared, individually unique environmental factors.

The search for evidence of a genetic influence on logevity has so far not yielded the kinds of results initially anticipated. Only one gene, apolipoprotein E (apoE), is currently showing indications of having general effects on longevity. Centenarians, as first reported by Schachter et al. (1994), tend to show a higher prevalence of the apoE e2 allele, relative to e4. More generally, the apoE e4 allele is remarkable, as its presence is the major susceptibility factor for elevated blood cholesterol, coronary artery disease, and Alzheimer disease (but not for cancer or diabetes). A recent review of mortality risk in Danish centenarians showed that, relative to the apoE e3 allele, the mortality risk from e4 from age 40 to 100 was 12% higher, whereas that of the rarer e2 allele was 8% lower (Gerdes et al, 2000).

This differential mortality results in the progressive enrichment of e2 at the expense of e4, so that by age 100 , 40% of survivors are apoE e2. Indeed Gerdes et al. argue that apoE should be considered as a frailty gene rather than a longevity one. Other frailty (or longevity) gene candidates proposed include MHC haplotypes, methylenetetrahydrofolate reductase, and angiotensin converting enzyme (Finch and Ranzi, 1997, Heijmans et al, 2000, Schachter et al, 1994). This focus on centenarians is not without significance since a rudimentary examination of age-specific mortality schedules in developed societies reveals long term trends in life expectancy outside the tails (understanding here by 'tails' things like the case of centenarians, or those who die in the first three months of life) which are hard to explain by either genetic or period-relative environmental factors alone, and of course the global rise of obesity and diabetes only adds to the problem for the 'genetic explanation' (understanding by genetic here the classic view, and not the more modern one which would incorporate elements like PARs and epigenisis), so it should not be too controversial to assert that at the current state of the epidemiological art the fetal origins of adult health hypothesis is the most plausible and widely accepted explanation for the observed phenomena, and, as Sekl puts it, that it is now axiomatic that early-life environmental factors influence prenatal development and may cause structural and functional changes which persist for the lifespan (Sekl, 2004) as such the burden of proof now must surely lie in the camp of those who would argue the contrary (Nathanielsz, 1999).

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Appendix, Conceptual Glossary

Phenotype Plasticity The term phenotypic plasticity refers to cases where a single genotype can produce alternative phenotypes, depending on the environment during ontogeny (1, 2). The set of phenotypes produced in a range of environments is referred to as the reaction norm of the genotype to this specific set of environments (3). In a laboratory setting a reaction norm may be determined by rearing randomly split clones or in a field context by studying families in several environments. There has been some debate regarding whether reaction norms can be selected for per se or whether they are only the sum of selection in specific environments (4). The current consensus seems to be that both types of selection and genetic determination of reaction norms may occur (5). Plasticity may be adaptive or nonadaptive, and reaction norms (or, rather, a given aspect of them) may or may not qualify as adaptations, in the narrower historical sense, to a variable environment. The distinctions are not always straightforward (6, 7, 8).

Reaction Norm The Norm of Reaction is the pattern of phenotypes produced by a given genotype under different environmental conditions. The exitence of norms of reaction complicates the issue of genetic and environmental influences enormously. The norm of reaction may be considered as a curve that relates, for a given genotype, the contribution of environmental variation to observed phenotypic variation. The shape of the curve may be essentially flat across environments, such that the expected phenotype of any given genotype is highly predictable, independent of the environment. The narrower the distribution, for example, the less variable the trait. This is what is typically meant when a trait is said to be genetic. Genotype A always may have a higher trait value than Genotype B, and this trait value is quite constant across environments. Alternatively, the Norms of Reaction for two genotypes may have parallel slopes, such that relative rankings of trait values of Genotypes A & B are always the same (A is superior to B, for example), but the absolute trait value is dependent on environment. If, for example, B may the higher trait value in either environment, but the trait value of B in the X environment may exceed that of A in the Y environment. Finally, the shape of the Norm of Reaction for two different genotypes may be quite different, such that it is not possible to predict from analysis of one genotype the response of the another. Consider two breeds of cattle (genotypes A & B). Among cattle raised in a free-range, nutrient-poor environment (environment Y), those cattle with genotype A will always produce more milk fat than do those with genotype B . The range of phenotypes within each breed could be relatively constant over a wide range of free-range environments. A conventional study of the heritability of milkfat production conducted in this environment would thus conclude that genes have a strong influence on milkfat production, that is, that the difference between breeds is mostly genetic. On the other hand, when the same two breeds are moved to a feed-lot environment with abundant nutrients (environment X), both breeds may show a marked improvement in average milkfat production. Further, cattle with genotype B may now typically produce richer milk than those with genotype A, the reverse of the previous situation. Both breeds may also show a wide range of milk fat production, depending on the exact environmental conditions (e.g., feed types). A study of heritability in this environment will conclude that genes have relatively low influence on milk fat production (low heritability), which is mostly a consequence of environmental variation. Thus the relative importance of genes and environment is not a unitary value, and may vary greatly depending on the environments in which the genes are expressed. Studies of heritability carried out in a single environment cannot accurately estimate the Norm of Reaction, and often may not predict

phenotypic response in a different environment.

DIRECT TIME/SIZE TRADE-OFFS A trade-off between juvenile development time and size at maturity is a typical component of life-history models (14, 15). Growth rates are explicitly or implicitly assumed to be fixed or are maximized within the constraints set by extrinsic factors. Current theory on optimal size, for example, typically involves a direct trade-off between the fitness advantages of large size, particularly high fecundity, and the disadvantage of a long development time (16 - 18). Such a trade-off is also invoked in theory on the relationship between early male emergence (protandry) and sexual size dimorphism (19, 20). A related body of theory deals with how nonadaptive variation in growth rate affects the outcome of the time/size trade-off. Stearns & Koella (21) and later, after critique of the early models, others (22, 23) have suggested models for optimal age and size at maturity when the growth rate varies because of extrinsic factors such as temperature or diet. These models, where mortality patterns in different developmental stages play an important part, suggest that the optimal reaction norm typically should be displaced towards maturing later at a smaller size when growth rate is reduced.

Epigenesis Epigenetics has been described as "the developmental processes by which genotype gives rise to phenotype." The term was first used by Waddington, but in its modern day useage epigenetics may be defined as the inheritance of information based on gene expression levels rather than on gene sequence (genetics). All of our tissues contain the same 30,000 genes; however, in a given tissue and at a given stage, owing to an epigenetic code, only a few of these genes are expressed, thus giving rise to a determinate phenotype. The epigenetic code comprises several levels of interconnected and interdependent codes: the DNA methylation code, the histone code (histone methylation, acetylation, and phosphorylation), and the coregulator code. These codes define a process involving the recruitment of a myriad of chromatin-remodeling complexes, enzymes, coregulators, and effectors, directing appropriate chromatin remodeling. Specific epigenetic patterns condition the accessibility of chromatin to transcription factors, facilitating the recognition by these factors of genes to be expressed (to various extents) and of genes to be silenced, transiently or permanently. Epigenetic chromatin marks may be propagated mitotically and, in some cases, meiotically, resulting in the stable inheritance of regulatory states. Transient nutritional stimuli

occurring at critical ontogenic stages may have lasting influences on the expression of various genes by interacting with epigenetic mechanisms and altering chromatin conformation and transcription factor accessibility. The importance of epigenetic changes in tumorigenesis has been acknowledged for some time now. However, the relevance of epigenetics to other physiopathological mechanisms in common diseases, such as metabolic syndrome, has been less clear. Steadily accumulating evidence now appears to offer support the hypothesis that, in addition to a thrifty genotype heritage, individuals with metabolic syndrome have been subject to some form of distorted epigenetic programming during fetal/postnatal development either as a result of inadequate maternal nutrition or some other metabolic disruption. Such individuals may also manifest transgenerational health effects due to the inheritance of epigenetic changes first experienced by their parents and/or grandparents.

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