Caloric Restriction, Metabolic Efficiency and Hormesis
Peter A. Parsons, Ph.D.
PO Box 906, Unley, SA 5061 Australia
Tel: 618-8373-6974, Fax: 618-8272-5557
Peter A. Parsons, Ph.D.
PO Box 906, Unley, SA 5061 Australia
Tel: 618-8373-6974, Fax: 618-8272-5557
A stressed world and energetic consequences
Famine and pestilence have been documented from the substantial growth of human populations in Neolithic times and throughout history thereafter (Harrison, 1988; Newman, 1995). Cultural processes decrease associations with habitat in human populations, but those from outlier habitats can be especially informative. For instance, for high-altitude Andean population sizes, the effects of environmental extremes in reducing caloric availability are most obvious at the level of food production, where irregular stresses especially droughts and frosts, have a prominent role in year-to-year productivity fluctuations (Thomas et al., 1982).
Cycles of climatic extremes, especially drought leading to starvation, affected many pre-contact hunter-gatherer populations, but are rarely well documented (Newman, 1995). An exception comes from the prehistoric populations of the Western Desert of Australia, where population sizes were lower than those of any other permanently occupied landscape in the world (Meehan and White, 1990). Here, severe droughts are common, perhaps every two to three years. They caused 10-25% deaths in one population (Kimber, 1990), so that up to 50% of children could be dead by the fifth year, due to a combination of heat-stroke, inadequate nutrition, and disease. Compared with adults, young children have low nutrient reserves and energy, so are more vulnerable to starvation. This follows from the high metabolic rate of the young and their general sensitivity to a range of stresses, including starvation, dehydration, disease and climatic extremes. In parallel, the major factors underlying lamb mortality in Australia are faulty nutrition of the ewe during pregnancy followed by climatic stress during parturition (Rowley, 1970). Numerous other examples of "The Inadequate Environment" for animals are comprehensively summarized in White (1993).
Based upon the interaction between environmental, genetic and developmental factors, some individuals will be particularly vulnerable to abiotic streses. Hence organisms should evolve broad biological characteristics enabling survival in their environments, expressed simply as a balance between the energetic (and metabolic) costs of environmental stresses and energy from resources (Parsons, 1996).
The scene changed abruptly from the pattern of high and unstable death rates covering most of human history, to greater stability in recent decades following advances in medical technology, and improved living conditions and nutrition. However unlimited resources for many populations today should be deleterious, assuming a struggle to survive under the variably inadequate energetic and nutritional scenario prior to recent favorable times (Williams and Nesse, 1991). Consequently on evolutionary grounds, some dietary restriction should remain advantageous today. In any case, any tendency towards unlimited metabolic capacity should be selected against because of its energetic and metabolic cost (Diamond and Hammond, 1992). Metabolic mechanisms implying adaptive advantage under some dietary restriction by comparison with a regime of unlimited resources, include (1) lipids in cell membranes in a more fluid state, (2) lesser exposures to free-radicals, and (3) maximal energy utilization efficiency especially involving the enzymes in intermediary metabolism, (Pieri et al., 1992; Masoro and Austad, 1996; Hart and Turturro, 1995).
Maximum fitness in populations therefore should occur under some dietary restriction, and estimates of components of fitness especially longevity and survival are in accord (Masoro and Austad, 1996; Hart and Turturro, 1998). For example, Turturro et al (1999) present convincing data indicating maximal survival in mice under some caloric restriction, when body weights are intermediate between extremes of high and low. Furthermore, this is indicative of stabilizing selection for highest fitness for intermediate-sized individuals compared with those of either extreme size (see Futuyma, 1986), as shown by numerous examples including the relation between birth weight and survival in our own species (Karn and Penrose, 1951).
Similarly, fitness is maximal at intermediate temperatures between high and low extremes, and for intermediate hydrological circumstances between the excesses of water - logging and drought. Together with nutrition, these various environmental variables give a non-linear fitness continuum which is negatively associated with a stress continuum, a conclusion which appears generally applicable to environmental variables.
From the fitness-stress continuum to hormesis
Maximum fitness occurs when stress levels and the consequent energetic costs are low, giving a fitness-stress continuum. The maximum should evolve in the environments to which populations are most commonly exposed. Exactly parallel arguments apply to agents that are exceedingly toxic at high concentrations but are part of our geological history, such as mercury and ionizing radiation. Accordingly, for these agents maximum fitness is expected at around background exposures (Parsons, 1992). Such deviations from linearity on the fitness-stress continuum close to zero are conventionally referred to as hormesis, and are incompatible with linear no-threshold, LNT, models that are frequently proposed for environmental agents, in particular ionizing radiation. Monotonic dose-response models are therefore invalid on evolutionary grounds.
There is increasing experimental and demographic evidence for hormesis substantially above background exposures of ionizing radiation. A suggested explanation derives from the energetic reserves that evolve following adaptation of free-living organisms to unpredictable but continuing extreme environmental stresses in their habitats. These reserves should then translate into metabolic protection directed towards ameliorating the effects of lesser correlated abiotic stresses, which would include non - catastrophic ionizing radiation. More specifically, the non-linear fitness-stress continuum for temperatures implies the evolution of energetic reserves enabling protection from lesser correlated abiotic stresses except under environmentally extreme circumstances (Parsons, 1999a,b). Furthermore, since high fitness is a feature of hormetic regions, high energetic (and metabolic) efficiency is expected compared with less environmentally benign regions, where energetic costs are necessarily higher than in hormetic regions (see also Emlen et al., 1998).
From this reductionist approach to hormesis, comes the need to incorporate more specific metabolic processes underlying fitness following exposure to particular agents for example for ethanol and acetaldehyde metabolism in the insect Drosophila melanogaster and in our own species (Graziano, 1995; Parsons, 1999b). Nutritional hormesis based upon caloric restriction is more complex, since it represents the maximization of metabolic efficiency for the combined effects of the utilization of many chemicals known to be toxic at high concentrations (Ames and Gold, 1990), but as a first approximation they should individually be hormetic at around background exposures. Reduced to this level, there is no qualitative difference between nutritional hormesis and that of the numerous components of resources ingested. It is merely a difference in complexity. For example, the analysis by Turturro et al. (1999) highlights a number of factors and their interactions involving growth stimulation, that are important for understanding the physiological basis of the hormetic zone under caloric restriction.
Non-linear fitness continuums are an expected feature of evolutionary adaptation to all environmetal agents. The outcome is hormesis, so rendering LNT models invalid. The term hormesis is mainly used for agents that are exceedingly toxic at high concentrations, but variations in caloric availability give a fitness-stress continuum of a similar form, where the maximum is distant from the zero point of no intake.
Under this scenario, hormesis is not primarily a subsidy, benefit, or low-level stimulatory effect (see for example, Parsons, 1992 Calabrese and Baldwin, 1997) although these affects are all consitent with the interacting physiological process leading to hormesis. With respect to caloric availability, hormesis is based upon a fitness-stress continuum primarily reflecting adaptation to resource availablity and predictability in the wild from which various physiological consequences follow. In particular, a hormetic zone appears under some caloric restriction where energetic and metaolic efficiency and hence fitness are high. Hormesis can therefore be viewed in terms of selection for metabolic efficiency in response to any environmental variable.
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