Recent Papers on Energy Metabolism and Longevity

Here I'll point out a couple of papers on the topic of energy, metabolism, and natural variations in longevity. One of the many ways of looking at the operation of metabolism is from the point of view of energy consumption and expenditure: how does energy flow around the system, how do these flows vary in different circumstances and between different species, and what can that tell us about the way in which our biology breaks down over the course of aging, or even why we age at all?

It is quite possible to measure a living being in the same way as one can measure an engine as a black box, assessing energy in, energy stored, energy expended. You can put an individual in an enclosed room and measure calorie intake, changes in gas fractions in the air, and so forth. Separately, within cells and tissues it is possible to catalog chemical reactions and the transfers of energy that accompany them, to build a picture of how the energy is ported from, say, food to movement of limbs, at both the high level and the very low level. Some types of model are pretty good and some are pretty sketchy since they depend on incomplete knowledge, but researchers have been working on aspects of this field of research for quite a long time, and both understanding and the quality of the models continues to improve.

One of the other fields tied in to considerations of energy metabolism is the study of calorie restriction, well known to extend healthy life span and improve health in near every species measured to date. Lowered intake of calories causes sweeping changes in the operation of cellular biology, and of course all of that can be considered in terms of energy. The two open access papers linked below both touch upon calorie restriction in the course of their discussion. This first is written from the minority programmed aging point of view, the second from the majority opposition viewpoint of aging as accumulated cell and tissue damage - though of course even with each of these factions there is a great deal of debate and many different theories of aging.

Energy excess is the main cause of accelerated aging of mammals

To date, over 300 theories explaining aging were put forward. Some of them, like the uncritically accepted free radical theory of aging, do not find unequivocal experimental support. Others, like the distinction between mortal soma and immortal germ line or disposable soma theory, can explain only general rules of aging, but are restricted to animals. Those, like antagonistic pleiotropy theory, are informative, but cannot explain the details of mechanisms of senescence and longevity. The closest to ideas presented in this paper is the postulate of hyperfunction.

The analysis of cases of unusually high longevity of naked mole rats and an alternative explanation of the phenomenon of calorie restriction effects in monkeys allowed for postulating that any factor preventing an excess of energy consumed, leads to increased lifespan, both in evolutionary and an individual lifetime scale. It is postulated that in mammals the most destructive processes resulting in shortening of life are not restricted to the phenomena explained by the hyperfunction theory. Hyperfunction, understood as unnecessary or even adverse syntheses of cell components, can be to some extent prevented by lowered intake of nutrients when body growth ceases. We postulate also the contribution of glyco/lipotoxicity to aging, resulting from the excess of energy.

Besides two other factors seem to participate in aging. One of them is lack of telomerase activity in some somatic cells. The second factor concerns epigenetic phenomena. Excessive activity of epigenetic maintenance system probably turns off some crucial organismal functions. Another epigenetic factor playing important role could be the microRNA system deciding on expression of numerous age-related diseases. However, low extrinsic mortality from predation is a conditio sine qua non of the expression of all longevity phenotypes in animals. Among all long-lived animals, naked mole rats are unique in the elimination of neoplasia, which is accompanied by delayed functional symptoms of senescence. The question whether simultaneous disappearance of neoplasia and delayed senescence is accidental or not remains open.

On the complex relationship between energy expenditure and longevity: Reconciling the contradictory empirical results with a simple theoretical model

The relationship between energy expenditure and longevity has been a central theme in aging studies. The oldest theory in the field - the rate of living theory (RLT) suggests that the rate of mass-specific energy expenditure (metabolic rate) is negatively correlated with longevity. The predicted correlation between energy expenditure and lifespan does not hold when comparisons are made across taxons, however. A typical example is that birds have higher metabolic rate than mammals with the same body mass, yet live much longer. The oxidative stress theory of aging (OST), another theory that links energy metabolism and longevity, suggests that the deleterious productions of oxidative metabolism (e.g., reactive oxygen species, ROS) cause various forms of molecular and cellular damage, and the accumulation of the damage is associated with the process of aging. Widely considered by many researchers as a modern version of the RLT at the molecular and cellular level, this theory shares all the supports and challenges of the RLT, as well as a few of its own.

In this paper, we present a simple theoretical model based on first principles of energy conservation and allometric scaling laws. We show that oxidative metabolism can affect cellular damage and longevity in different ways in animals with different life histories and under different experimental conditions. Qualitative data and the linearity between energy expenditure, cellular damage, and lifespan assumed in previous studies are not sufficient to understand the complexity of the relationships. Our model provides a theoretical framework for quantitative analyses and predictions. The model is supported by a variety of empirical studies, including studies on the cellular damage profile during ontogeny; the intra- and inter-specific correlations between body mass, metabolic rate, and lifespan; and the effects on lifespan of (1) diet restriction and genetic modification of growth hormone, (2) the cold and exercise stresses, and (3) manipulations of antioxidant.

The oxidative damage producing process starts from the overall energy expenditure (measured as oxygen consumption rate). Under many circumstances, energy expenditure is proportional to the production rate of ROS, which is in turn proportional to the net oxidative damage. Assuming that the net oxidative damage is the cause of aging and the determinant of lifespan, in these cases there is a direct and simple link between lifespan and metabolic rate. However, two factors, namely antioxidant scavenging and damage repair mechanisms, can alter the damage level (the output of the process) while keeping the energy expenditure rate (the input) roughly unchanged. Enhancing or weakening these two factors can result in a nonlinear correlation between net cellular damage level and oxygen consumption, and therefore a complex relationship between energy expenditure and longevity. The nonlinearity between damage and oxygen consumption may also be partially attributed to the incomplete mitochondrial coupling due to proton leak and electron leak, which causes a fraction of consumed oxygen not to produce ROS.

We need to emphasize that the protective mechanisms of anti-oxidative scavenging and damage repair require energy. So, the overall protective efficacy depends on the amount of energy allocated to these mechanisms and the efficiency of energy utilization for this purpose. Thus, we hypothesize that there are two ways to enhance the protection. The first way is to allocate more energy to protection. More energy for protection does not necessarily require an increase in overall energy expenditure. Some lifespan extension interventions can reshuffle the energy allocation and induce tradeoffs between protection and other life history traits. One of the most important traits that is often manipulated to tradeoff with protection is biosynthesis during growth. For example, when growth is retarded by diet restriction or genetic modification of growth hormone, the energy requirement for biosynthesis is reduced accordingly. The second way is to enhance the protective efficiency, so that one unit of the energy is associated with less molecular damage. Protective efficiency can be altered by experimental manipulations, such as down- or up-regulating genes for antioxidant enzymes, or altering the structures of molecules, such as the fatty acid composition of membranes, to change their vulnerability to oxidative insults.

In the RLT, the overall energy expenditure is the determinant of longevity, whereas in the OST, the determinant is the net cellular damage. As discussed above, because energy allocation and protective efficiency can both change in a variety of situations, these two determinants are not simply proportional to each other, and the link between longevity and energy expenditure is far more complex. Thus, we argue that the OST is not merely the modern version of the RLT at the cellular and molecular level.

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