Mimicking Caloric Restriction: The extended life span and resistance to age-related diseases in animals exposed to caloric restriction has focused attention on the biochemical mechanisms that produce these effects. Selman et al. (p. 140 ; see the Perspective by Kaeberlein and Kapahi ) explored the role of the mammalian ribosomal protein S6 kinase 1 (S6K1), which regulates protein translation and cellular energy metabolism. Female knockout mice lacking expression of S6K1 showed characteristics of animals exposed to caloric restriction, including improved health and increased longevity. The beneficial effects included reduced fat mass in spite of increased food intake. Thus, inhibition of signaling pathways activated by S6K1 might prove beneficial in protecting against age-related disease.

Summary: Two theories of how energy metabolism should be associated with longevity, both mediated via free‐radical production, make completely contrary predictions. The ‘rate of living‐free‐radical theory’ (Pearl, 1928;Harman, 1956;Sohal, 2002) suggests a negative association, the ‘uncoupling to survive’ hypothesis (Brand, 2000) suggests the correlation should be positive. Existing empirical data on this issue is contradictory and extremely confused (Rubner, 1908;Yan & Sohal, 2000;Ragland & Sohal, 1975;Daanet al., 1996;Wolf & Schmid‐Hempel, 1989]. We sought associations between longevity and individual variations in energy metabolism in a cohort of outbred mice. We found a positive association between metabolic intensity (kJ daily food assimilation expressed as g/body mass) and lifespan, but no relationships of lifespan to body mass, fat mass or lean body mass. Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein‐3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest – supporting the ‘uncoupling to survive’ hypothesis.

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMCα2KO and AgRPα2KO mice lacking AMPKα2 in proopiomelanocortin– (POMC-) and agouti-related protein–expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMCα2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRPα2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPKα2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMCα2KO and AgRPα2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

The direct effects of physical activity interventions on energy expenditure are relatively small when placed in the context of total daily energy demands. Hence, the suggestion has been made that exercise produces energetic benefits in other components of the daily energy budget, thus generating a net effect on energy balance much greater than the direct energy cost of the exercise alone. Resting metabolic rate (RMR) is the largest component of the daily energy budget in most human societies and, therefore, any increases in RMR in response to exercise interventions are potentially of great importance. Animal studies have generally shown that single exercise events and longer-term training produce increases in RMR. This effect is observed in longer-term interventions despite parallel decreases in body mass and fat mass. Flight is an exception, as both single flights and long-term flight training induce reductions in RMR. Studies in animals that measure the effect of voluntary exercise regimens on RMR are less commonly performed and do not show the same response as that to forced exercise. In particular, they indicate that exercise does not induce elevations in RMR. Many studies of human subjects indicate a short-term elevation in RMR in response to single exercise events (generally termed the excess post-exercise O₂consumption; EPOC). This EPOC appears to have two phases, one lasting 2 h and a smaller much more prolonged effect lasting up to 48 h. Many studies have shown that long-term training increases RMR, but many other studies have failed to find such effects. Data concerning long-term effects of training are potentially confounded by some studies not leaving sufficient time after the last exercise bout for the termination of the long-term EPOC. Long-term effects of training include increases in RMR due to increases in lean muscle mass. Extreme interventions, however, may induce reductions in RMR, in spite of the increased lean tissue mass, similar to the changes observed in animals in response to flight.

The idea that resources are limited and animals can maximise fitness by trading costly activities off against one another forms the basis of life-history theory. Although investment in reproduction or growth negatively affects survival, the mechanisms underlying such trade-offs remain obscure. One plausible mechanism is oxidative damage to proteins, lipids, and nucleic acids caused by reactive oxygen species (ROS). Here, we critically evaluate the premise that ROS-induced oxidative damage shapes life history, focussing on birds and mammals, and highlight the importance of ecological studies examining free-living animals within this experimental framework. We conclude by emphasising the value of using multiple assays to determine oxidative protection and damage. We also highlight the importance of using standardised and appropriate protocols, and discuss future research directions.