Caloric Restriction and Life Expectancy

Highlights of the 5th European Molecular Biology Organization Interdisciplinary Conference on Science and Society -- Time & Aging: Mechanisms and Meanings; November 5-6, 2004; Heidelberg, Germany

Elena Armandola, PhD

In This Article

Caloric Restriction and Lifespan

L. Demetrius,[1] of Harvard University, Boston, Massachusetts, addressed the applicability of the findings of a caloric restriction (CR) regimen from short-lived animal species to humans. The first evidence that CR could retard aging and extend lifespan was presented in the 1930s.[2] Since then, similar findings have been confirmed in a variety of species, including mice, rats, fish, flies, worms, and yeast.[3,4,5] Despite the extensive studies, however, the molecular basis for the slowing of aging is still unclear, although the effects of CR on the physiology of an organism are well known.

One central question is whether CR will have the same life-prolonging effects in humans.

According to Demetrius, to make any kind of prediction, we have to carefully analyze the similarities and differences between humans and the species in which the studies have been performed up to now. If we compare, for example, mice and humans, we make the hypothesis that mice are a miniaturized form of humans. Extrapolating the data about lifespan extension and CR obtained in mice to humans, we would predict that the mean lifespan could go from 75 to 90 years and the maximum lifespan from 120 to 150 years with CR. But is the initial assumption that mice are miniaturized humans valid?

"Mice are not small people," argued Demetrius. Great differences exist in life history and physiology, in cancer susceptibility, in the rate of senescence, and several other factors. The metabolic rate is very different (16 kJ/day in mice vs 7200 kJ/day in humans). The rate of senescence in mice follows a curve in which mortality increases exponentially with age, in the absence of a mortality plateau that is, instead, seen in humans in whom mortality abates with age. There is also a difference in biological stability between mice and humans, exemplified by the finding that mouse fibroblasts can convert to tumorigenic cells by the perturbation of just 2 signaling pathways. Conversely, in human fibroblasts the perturbation of at least 6 signaling pathways is necessary for tumorigenic conversion.

Mice and humans have been subjected to different ecologic and evolutionary forces. Mice (in the wild) are an opportunistic species, for which resources are intermittently available, with alternating periods of population growth and decrease that occur rather quickly. On the other hand, humans are an equilibrium species in stable growth, for which resources are constant, although limited. If we look at the concept of Darwinian fitness (eg, the capacity of a population to survive and reproduce under given environmental conditions), we find that the fitness of an opportunistic species is based on demographic flexibility, whereas the fitness of an equilibrium species is based on demographic robustness.

In an opportunistic species, evolution will result in early sexual maturity, large litter size, and metabolic flexibility due to the high vulnerability to random changes in metabolic networks. In an equilibrium species, evolution will result in late sexual maturity, small litter size, and metabolic robustness due to the relative insensitivity of the system to random changes.

The effect of CR on the 2 species will then be different. If we make the hypothesis that CR increases the stability or robustness of the metabolic network by increasing the metabolic efficiency and enhancement of homeostatic regulation in cells, we can predict that CR will induce large changes in an opportunistic species by increasing its robustness, whereas it will have weaker effects on an equilibrium species, in which robustness is already achieved. From this, Dr. Demetrius predicted that the response to CR with an increase in lifespan will be marginal in humans owing to the robustness or stability of their metabolic networks and the evolutionary history of the species.


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