It has been known for sometime that reduced intake of calories increases the lifespan of many species, including mammals, but just exactly how this works is unclear. One theory suggests that reduced metabolic rates minimize exposure to damaging reactive oxygen species (ROS), which are byproducts of respiration. However, work from Leonard Guarente’s lab at MIT, published in the July 18 Nature, suggests that increased respiration is what extends lifespan-at least in yeast.

First author Lin, and colleagues from MIT and Johns Hopkins University, examined the effect of switching yeast metabolism from anaerobic fermentation to oxidative respiration. They achieved this by a variety of means including using a strain that lacks hexokinase, an enzyme required to initiate glycolysis, and by overexpression of the transcription factor Hap4, which is known to induce yeast to respire. In all cases the yeast lived longer, i.e. more generations, while consuming more oxygen, just as they do when grown on 0.5 percent glucose as opposed to 2 percent. What’s more, the authors found these longer-lasting yeast had normal levels of most antioxidant genes and, if anything, slightly decreased resistance to oxidative stress, suggesting that ROS play no role in determining lifespan.

So what does this mean for humans? Well, in contrast to yeast cells which are constantly dividing, most human cells are postmitotic, stationary phase cells, so the same rules may not apply. However, the increased lifespan of the respiring yeast seems to be tightly associated with expression of the protein Sir2, which is responsible for gene silencing and is regulated by the cofactor NAD +. Levels of NAD + are sensitive to the respiratory state of the cell and increase with respiration, thus tying Sir2 in with caloric restriction. Why is this important? Well it just so happens that Sir2 homologs are also found in humans.—Tom Fagan


  1. Eat Less, Live More —But Why? Comment by George Perry and Mark A. Smith
    Institute of Pathology, Case Western Reserve University, Cleveland, Ohio USA

    A well lived life can only be seen in retrospect of a lifetime of living and, in the view of the ancient Greeks, by one of moderation. Scientific support for this view is found in the health benefits of a balanced diet rich in fruits and vegetables ( Lin et al., 2002; Luchsinger et al., 2002) with the greatest health benefit, and increase in longevity, coming from dietary restriction. In this regimen, organisms consuming around 30 percent of calories below ad libum have an approximately 30 to 50 percent increase in lifespan. Decreased free radicals, increased cellular stress, and altered hormonal balance are all thought to play a role but have not been confirmed by mechanistic studies. A link between Alzheimer disease (AD) and caloric intake has been made by case control studies showing that patients who go on to develop AD eat up to 500 more calories per day than controls in the decade prior to disease ( Smith et al., 1999.). Meta-analysis of world dietary habits shows that there is a strong correlation between the prevalence of AD and average caloric intake (Grant et al., 1999).

    The complexity of the relationship between diet, aging and AD has been made all the more apparent by recent studies. In evaluating the contribution of caloric and fat intake in AD, Mayeux and colleagues (Luchsinger et al., 2002) found high caloric intake was associated with an increased risk of AD. The risk was most significant for those people having at least one copy of the apolipoprotein E4 allele. In consideration that high caloric diets are usually rich in fats, these data are consistent with work by Petot and Friedland in which a link between fat intake and risk of AD was shown and, again, this was dependent on apolipoprotein -E genotype with E4 showing the most pronounced result (Friedland et al., 2002).

    Understanding the mechanism for increased risk from AD through high caloric intake may provide important insights into AD pathogenesis. The link between apolipoprotein-E genotype and fat intake suggests that lipid transport and metabolism may be critical to AD. Lessons might also be learned from studies of dietary restriction, which have been suggested to prolong lifespan through reduction of reactive oxygen formation, another mechanism involved in AD pathogenesis ( Perry et al., 1998). The recent finding of Lin and colleagues (2002), that the lifespan extending effect of dietary restriction relates to whether glycolysis or Krebs cycle metabolism dominates in yeast, is important because it suggests that it is not the total caloric intake but the outcome of dominance of one pathway or another that is critical to lifespan control. Therefore, caloric restriction may miss the point in that the consequences of differing metabolism strategies may have critical outcomes. Seen in light of the admonition for moderation by the ancient Greeks, it appears that the good life is not marked by extremes of diet but rather by a balance in metabolism.


    . Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature. 2002 Jul 18;418(6895):344-8. PubMed.

    . Caloric intake and the risk of Alzheimer disease. Arch Neurol. 2002 Aug;59(8):1258-63. PubMed.

    . Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer's disease. J Alzheimers Dis. 1999 Nov;1(4-5):203-6. PubMed.

    . Dietary links to Alzheimer's disease: 1999 update. J Alzheimers Dis. 1999 Nov;1(4-5):197-201. PubMed.

    . Reactive Oxygen Species Mediate Cellular Damage in Alzheimer Disease. J Alzheimers Dis. 1998 Mar;1(1):45-55. PubMed.

    View all comments by George Perry

Make a Comment

To make a comment you must login or register.


No Available References

Further Reading

No Available Further Reading

Primary Papers

  1. . Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature. 2002 Jul 18;418(6895):344-8. PubMed.