Skepticism about Sir2’s role in yeast CR

Two excellent recent reviews by Matt Kaeberlein and colleagues address issues in the budding yeast model of aging.

The first covers the history of yeast as a model system of aging (and Prof. Kaeberlein would know, inasmuch as he’s been involved in the field for a decade, and has broke some of its earliest stories), and provides a thorough background on a matter that might seem to require some explanation: specifically, why we believe that a single-celled fungus can teach us about the genetic control of aging in the metazoans. From the article in PLoS Genetics (with co-author Brian Kennedy, himself an old hand in yeast lifespan):

In the last decade, research into the molecular determinants of aging has progressed rapidly and much of this progress can be attributed to studies in invertebrate eukaryotic model organisms. Of these, single-celled yeast is the least complicated and most amenable to genetic and molecular manipulations. Supporting the use of this organism for aging research, increasing evidence has accumulated that a subset of pathways influencing longevity in yeast are conserved in other eukaryotes, including mammals. Here we briefly outline aging in yeast and describe recent findings that continue to keep this “simple” eukaryote at the forefront of aging research.

That review is required reading before you jump into this next one, in which Matt takes on the question of whether Sir2 (the founding member of the sirtuins, which certainly do regulate lifespan in yeast, and possibly in other organisms) is involved in the life extension resulting from calorie restriction (CR) in yeast. From Kaeberlein & Powers:

Activation of Sir2-family proteins in response to calorie restriction (CR) has been proposed as an evolutionarily conserved mechanism for life span extension. This idea has been called into question with the discovery that Sir2-family proteins are not required for life span extension from CR in yeast. We present here a historical perspective and critical evaluation of the model that CR acts through Sir2 in yeast, and interpret prior reports in light of more recent discoveries. Several specific cases where the Sir2 model of CR is inconsistent with experimental data are noted. These shortcomings must be considered along with evidence supporting a role for Sir2 in CR in order to fully evaluate the validity of this model.

The article is valuable not only as a treatment of a controversy (on which Kaeberlein definitely falls on one side), but also as an exemplar of the types of genetic reasoning (and associated challenges) involved in lifespan studies of many kinds in all types of organisms.

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