Lowering caloric intake, a dietary process known as caloric restriction (CR) is the only reproducible non-genetic method that extends lifespan for most of the organisms tested, yet our understanding of how this diet works remains poor. One group of enzymes, the sirtuins, has recently emerged as leading candidates for mediators of the benefits of CR across species. In Chapter 1, the sirtuin family of deacetylase enzymes is reviewed within the context of CR-mediated biological effects in organisms.
The mammalian sirtuins have emerging roles in a variety of important basic and age-associated processes like cancer, diabetes, obesity, inflammation, muscle differentiation, heart failure, and neurodegeneration, thereby attracting wide interest for promising therapeutic intervention. However, many of the mammalian sirtuins remain poorly characterized, such as the case of the mitochondrial sirtuin SIRT3.
In human cell-culture studies, as discussed in Chapter 2, a new biological role is elucidated for SIRT3 as an anti-apoptotic sirtuin that protects against stress/nutrient deprivation. Prior to this work, virtually no connection existed between this sirtuin, the unique biochemical microenvironment inside of mitochondria, and cellular survival. Furthermore, in skeletal muscle studies explained in Chapter 3, a new biological role for SIRT3 is also described. As detailed in this Chapter, exercise training and CR raise SIRT3 expression in vivo, which leads to downstream activation of key pathways affecting muscle energy homeostasis.
In Chapter 4, the role of sirtuins and PNC-1/nicotinamidase is considered in the model organism C. elegans. In this Chapter, it is demonstrated that the nematode PNC-1 has robust nicotinamidase enzymatic activity in vitro and that over-expression in vivo protects against stress and extends lifespan by mimicking the effects of CR. Lastly, evidence is presented that some of the sirtuins in this organism mediate the effects of CR-induced longevity, contrary to some past literature.
Collectively, all of these biochemical and genetic studies, as summarized and discussed in Chapter 5, will help to further explain sirtuin-mediated mechanisms of homeostasis and aging in animals, thereby opening new routes for potential therapeutic intervention and for studying the biology of aging in vivo.
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 71/02, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Evolution and Development, Aging|
|Keywords:||Aging, Caloric restriction, Sirtuins|
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