Insights Into Calorie Restriction and Life Span Extension
Author | : Craig Brendon Skinner |
Publisher | : |
Total Pages | : |
Release | : 2011 |
ISBN-10 | : 112490848X |
ISBN-13 | : 9781124908489 |
Rating | : 4/5 (8X Downloads) |
Book excerpt: The search for the fountain of youth, undertaken by Juan Ponce de Leon in the 16th century and continued by longevity researchers around the globe, has evolved from a seemingly impossible expedition into the pursuit of a very real phenomenon: the life span-extending dietary regimen of calorie restriction (CR), and knowledge of its mechanism. CR in mammals is known to promote longevity and delay the onset of age-related diseases such as cancer and diabetes, while promoting processes such as mitochondrial respiration and the oxidative stress response. CR extends the life span of a wide variety of model organisms including worms, flies, mice, and monkeys, but many of the greatest revelations came from an unlikely place, the single-celled budding yeast Saccharomyces cerevisiae. The determination and characterization of many important longevity pathway components originated from studies on this humble organism. Mitochondrial respiration and stability are critical to CR-based life span extension, and are central to longevity in budding yeast, as they are in mammals. Mitochondria promote long life through activation of sirtuins, a family of NAD+-dependent protein deacetylases, and promotion of metabolic health, but also mediate cell death through apoptosis. They are the cellular reactors, capable of immensely efficient energy harvesting, yet produce the majority of cellular free radicals which, when unchecked, can cause irreparable damage to cellular machinery. Unsurprisingly, life span extending manipulations often impact the status of this organelle, often in ways similar to those of CR. Life span prolonging manipulations in budding yeast are often resistant to reactive oxygen species (ROS), which are associated with mitochondrial decline during the aging process. Originally identified as a mediator of cell size in budding yeast, cells without WHI2 continue to grow in stationary phase, possess unstable mitochondria, and display sensitivities to a wide variety of stresses, including oxidative stress. A screen for long-lived yeast revealed WHI2 as a life span-extending gene when over-expressed, and here we determine that WHI2 is a dosage-dependent mediator of longevity. Additionally, Whi2 requires the Msn2/4 transcription factors and Psr1/2 phosphatases for full life span extension. Psr1/2 was also found to mediate stability of Whi2 protein after the diauxic shift and into stationary phase, where the Whi2 phenotype is the most evident. Whi2 also regulates activation of Hsf1 transcription factor, and between Msn2/4 and Hsf1, promotes the oxidative stress response to protect mitochondria during stationary phase. The interaction between Hsf1 and Whi2 is complicated, and Whi2 appears to suppress Hsf1 before the diauxic shift, yet activate it afterwards. Investigating the relationship between Whi2, Hsf1, and growth phase may help us better understand the function of Hsf1 in cancer cells and during CR. CR is characterized by an increase in mitochondrial respiration and oxidative stress defense, but also induces production of a specific ROS, nitric oxide (NO). Production of NO by CR is important in both mammals and, as determined in this volume, budding yeast. Using NO as a biomarker of CR, several single-gene deletions that share CR phenotypes were identified and verified to be novel life span-extending mutants. In addition, the mechanisms behind CR-mediated NO production in yeast was analyzed. CR-linked NO production in yeast requires a functional electron transport chain, suggesting that the origin of NO during CR is cytochrome c oxidase (COX), as COX was previously demonstrated to generate NO from nitrite. NO is therefore a mitochondria-derived life span mediating molecule, adding yet another facet to the relationship between CR and mitochondria. Life span studies in yeast continue to contribute to our understanding of the molecular mechanisms of CR and aging. The following studies should further illuminate the connection between CR, mitochondria, and longevity, and it is my hope that these new revelations will contribute to our knowledge of longevity in mammals as well.