Lab. of Plant Molecular Genetics General Manager of Histogenetics-Korea Inc. Sungmoo Byeon

Introduction Elixir of life? As always, greed blinds our eyes! and God’s gift of longevity lay in eating less!!! = CR(Calorie Restriction) Providing diet low in calorie without malnutrition

Introduction Nutrient uptake ↓ Respiration in mitochondria ↓ ROS(Reactive Oxygen Species) Production ↓ oxidative damage to DNA & Macromols. ↓ loss of cellular functions ↓ Aging Shino Nemoto and Toren Finkel, Nature 429, (13 May 2004) Too Much More More Faster ?

So we can summarize that into Calorie Restriction is effective because it… Slows the use of carbohydrates Slows respirations Slows the production of ROS Slows the damaging And so Slows aging! Not Exactly True!! Introduction

1.Mitochondrial activity is enhanced instead of being depressed! 2.Calorie Restriction(CR) is a regulated process rather than a passive process! Sirtuins : SIR2(yeast), SIRT1(mammals) is Regulatory protein Yeast, C. Elegans & D. Melanogaster : increase life span In this essay, author wants to… 1.Summary the positive effects of CR and sirtuins on mitochondrial activity. 2. Present models to explain anti-aging results of CR and sirtuins. Actually,

Mitochondria and CR-induced longevity eNOS↑ Mitochondiral Number ↑ Figure 1.

‘The French Paradox’ Americans and French both eat high fat, high calorie food but French suffer less from heart and circulatory diseases. Resveratrol is a natural compound found in the skin of red grape and was suggested to explain this paradox because mostly French drink more red wine than Americans. It is one candidate of elixir of life. Mitochondria and CR-induced longevity

Why is Activation of Mitochondria Good? ‘Increased respiration in yeast and worms is required for CR-induced longevity, but the situation in mammals is only correlative.’ it says in this paper but… But in July of 2009, UW research team reported in Science that CR- induced life span extension in primates. Ricki J. Colman et al. Science July 10; 325(5937): 201–204.

Five possible relationship between CR anti-aging and Mitochondrial increase & activity. Model 1. A Mitochondrial Buffer to Aging. CR triggers the reproduction of mitochondria in order to be prepared for DNA damage and activity loss. Model 2. Mitochondrial Regulation of Sirtuins As in yeast, mammalian Sirtuins might be regulated by the activity of mitochondria at a downstream level. SIRT3,4 and 5 is located inside the mitochondria.

Five possible relationship between CR anti-aging and Mitochondrial increase & activity. Model 3. Mitochondrial Regulation of ROS Long living species might produce high levels of antioxidant enzymes and CR might lead to a reduction of ROS production. Objection: More mitochondria and less ROS? Most ROS are produced by complex 1 and 3 in electron transport chain. ROS production is increased when electron is stalling at these complexes. During CR, electron transit through complex 4 and 5 is fast so stalling do not occur.

Five possible relationship between CR anti-aging and Mitochondrial increase & activity. Figure 2.

Five possible relationship between CR anti-aging and Mitochondrial increase & activity. Model 4. Mitochondrial Reprogramming to Fat Oxidation During CR, all energy sources are used up and β-oxidation must take place in peripheral tissues. β-oxidation takes place in mitochondria and utilizes complex 3 in electron transport chain. Model 5. Recycling of Damaged Mitochondria Mitochondria biogenesis during CR might be due to autophagy of damaged mitochondria and production of new and healthy ones. Autophagy is reported in CR induced life span extension of C. Elegans.

Conclusion 1.Sirtuins seems to play a significant role during aging. 2.CR which have been proved to show life span extending effect in other species increases SRIT1 level in mammals. 3.4 out of 7 Sirtuins’ functions are related to mitochondria. Among the models, I think model number 3 and 5 are most convincing. We shall see…