Lab. of Plant Molecular Genetics Lab. of Plant Molecular Genetics

General Manager of Histogenetics-Korea Inc.General Manager of Histogenetics-Korea Inc.

Sungmoo Byeon 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 caloriewithout malnutrition

Introduction

Nutrient uptake

↓

Respiration in mitochondria

↓

ROS(Reactive Oxygen Species)

Production

↓

oxidative damage to DNA & Macromols.

↓

loss of cellular functions

↓

AgingShino Nemoto and Toren Finkel, Nature 429, 149-152(13 May 2004)

Too Much

More

More

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

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↑

MitochondiralNumber ↑

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. 2009 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…