Calorie restriction 02/04

Question 1

Calorie restriction

Answer 1

This is the most reliable intervention in slowing down the processes of ageing.

Question 2

What are the five main mechanisms by which calorie restriction acts to slow ageing processes?

Answer 2

1. reducing formation of advanced glycosylation end products
2. changing the production of ROS from the mitochondria
3. altering the expression of genes: SIRT1 and PGC1α
4. nutrient sensing pathways
5. FOXO and TOR pathways

Question 3

What is calorie restriction?

Answer 3

Dietary restriction of energy intake by 30-40%, while maintaining intake of vitamins, minerals, essential amino acids and fats - this differentiates calorie restriction from starvation and malnutrition, which would not increase lifespan.

Question 4

What insights have been gained from population studies?

Answer 4

During WW1 in denmark there was involuntary calorie restriction for two years. Precise CR is unknown. However, local government ensured sufficient vegetables, wholegrain cereals and milk. Mortality reduction was 34%.

During WW2 in Oslo norway the same sitatuation occured for 4 years where calories were restricted by 20% - government ensured sufficient sufficient vegetables, wholegrain cereals, fish and milk. Mortality reduciton was 30%

Okinawa population - an isolated Japanese population. 4x centenarians. 50% less stroke, cancer and CVD than japan mainland. Total intake is 20% less than NA and 40% less that American average.

Question 5

Why are lifelong calorie restriction diets not recommended?

Answer 5

Calorie restriction from an early age is associated with a number of negative effects. These include:
Slowed growth and smaller maximum body size
Delayed puberty
Reduced fertility
Compromised thermogenesis

Question 6

What are the effects of CR on AGEs

Answer 6

• reduction found in rat tissues
• however CR combined with high levels of exogeneous (dietary AGEs) show increased mortality rates compared to controls.

Question 7

How does the electron transport chain become altered in ageing - 5 stage

Answer 7

1. Ageing is associated with accumulated mutations, along with increase in sedentary lifestyle and excess calorie consumption. Lack of movement causes a build up of unused ATP, and excess calories causes a build up of NADH.
2. NADH continues to donate electrons to complex, protons are transferred.
3. However, due to ATP build up and mutations, complex V and ATPase does not use the proton gradient to create ATP. Protons remain in the intermembrane space, creating heat.
4. More superoxide is produced, and electrons build up in the chain (complex IV) . The electron transport chain can stall. Protons leaked as heat, electrons leaked as ROS. Membrane potential increases.
5. As the inner mitochondrial membrane potential increases, H202 production increases.

Question 8

How can calorie restriction improve functioning of ETC?

Answer 8

1. There is less NADH build up, and so all electrons are used to make ATP.
2. Alongside this, the membrane becomes more permeable to H+, therefore the membrane potential is reduced. One study has shown that reduction of membrane potential by 10% results in 50% less H202 production

Question 9

What is the effect of CR on SIRT1?

Answer 9

SIRT1 is an NAD+ dependent protein. CR increases the ratio of NAD+ : NADH and therefore increases expression of SIRT1.
SIRT1 +/+ calorie restricted mice show a greater lifespan. Sirt1-/- calorie restricted mice have even shorter lifespan that sirt1 +/+ ad libitum mice.

Calorie restriction increases SIRT1 expression in skeletal muscle.

Question 10

What are the effects of resveratol on SIRT-1

Answer 10

It is a naturally occuring polyphenol that induces SIRT-1. Some animal studies show it to increase lifespan, however there is controversy over whether SIRT1 activation in the absence of CR is effective in mammals.

There are currently synthetic mimetics of resveratol being developed as a pharmacological strategy for prolonging life.

Question 11

What effect does calorie restriction have on energy ratio?

Answer 11

There is less build up of ATP, so there is a higher AMP:ATP ratio

Question 12

What effect does calorie restriction have on PGC-1α?

Answer 12

increased AMP:ATP ratio cause by CR activates AMPK (intracellular energy sensor).
AMPK inhibits TOR and upregulates expression of PGC-1α.

PGC-1α stimulates mitochondrial biogenesis

This increases number of mitochondria and ETC activity.

Question 13

What is TORC?

Answer 13

An upstream regulator of PGC-1α that increases its expression.

Tranfection with TORC has been shown to increase expression of mitochondrial proteins such as cytochrome c

Question 14

Why are more mitochondria beneficial?

Answer 14

More mitochondria = more ETC.

This means that NADH (& e-) spread over a greater number of complexes. Fewer e- build-up in each mitochondria: less e- leak to form ROS

IMPORTANT: Metabolic rate does not change in CR. Same O2 used.

Question 15

What is the relationship between PGC-1alpha and SIRT1?

Answer 15

SIRT1 increases expression of PGC-1α through de-acetylation. This increases support for SIRT1 as highly beneficial therapeutic target for many disorders as it could modulate mitochondrial dysfunction

Question 16

What is the effect of CR on nutrient sensing?

Answer 16

Normally nutrients activate systems to promote cell growth through raising blood levels of insulin like growth factor (IGF-1)

They also increase blood levels of insulin to promote storage of glucose.

CR reduces IGF-1 . Less activation of IGF-1R.
Small size animals when CR.

Question 17

What is the effect of IGF-1R on lifespan?

Answer 17

Mice heterozygous for IGF-1 KO show 23% increase in lifespan.

Question 18

What is the effect of blocking IGF-1R on reactive oxygen species?

Answer 18

It decreases ROS production.
Reduced IGF-1R activation prevents its inhibitory actions on FOXO3a.
FOXO3a is translocated to the nucleus where it induces the expression of mitochondrial antioxidants such as mgSOD and glutathione.

Other effects: increased autophagy, increased heat shock proteins (protect and repair), reduced apoptosis, increased antioxidants, ANTI-AGEING