KEY PATHWAYS (IGF-1, mTOR, AMPK)

Question 1

Pathways and factors associated with longer lifespan

Answer 1

1. Dietary restriction
2. AMPK signalling
3. Autophagy
4. Exercise

Question 2

Pathways and factors associated with shorter lifespan

Answer 2

1. Nutrients (excess/lack)
2. Insulin/IGF-1 signalling
3. mTOR signalling
4. Reproduction

Question 3

Obesity and healthspan

Answer 3

Overweight and obese ppl have shorter health AND lifespan
* Longer period of diease before death
* More obvious in females

Question 4

Insulin/IGF-1 signalling and FOXO

Answer 4

Cascade to activate AKT
* inhibit FOXO1, which generates PRO AGEING genes
* but if FOXO active > PRO LONGEVITY

Question 5

IGF-1 impact in dogs

Answer 5

• More IGF-1, much larger dog
• SMALL dogs live longest

Question 6

How to reduce plasma IGF-1?

Answer 6

IF and Genetic manipulation
* nematode mutant worm living 2x as long
* Daf-2 deletion (no receptor for IGF-1/insulin)

Question 7

Where does FOXO hangout when their is NO insulin/IGF-1 signalling?

Answer 7

In the nucleus
* bound to DNA targets
* transcription of prolongevity genes

Question 8

What genes if FOXO transcribing when it is active?

Answer 8

Defensive genes
* Stress (oxidative, cell cycle)
* SUPPRESS cellular proliferation
* Apoptosis upregulated
* Preserve organ function

Question 9

What is mTOR?

Answer 9

Key kinase that responsds to HIGH nutrient levels
* Active > triggers protein synthesis

Question 10

mTOR activation

Answer 10

AKT and AAs (Leucine and Arginine)

Question 11

mTOR inhibition

Answer 11

Rapamycin (drug)
* extends lifespan in mice
* sig. deviation in males and females

Question 12

What is AMPK?

Answer 12

AMP Kinase that sense lack of nutrients in cell
* bind nucleotide AMP
* STOP anabolic
* ACTIVATE catabolic

Question 13

What causes an increase in AMP

Answer 13

Lack of ATP and ADP
* Nutrient starving
* Exercise
* Mitchondrial poisons

Question 14

What processes does AMPK activate?

Answer 14

Catabolic
1. Lipid oxidation
2. Glucose metabolism
3. Autophagy

Question 15

What is autogaphy?

Answer 15

Consuming some contents of cell > digesting to make more nutrients

Question 16

What processes does AMPK block?

Answer 16

Anabolic
1. Protein and Lipid synthesis
2. Gluconeogenesis
3. Glycogen storage
4. Translation

Question 17

Metformin

Answer 17

Activates AMPK
* First line therapy for T2D
* EXTEND lifespan

Question 18

Autophagy process

Answer 18

AMPK active > isolation membrane forms
* Wraps around cell constituents
* Closes off to form autophagosome
* Fusion with lysosome > degradation
* Pumped out to cytoplasm for use

Question 19

Mitophagy

Answer 19

Distinct signalling mechanism
* Flag with phosphorylated proteins
* Target non-functional parts of mitochondria

Question 20

Aggrephagy

Answer 20

Enclose aggregated proteins and digest
* stop neurodegen

Question 21

Parkinson’s disease

Answer 21

Defect in Parkin
* Mitophagy inefficient
* Release ROS

Question 22

Integration of signalling (food and mTOR)

Answer 22

Food inhibits AMPK and activates Insulin
* Insulin > AKT > activate mTOR and inhibit FOXO
* AMPK > inhibit mTOR and activate AUTOPHAGY

Question 23

Reproduction

Answer 23

Trade off with lifepsan
* High protein and low carb is better for reproduction