Module 3- Aging and Longevity

Question 1

What is aging?

Answer 1

• Evolutionary natural selection has no reason to keep our “mechanisms” working once we have passed the reproductive years — our only purpose genetically speaking is the propagation of our genes.
• Aging is a process that converts an optimally healthy, fit organism into a less healthy, less fit organism

*Reduced tissue/physiological function
*Increased susceptibility to disease (age-related diseases)
*Decreased resistance to stress (physical and psychological)

Question 2

The Case for Calories and Primates

Answer 2

Question 3

Restricting calorie intake enhances lifespan in animals

Answer 3

Studies have shown that a 30 - 40% calorie restriction without malnutrition extends a healthy lifespan by 40 - 50% Sci. Amer.
in worms, flies, mice, rats, and potentially monkeys

A life-extending eating strategy with “profound and sustained beneficial effects,” according to the Proceedings of the National Academy of Science (PNAS)

Question 4

Aging is a combination of our ___

Answer 4

Chromosomes, genes, and environment

Question 5

What is cellular senescence?

Answer 5

A process in which cell growth and development is irreversibly halted. Senescent cells no longer divide, but maintain metabolically active.

Question 6

The Senescence Process

Answer 6

Question 7

Telomeres

Answer 7

• A region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from
  deterioration or from fusion with neighboring chromosomes.
• The Hayflick limit is the number of cell divisions a normal cell can undergo before its telomeres are too short — typically between 50 to 70 cell divisions.

Question 8

Removing senescent cells to prevent aging- Proxofim

Answer 8

A small peptide that clears senescent cells and stimulates surrounding stem cells to create new tissue, with results seen within 10 days.

Question 9

Species-specific genes play a role in determining lifespan

Answer 9

Question 10

Species-specific longevity genes

Answer 10

• Life spans ranging from 2-3 weeks to 100-200 years!
• Flies (Drosophila melanogaster) (weeks) Nematodes (Caenorhabditis elegans) (months)
• Mice (Mus musculus) (<4 years)
• Humans (Homo sapiens) (<100 years) Galapagos turtles (Geochelone elephantopus)
• What are the genes that determine why mice live <4 years, whereas humans live >100 years?

Question 11

Aging in Mice and Men

Answer 11

Question 12

Genes that have been shown to affect stress resistance and lifespan in laboratory models

Answer 12

Human homologs do not show the same relationship.

Question 13

Sirtuins

Answer 13

Sirtuins are a longevity gene, originally studied in yeast (SIR2), that has been shown to be significant to cellular processes in mammals (SIRT1).

• In yeast :
• Increased sirtuins =Increased lifespan
• Decreased sirtuins =Decreased lifespan

Question 14

Sirtuins in aging

Answer 14

• Sirtuins are longevity genes originally studied in yeast (SIR2) that has been shown to be significant to cellular processes in mammals (SIRT1).
• In yeast, increased sirtuins → increased lifespan while decreased sirtuins → decreased lifespan
• Role of sirtuins and aging:
  ● Energy expenditure
  ● Senescence
  ● Stress resistance
  ● Histone acetylation/deacetylation

Question 15

Sirtuins and nutrient availability

Answer 15

• Sirtuins respond to decreases in nutrient availability and cellular stress to promote cell survival by deacetylating histone and non-histone targets in the nucleus.
• Deacetylation promotes survival rather than apoptosis.

Question 16

What does high SIRT1 level promote?

Answer 16

High SIRT1 activity promotes deacetylation of Ku70, FOXO and p53, (transcription factors) promotes DNA repair and cell-cycle arrest, and blocks apoptosis induction.

Question 17

Resveratrol

Answer 17

• The magic pharmacological bullet?…Sirtuins, drugs that can modulate the activities of SIRT1
• Resveratrol is a molecule present in red wine and manufactured by other plants in response to stress
• High concentration pill of resveratrol extended mouse lifespan 44%
  Now undergoing clinical trials in humans

Question 18

Putting it all together

Answer 18

● Calorie restriction
● Sirtuins
● Mitochondria
● Decreased stress

Question 19

Flow chart of how calorie restriction leads to longevity

Answer 19

Question 20

Has modern medicine changed the demographics of aging?

Answer 20

Virtually all of the topics that have been covered in this course have been developed either to enhance or prolong life.

Now that you see the tool box…do you want to live to 100 yrs?