Lecture 4: Hallmarks part 2 Flashcards
“When does ageing start?” -> depends on the definition.
1 After peak functionality:
2 After Essential Life Span:
3 Or even before
1 30-40 y
2 45 y
3 you were born
What is low birth weight correlated to?
● Lower lean mass at later age
● Lower strength at later age
● Increased risk of sarcopenia
● Increased risk of frailty
● Lower bone mineral density at later age
What happens when you catch up your low birth weight?
increased risk of CVD
Dutch Hunger winter: left an epigenetic signature, namely..
Specifically: lower DNA methylation of IGF2 genes compared to same-sex, non-exposed siblings
Parietal famine negatively impacts:
- Blood pressure
- Glucose tolerance
- Diabetes type 2 occurrence
Maternal overnutrition: what happens?
- Decrease in catabolic processes, increase in anabolic processes.
- Increased adipocyte size.
- Impaired GH/IGF-1 axis
High birthweight
Obesity
Tumors
Colorectal cancer
Prostate cancer
Breast cancer
Maternal undernutrition: what happens?
Increase catabolic processes
Decrease anabolic processes
Apoptosis
Insulin/leptin resistance
Impaired GH/IGF axis
Low birthweight
Nutrient poor environment: survival advantage
Nutrient rich environment: catch-up growth:
metabolic syndrome
CVD
T2D
What can we conclude from the maternal under/overnutrition story?
In utero circumstances leave epigenetic mark that affects ageing trajectory
What happens during ageing in terms of epigenetics?
During ageing, cell exposure to environmental factors results in accumulated negative changes in the genome through epigenetic alterations -> resulting in lower functioning of cell/tissue/organ
X is important in development, while detrimental during ageing
Methylation
What is methylation?
o DNA methylation changes the expression by the addition of a methyl group (CH3) to the CpG site (always the same locations)
What is a CpG island?
- CpG island: place in the genome with a high frequency in CPG sites
There are approximately 28 million CpG sites on the human genome, and 27 thousand CpG islands.
What are the three ageing clocks? What do ageing clocks do? What are they based on and what does it mean when the clock is accelerated?
(Horvaths, PhenoAge, Hannums)
Estimate biological age (vs chronological age)
▪ Based on DNA Methylation
▪ Accelerated clocks -> elevated risk on mortality and morbidity
Which of the clocks has the best correlation with chronological age? How does it work?
Horvath’s clock
Input: methylation (1 or 0) of 353 CpG sites of thousands of cells (proportion methylated, value between 0 and 1)
A formula calculates biological age from the input
Which clock is trained on age-related diseases and phenotypes instead of chronical age? Characteristics?
PhenoAge
o More predictive of mortality than Hannum or Horvath
o Age acceleration can be linked to lifestyle (red meat, exercise)
What type of interventions can be done to rewind the ageing clock?
1 year intervention with growth hormone, DHEA (precursor testosterone) and metformin
-> to maximize IGF-1 (insulin-like growth factor 1) and minimize insulin (and induce thymic regeneration)
1 year intervention with MED diet rejuvenates epi clock
Intervention with folic acid + B12 or flavonols decrease epi age
o However, limited evidence of these small studies.
What other ageing clocks are there: what biomarkers?
Urinary peptides, inflammatory markers
Inflammatory markers: based on? Secreted by?
Inflammatory markers:
▪ Based on immune markers
> Secreted by monocytes, endothelial cells, fibroblasts and cancer cells
Urinary peptides (UPP): strong contributor of ..
This could mean..
Strong contributor of peptides indicating abnormalities in collagen-related pathways
> Could mean: fibrosis, stiffening of organs, arthritis
What is the theory of hormesis? Examples?
The concept that biologic systems can respond in a positive way, or be stimulated by, physical or biologic exposure to low doses of an agent that is toxic at higher doses
● Stress response
● Damage control
● Remodelling
Small stressors improve functioning of cell
Defence mechanisms are triggered, cell adapt. Stressors can be
● ROS
● Heat / cold
● Fasting
● Nutrients
Nutrient hormetins are..
- Fasting, calorie restriction
- Flavonoids
- Polyphenols
Hypothesis: their chemical properties cause molecular damage, which is
followed by a biphasic stress response
o Hallmark of ageing measured by Horvaths clock = ?
Epigenetic alterations
o Hallmark of ageing targeted by FOXO4-DRI = ?
cellular senescence
o Twin studies estimate the heredity of lifespan to be ?
12-25%
o Increased ageing in the sunlight side of the face of a truck driver is mainly caused by ?
DNA damage
o Argument for an evolutionary adaptive role of menopause?
A Canadian study showed that women with a living mother had more offspring than women with a diseased mother
o How many gene locations play a role in longevity (with strong evidence)?
2
o In which place does DNA methylation occur?
CpG
o DNA polymerase protects DNA from
replication errors
o Which enzyme protects the DNA from metabolism-induced damage, in addition to SOD and GPx?
= Catalase
o The hayflick limit is especially connected to which two hallmarks?
Telomere attrition + cellular senescence
