Lecture 3 (hallmarks) Flashcards
Definition of ageing?
Ageing definition: Ageing is the process during which structural and functional changes
accumulate in an organism as a result of the passage of time. The
changes manifest as a decline from the organism’s peak fertility and
physiological functions until death
Accumulation of damage:
Partly inevitable, from the inside
Preventable, from the outside
Examples?
Inside:
* Metabolism
* DNA replication damage
* Genetic predispositions
Outside:
* Exposure to toxins
* Sunlight
* Alcohol
* Smoking
* Radioactivity
What are three criteria for the hallmarks of ageing?
- Should manifest during normal ageing
- Its experimental aggravation should accelerate ageing
- Its experimental amelioration (improvement) should retard the ageing process and thus increase healthy lifespan
Mention the 9 hallmarks of ageing
LETS MAC D, G
- Loss of proteostasis (protein misfolding)
- Epigenetic alterations
- Telomere attrition
- Stem cell exhaustion
- Mitochondrial dysfunction
- Altered intracellular communication
- Cellular senescence
- Deregulated nutrient sensing
- Genomic instability
What is ‘loss of proteistasis’?
- Stress: protein misfold
- Unfolded proteins should refold/be disposed
- If not -> aggregation
What nutrients activate autophagy in mice and nematodes and thereby increase lifespan?
- spermidine
- omega-6-fatty acids
Autophagy vs ubiquitin-proteosomal degradation: what are three differences?
Autophagy:
1. LARGER proteins/organelles
2. Protein aggregates
3. Under stress (nutrient depletion)
Ubiquitin-proteosomal degradation:
1. SMALLER proteins
2. Misfolded proteins
3. Always running
Protein aggregation is a common pathogenic mechanism in what type of diseases?
ageing-related neurodegenerative diseases:
- Alzheimers
- Parkinson’s
- Huntington’s
What do HSP do?
Regulate folding of the protein
HSP:
- increased expression of HSP could be 1
- Does not only react to cold, but also other stressors such as 2
- 3 is linked to decreased HSP
- These things also affect HSP: 4
1 carcinogenic
2 cold, UV-light, exercise, alcohol, fasting
3 essential amino acid deprivation
4 pre-and probiotics, dietary restriction
What can cause the Werner syndrome and what is it? Symptoms?
increased DNA damage
Werner syndrome = premature ageing syndrome
- Decreased DNA ability to repair itself
- Early hair greying, hair loss, wrinkling
- Early death (around 54 years), often due to cardiovascular disease or cancer
What are typical sources of DNA damage (very very broadly)?
Endogenous DNA damage: metabolism/replication
Exogenous damage
Explain endogenous induced DNA damage: metabolism
mitochondria induces ROS. Destabilize molecules around them and are unstable themselves. Disbalanced electrons.
How to prevent mito damage by ROS?
to prevent damage by this: anti-oxidants (donate electrons). Anti-oxidant will not lose its own stability after donation.
Recall three types of anti-oxidants
SOD: superoxide dismutase: attacks destructive oxygen free radicals like superoxide
Catalase: detoxifies peroxide
GPx: glutathione peroxidase
Why does ROS damage mito’s specifically?
ROS damages targets mitochondria quickly, as they are closest by.
Explain endogenous induced damage: replication
DNA polymerase is extremely accurate, but can still make mistakes.
Explain: exogenous damage (examples)
Formation of free radicals by..
- Inflammation (increased ROS)
- Smoking: breathing in ROS
- Radiation
- UV
- Air pollution
Explain the hallmark of ageing: telomere attrition
Telomeres are protective caps at the ends of chromosomes
- shorten per reproduction cycle until they reach replicative senescence
What is the Hayflick limit?
Normal human cell cannot replicate anymore after 40-60 cycles and will then reach replicative senescence.
How to increase telomere length?
Telomerase. It is however not expressed in many cells.
In human beings, , telomere length is not a better predictor of mortality than chronological age
What does lengthening/decreasing telomeres do in mouse models?
lengthening of telomeres increases lifespan, and shortening decreases lifespan
In human beings, telomere is as good a predictor for mortality as..
..chronological age
Higher paternal age =
Higher maternal age =
Longer/shorter telomeres
paternal: longer
MAternal: shorter
What is the evolutionary argumant for the ‘advantage of an old father’ in terms of telomeres?
Evolutionary hypothesis: descendants of males who reproduced at a later age are likely to find themselves in a harsh environment, allowing later reproduction. Longer telomeres prepares them for this.
Altered intracellular communication: name two examples and explain them
- Inflammaging:
> imflammatory cyto- and chemokines are released
> due to dysregulated intracellular homeostasis - Immunosenescence:
> age-related impairments in innate and adaptive immune system
Immunonescence and COVID: older people are more susceptible, because..
Suppressed immune system
Cannot cough well
Permeability in membranes
Increased risk cytokine storms etc
When old mice get the blood of young mice, they..
get ‘younger’
Explain stem cell exhaustion
Ageing: decline in regenerative capacity.
There is a decrease in stem cells compartments, such as:
Immune cells
Muscle fibers
Bone cells
What is cellular senescence? What can cause it?
Senescence = dormant state. Arrest of the cell cycle.
o Caused by:
* Telomere shortening
* DNA damage
senescent cells make up a 2x larger part of total cells in older mice compared to younger
Which hallmark of ageing can be used as a defence mechanism in younger people/mice?
Cellular senescence. In young, it promotes tissue homeostasis
Supplement stopping cellular senescence regained …. appearance in old mice
youthful
Deregulated nutrient sensing: which pathways increase ageing, which pathways decrease ageing?
- Overactive Insulin/IGF and mTOR increase ageing
- Overactive AMPK and SIRT decrease ageing
What does caloric restriction do to the nutrient-sensing pathways in mice? What happened to the mice?
Caloric restriction: increase AMPK and decrease mTOR and Insulin/IGF in mice
- Increased lifespan, maintenance of youthful appearance, delays in age-related diseases
What nutrient sensing pathways are there? What do they sense?
MAIS
mTOR
AMPK
Insulin/IGF-1
SIRT
mTOR -> senses amino acid availability
AMPK-> senses low energy states (by sensing increased AMP/ATP-ratio)
Insulin/IGF-1-> senses glucose availability
SIRT-> senses low energy states (by sensing increased NAD+-levels)
How could calorie-restriction slow down ageing?
By allocating resources for repair.
All resources are divided between vital functions (growth, reproduction) on one hand, anti-ageing repair on the other
In which types of cells can you find..
(1)Low/no turnover
(2)Medium, self-duplicating turnover
(3)High, stem cell based turnover
(1) Heart muscle, retina, lung, kidney
(2) Liver, pancreas, skeletal muscle, small vasculature
(3) Gut epithelium, prostate, blood cells, epidermis, epithelium
Ageing starts around..
30 years old
