Lecture 3 (hallmarks) Flashcards by Tara van Baarle

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

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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

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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

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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

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What is ‘loss of proteistasis’?

Stress: protein misfold
Unfolded proteins should refold/be disposed
If not -> aggregation

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What nutrients activate autophagy in mice and nematodes and thereby increase lifespan?

spermidine
omega-6-fatty acids

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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

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Protein aggregation is a common pathogenic mechanism in what type of diseases?

ageing-related neurodegenerative diseases:
- Alzheimers
- Parkinson’s
- Huntington’s

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What do HSP do?

Regulate folding of the protein

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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

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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

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What are typical sources of DNA damage (very very broadly)?

Endogenous DNA damage: metabolism/replication
Exogenous damage

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Explain endogenous induced DNA damage: metabolism

mitochondria induces ROS. Destabilize molecules around them and are unstable themselves. Disbalanced electrons.

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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.

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Recall three types of anti-oxidants

SOD: superoxide dismutase: attacks destructive oxygen free radicals like superoxide
Catalase: detoxifies peroxide
GPx: glutathione peroxidase

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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