The Hallmarks of ageing
17 important questions on The Hallmarks of ageing
What is ageing, looking at partly inevitable, from the inside and preventable, from the outside
Partly inevitable, from the inside
- Metabolism
- DNA replication damage
- Genetic predispositions
Preventable, from the outside
- Exposure to toxins
- Sunlight
- Alcohol
- Smoking
- Radioactivity
What is ageing, looking at partly inevitable, from the inside and preventable, from the outside
Partly inevitable, from the inside
- Metabolism
- DNA replication damage
- Genetic predispositions
Preventable, from the outside
- Exposure to toxins
- Sunlight
- Alcohol
- Smoking
- Radioactivity
What are the three criteria of the hallmarks of ageing?
- Should manifest during normal ageing
- Its experimental aggravation should accelerate ageing
- Its experimental amelioration should retard the ageing process and thus increase healthy lifespan
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What is the hallmark loss of proteostasis
- stress causes protein to unfold
- unfolded proteins should refold / be disposed
- if not --> aggregation
- Nutrients Spermidine and omega-6 fatty acids activate autophagy in mice and nematodes and thereby increase lifespan
Alzheimers; Parkinsons; Huntingtons; ALS; Cataract
What can lead to a folded protein being unfolded?
- Heat shock
- ER stress
- Oxidative stress
How can you get ride of the unfolded protein?
- Chaperone-mediated folding --> refolded protein
- proteasomal degradation
- chaperone-mediated autophagy
- macroautophagy
- aggregation --> aging
Protein aggregation is a common pathogenic mechanism in aging-related neurodegenerative diseases, which ones
- amyloid plaques
- neurofibrillary tangles
- Lewy bodies
- Aggregated huntingtin
What are the functions of ROS for pathology and homeostasis
- lipid peroxidation
- protein oxidation
- mtDNA damage
homeostasis
- growth factor signalling
- activation of uncoupling proteins
- mtDNA replication
What is the ROS-induced damage?
- mitochondrial damage
- lipid per oxidation
- DNA damage and mutatio
n
- protein damage
DNA replicates all the time; what can you tell about it?
- DNA Polymerase enzymes are very accurate in their choice of nucleotides
- Still they make on average one mistake per 100.000 nucleotides
- With 6.000.000.000 base pairs in each cell, that makes around 120.000 mistakes per cell division
- Luckily, cells have evolved proofreading
- During proofreading, DNA polymerase recognizes mistakes and replaced them - fixing ±99% of errors!
How can DNA be damaged from the outside?
- UV light
- Ionizing radiation
- Smoking
- Air pollution
- Inflammation
- Metabolism
What is the hallmark telomere attrition?![]()
- Telomeres are protective caps at the ends of chromosomes
- Telomeres shorten per reproduction cycle until they reach replicative senescence (Hayflick Limit - after ±40-60 replications in vitro fibroblasts)
- Telomerase increases telomere length, but telomerase is not expressed in many cells
- In mouse models: lengthening of telomeres increase lifespan, and shortening decreases lifespan
- However, in human beings, telomere length is not a better predictor of mortality than chronological age
What is the hallmark stem cell exhaustion
- Ageing: decline in regenerative capacity
- Stem cell: undifferentiated cell that can 'become any type of cell'
- During ageing, decrease in stem cells compartments:
- immune cells
- muscle fiber
- bone cells
What is the hallmark cellular senescence![]()
(also have a look at the picture, not that important for the hallmark)
- Arrest of the cell cycle
- Caused by
- telomere shortening
- DNA damage
- In mice, senescent cells make up
- ± 8% of cells in young mice
- ±17% of cells in very old mice
- Data of liver, lung, skin
- No changes were observed in skeletal muscle and kidney
FOXO4 + p53 --> senescence
FOXO4-DRI --> apoptosis [=senolytic]
What is the hallmark deregulated nutrient sensing
- Insulin/IGF-1 patyway --? Senses glucose availability
- mTOR --> senses amino acid availability
- AMPK --> senses low energy states (by sensing increased AMP/ATP-ratio)
- SIRT --> senses low energy states (by sensing increased NAD+ - levels)
basically
- overactive insulin/IGF and mTOR increase ageing
- Overactive AMPK and SIRT decrease ageing
Caloric restriction; 1986: Walford & Weindruch reported that restricting the calorie intake of laboratory mice caused ...
- An increased life span
- the maintenance of a youthful appearances and activity levels
- delays in age-related diseases
1934:McCay &Crowell discovered a simple diet containing 40% less energy starting after weaning extended the maximum life span of rats from 33 months to 47 months
Where does caloric restiction has influence on?
- Preserves cognition
- delays sarcopenia
- protects colon health
- delays brain atrophy
- lowers incidence and progression of cancer
- prevents age-related diabetes
- protects against cardiovascular disease
- protects against arthritis
- delays osteoporosis
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