The hallmarks of ageing Flashcards
primary hallmarks
= cause of damage
- genomic instability
- telomere attrition
- epigenetic alterations
- loss of proteostasis
antagonistic hallmarks
= response to damage
- deregulated nutrient signalling
- mitochondrial dysfunction
- cellular senescence
integrative hallmarks
= culprits of the phenotype
- stem cell exhaustion
- altered intercellular communication
cellular senescence - induction
- Caused by telomere erosion, oncogene overexpression, ROS-mediated DNA damage, mitochondrial dysfunction, inflammation
- p53-p21 pathway
- p16-Rb (INK4/ARF) pathway
cellular senescence - definition
Senescence is cellular program (induced by TSG networks) that induces a stable growth arrest accompanied by distinct phenotypic alterations, including chromatin remodelling, metabolic reprogramming, increased autophagy, and the implementation of a complex proinflammatory secretome (SASP)
- In young organisms cell senescence is functional and occurs at low levels–> anti aging and anti cancer
- In older organisms cell senescence occurs at a much higher level –> pro aging and pro cancer
p53-p21 pathway
- DNA is damaged via ROS (for example)
- Damage accumulates
- DDR activates p53
- p53 activates p21
- p21 inhibits cdk4/6
- This lifts the inhibition of Rb
- Rb now causes G1 arrest
p16-Rb (INK4/ARF) pathway
- The INK4/ARF locus is normally inhibited (methylated) but epigenetic alterations due to ROS, inflammation or telomere attrition it can become active
- p16 is transcribed
a. Additionally ARF is transcribed which inhibits MDM2 which is a p53 inhibitor (activated the p53-p21 pathway) - CDK4/6 is again inhibited (by p16 and p21)
- Rb induces G1 arrest
Senescence associated secretory phenotype
- SASP factors include:
• Cytokines: TNF-alfa, IL1beta, IL6 and IL8
• MMPs (matrixmetalloproteases)
• VEGF (vascular endothelial growth factor), TFG-beta
• DAMPs - SASP mediates many of the cell-extrinsic functions of senescent cells:
• It reinforces the cell cycle arrest via autocrine signalling
• Recruits immune cells to phagocyte the senescent cell
• MMPs and VEGF can remodel the surrounding tissue (angiogenesis and reduce fibrosis)
• TGF-beta can spread the senescence phenotype in a paracrine manner to other cells
telomeres
- Telomeres are nonsensical strings of nucleotides that cap the ends of chromosomes and provide protection from fraying, fusing with other chromosomes, inappropriate repair, and losing genes,
• In human telomeres, the base sequence TTAGGG is repeated a thousand times or more
• Telomeres (the T loops at the tips) are protected by a multiprotein complex known as shelterin –> prevents the activation of a DNA damage response, thereby preventing end-to-end chromosome fusions that would result in a telomere crisis
telomere attrition
Though telomeres carry no genes, they appear to be vital for chromosomal survival, because each time DNA is replicated, 100 to 200 of the end nucleotides are lost and the telomeres get a bit shorter.
- The lagging strand is produced backwards in okazaki fragments, to do this an RNA primer is needed to start the polymerising of the fragment.
- However at the end of a chromosome the primer would have to be placed beyond the chromosome end –> telomere attrition
• When telomeres reach a certain minimum length (hayflick-limit), it is thought that the stop-division signal is given –> yH2AX is activated which leads to DDR and p53 activation
- Telomeres are involved in epigenetic gene expression so telomere erosion can cause over/under expression of genes
- Telomerase solves the telomere erosion problem in germ-line cells and stem cells by re-polymerizing the strand (and also in some cancer cells)
loss of proteostasis
- Normally proteins are folded correctly but due to heat shock, ER stress or oxidative stress proteins may be misfolded or unfolded
- Normally these unfolded proteins are either dealt with by:
• An autolysosome –> autophagy
• A heat shock protein (chaperone) that guides the misfolded protein to a lysosome –> chaperone-mediated autophagy
• Proteasomal degradation –> UPS
• Chaperone mediated refolding - However due to DNA damage, epigenetic alterations, telomere attrition, etc. there might be a loss of function of proteins involved in the refolding of proteins or the degradation of proteins –> aggregation of misfolded proteins –> ageing
garb-ageing
Extracellular spill-over (or extracellular vesicles) of endogenous damaged molecules/organelles due to ER stress, dysfunctional organelles, dysfunctional UPS (loss of proteostasis), etc.
These misplaced molecules are recognised by PRRs and cause systemic inflammation (due to age related loss of proteostasis and age related increase of misplaced damaged molecules it is called garb-ageing)
'’inflammageing’’
A prominent aging-associated alteration in intercellular communication is “inflammaging” caused by:
- accumulation of DAMPs –> NFkB (in hippocampus this leads to decreased GnRH and thus decreased sex hormones - contributes to meno and andropause)
- dysfunctional immune system (immunosenescnce)
- SASP (senescent cells)
- ROS (mitochondrial dysfunction)
All this leads to chronic systemic inflammation and ageing
Epigenetic alterations
- DNA methylation:
• Global methylation decreases
• Local methylation increases - Histone modification:
• Histones are more often acetylated causing chromatin to be more loose –> more genes expressed - This can lead to altered miRNA production and thus altered silencing of genes
- Certain genes like ARF/INK4a will be unintentionally expressed while others are silenced (TSGs, DNA repair)
deregulated nutrient signalling
During over consumption of macromolecules the (GH)-insulin-IGF-1-signalling (IIS) pathway is very active which leads to ageing:
• Via mitochondrial ROS production
• More protein produced and more damaged proteins form (aggregates)
To counteract this caloric restriction can work:
- leads to IFG and thus mTOR inhibition (and thus FoXO stimulation –> repair and defence gene transcription)
- stimulates SIRT which stimulates PGC-1alga (mitochondrial biogenesis, lower ROS) and used NAD (which is available due to CR - not used for glycolysis) to silence glycolysis genes by acetylation
