Please enable JavaScript.
Coggle requires JavaScript to display documents.
Hallmarks of Ageing (Primary Hallmarks (Epigenetic alterations :non…
Hallmarks of Ageing
Primary Hallmarks
loss of proteostasis: is involved in mechanisms for stabilization of folded proteins and the degradation of proteins by lysosomes and proteosomes - proteostasis decreases with ageing
CHAPERIONE MEDIATED PROTEIN FOLDING:impaired with ageing, chaperones in health are activated during stress responses to protect the body, which is also impaired in ageing
- HSF-1 is a chaperone involved in the heat response which increases life span and thermotolerance
- deactylation of HSF-1 in mammals decreases life span, increasing the effects of heat shock proteins
PROTEOLYTIC SYSTEMS; including the autophagy-lysosmal system and the proteosome-ubiquitin system- both decrease with age.
- the ubiquitin-proteosome system is responsible for clearance of abnormal or damaged proteins
- activation of EGF signalling causes an increase in the ubiquitin-proteosome pathway, increasing thee life span of nematodies
-
Telomere attrition- Somatic cells do not contain telomerase, an enzyme which lengthens the ends of shortens telomeres to prevent cell senescence, so somatic cells will shorten every replication cycle until they reach there hayflick limit and go into cell senescence
SHELTERIN: telomeres on somatic cells are bound by shelterin which prevents access of DNA repair proteins and hence preventing the production of fusion genes
- experimental lengthening and shortening of telomeres in mice lead to increased and decreased life spans
- reactivation of telomerase can also reverse the effects of ageing in mice
Genomic instability- due to accumulation of DNA damage (endogenous and exogenous products causing lesions to DNA) or insufficient DNA repair, both which accelerate the ageing process
DEFECTS TO NUCLEAR LAMINS: defects to nuclear lamins increase with age
- decrease in lamin B1 levels are associated with premature ageing and cell senescence in mice
- nuclear lamin abberations also trigger stress pathways which activate P53, triggering apoptosis and decreases the effectiveness of adult stem cells
MITOCHONDRIAL MUTATIONS: increase with age due to increase in oxidative environment and lack of protective histones
- mice deficient in MtDNA polymerase, causing accumulation of mutations causing cell sensescence and premature ageing
DNA MUTATIONS: accumulation of DNA mutations causes cell senescence and altered tissue homeostasis
- Bub1 is a kinase involved in the cell cycle which decreases with age
- experimental decrease in Bub1 leads to premature ageing and aneuploidy in mice
Antagonistic Hallmarks
Deregulated nutrient sensing - involves the somatotropic axis which sends signals from the hypothalamus to the anterior pituitary causing release of growth hormone and thus the release of insulin like growth factor from the liver
IIS PATHWAY: decrease in insulin and insulin-like growth factor with age, but constant decrease in both these hormones can actually increase life span by activating defensive responses against damage, by decreasing the rate of cell growth during metabolism
- worms and flies with mutations causing continual decrease of IIS pathway show an extended life span
- IIS pathway can also increase beneficial effects of dietary restriction, as in mice FOXO is downstream from IIS, which activates the tumour suppressor qualities of dietary restriction
MTOR PATHWAY: mTOR kinases, in particular mTORC1 and mTORC2 which are involved in anabolic metabolism
- genetically modified mice with low mTORC1 levels but normal mTORC2 levels show increased life spans
- decreases in mTORC1 also increases beneficial effects of dietary restriction in worms and flies
- in mice, rapamycin, inhibits mTOR kinases increasing life span
AMPK AND SIRT SIGNALLING: works in opposite way to both IIS and mTOR kinases as its involved in nutrient scarcity and catabolic metabolism.
- AMPK senses low energy levels due to high AMP levels
- SIRT senses low energy levels due to high NAD+ levels
both AMPK and SIRT increase with healthy ageing
- AMPK inhibits mTOR kinases mediating longevity
- SIRT activates PGC-1alpha which enhances antioxidant effects
-
Cellular Senescence- the stable arrest of the cell cycle, increased damage and decreased repair trigger cell senescence which can also cause inflammation and decreased tissue function which increases ageing
INK4A, APK LOCUS AND P53 PATHWAYS: contribute to cell senescence and increased ageing
- in progeroid mice , disorders improve with elimination of INK4a locus and P53
- but mice with mild increases in all pathways have also been seen to increase life span (not linked to P53 and cancer inhibition)
Integrative Hallmarks
-
altered intercellular communication- neurohormonal signalling decreases due to increases in inflammatory reactions and decreases in immuno-surveillance against pathogens
INFLAMMAGEEING: increase in inflammation as we age inflammageing , caused by accumulation of pro-inflammatory tissue damage, and failure of immune system to clear pathogens
IL-1B , TNF, NF-KBETA PATHWAY: increase in IL-1b and TNF as well as overactivation of the NF-Kbeta pathway, a trinscriptional signature of ageing,effects ageing
- expression of NF-K beta pathway leads to rejuvination of skin on mice
INDUCTION OF AGE RELATED CHANGES: also evidence to suggest that age related changes in some cells can cause age related changes in neighboring cells
- senescent cells can induce senescence in neighboring cells via gap junctions
- life span extending changes in cell can retard normal ageing in other tissue