Ferrari and Aprile: Lecture XXVI Flashcards
Aging: The Cellular Mechanisms of Getting Old
What is aging?
a time dependent decline of the function of tissues and organs
What causes aging?
progressive deterioration and loss of the physiological function of the organs
What is time dependent in again?
genetical and functional damages
What is a way to intervene and go against the concept of aging?
rejuvenation
What is the organism trying to do during aging?
contrast functional decline by compensatory responses that ry to reestablish the homeostasis of tissues
What are the 9 candidate hallmarks of aging?
genomic instability
telomere attrition
epigenetic alterations
loss of proteostasis
deregulation of nutrient sensing
mitochondrial dysfunction
cellular senescence
stem cell exhaustion
altered intercellular communication
What causes genomic instability?
accumulation of DNA damage (accumulates in the telomere and leads to telomere attrition) that can be caused by intrinsic or extrinsic factors
What kind of mutation can affect nuclear or mitochondrial DNA?
point mutations
gain/loss of chromosomes
(both lead to telomere shortening and gene disruption due to reactivation of transposons or integration of viruses)
What kind of mutations give rise to premature aging syndromes like progeria?
mutations in genes that code for the nuclear lamina
What is lost or impaired as we age?
DNA repair mechanism, and it leads to the further accumulation of DNA damage
What activates the DNA Damage Response (DDR)?
different sources of stress that cause ss or ds breaks
What is the main and 1st mechanism that activates cellular senescence?
checkpoint arrest
What happens if the checkpoint arrest does not give rise to DNA repair?
cellular senescence occurs
What is the difference in aging and senescence?
aging is a more complex mechanism that includes several features, including senescence
senescence is the loss of the cell’s power to divide and grow (it is a process of deterioration with age)
What is telomere attrition?
deterioration of telomeres due to the progressive loss of the protective sequences of telomeres
Why is sheltering important to protect the edge of chromosomes?
prevent the access of DNA repair machinery at the edge of chromosomes
if the DNA repair machinery accesses the edge of the chromosome, the chromosome will be fused with another molecule of DNA (all of the chromosomes will be fused together)
What is the most susceptible part of chromosomes that is lost with aging?
telomeres in the presence of shelterings
What is reduced with aging that creates transcriptional noise and the repression of transcription?
global reduction of methylation
Why is it not okay for methylation to be reduced?
genes are reactivated and this leads to aberrant production of mRNA and aberrant proteins
What is aging characterized by?
imbalance of histone modifications, transcriptional changes, loss/gain of heterochromatin, breakdown of nuclear lamina with the involvement of Lamin genes, global hypomethylation, focal hypermethylation, and general changes in chromatin remodelling
What is proteostasis?
mechanism that is well-conserved that guarantees the proper folding and managinf of proteins inside the cells
What does the decrease of the activity of chaperones (hsp) or autophagy and proteosome give rise to?
accumulation of unfolded or misfolded proteins in aging (known as the loss of proteostasis)
What are some diseases that are a result of protein aggregation or misfolded proteins?
neurodegenerative proteins
What drives the somatotrophic (anabolic) axis in mammals?
growth hormone (GH) that is produced by the pituitary gland using insulin growth factor 1 (IGF1)
Describe the anabolic pathway:
IGF1 leeads to the production of GH in the pituitary gland
mTOR is the central regulator (so mTOR inhibition using Rapamycin) is one of the main mechanisms that has been used to reduce the anabolic pathway and prevent aging
What is mitohormesis?
a hermetic response where the mitochondria try to regenerate and rebalance ROS (detoxification) and reach homeostasis (balance)
How can mitochondria be involved in aging?
mutations in mitochondrial DNA gives rise to aberrant mitochondria and mitophagy is impaired, which leads to reduction in ATP production and ROS accumulation…cells try to recover the damage through mitohormesis
What is cellular senescence?
the stable arrest of the cell cycle coupled to stereotyped phenotypic changes
What happens when senescence is transient (temporary)?
cell uses it to stop thee proliferation of aberrant cells and produce inflammatory cytokines to recruit immune system cells
immune cells can then clear aberrant cells
What happens when the mechanisms of senescence are no longer temporary?
they are no longer balanced
Describe the function of senescent cells in diseases:
positive function in cancer
they have a negative function in other diseases
What is quiescence?
a way to preserve the genomic stability and preserve the long-term function of the cell
*reversible state
What are 2 things that can occur when a senescent cell is in a state of cell-cycle arrest?
immune cells can be recruited and clear the senescent cells
senescent cells can accumulate
What happens when stem cells are in a state of exhaustion?
they go through differentatiation and lose their self-renewal potential
What are some common features of senescent cells?
they express and have a higher activity of β-galactosidase
expression of specific cell cycle inhibitors (P53, P16, P21, and DNA damage) can be used to see if a cell is going through quiescence
What is SASP?
senescence-associated secretory phenotype, and it is associated to inflammatory cytokines that are produced by senescent cells
What is cell echaution?
when cells have a decline in their regenerative capacity (lose their ability to maintain their lifelong function)
What is the diffeence between old somatic cells and new ones?
old ones have fewer cell divisions and overexpression of cell cycle inhibitory proteins like P16, and they also have shorter telomeres
What happens when there is excessive proliferation of stem cells?
they lose their self-renewal capacity, which leads to defects in different organs
What doe the accumulation of damage in hematopoietic stem cells give rise to?
immunosenesence and anemia or myeloid malignancies
in bone: osteoporosis
in muscle fibers: sarcopenia
What is “inflammageing”?
inflammation associated with aging
What are some diseases that have been associated with inflammageing?
cardiovascular diseases
type II diabetes
depression
anemia
What characterizes inflammageing?
high levels of inflammatory cytokines and a higher susceptibility of a chronic disease
How does altered intercellular communication cause aging?
it leads to systemic deterioration of the system
What 3 categories can the hallmarks of aginf be divided into?
primary hallmarks
antagonistic hallmarks
integrative hallmarks
What do primary hallmarks involve?
genomic instability
telomere attrition
epigenetic alterations
loss of proteostasis
*these are the causes of aging and they are unequivocally negative
What do the antogonistic hallmarks involve?
deregulated nutrient sensing
mitochondrial dysfuction
cellular senescence
*activated in response to damage
What do the integrative hallmarks involve?
stem cell exhaustion and altered intercellular communication
*affect tissues’ architecture, homeostasis, and function
What is an example of premature-aging syndrome?
Hutchinson-Gilford progeria (HGPS): life expectancy of 20 years
What causes HGPS?
mutation in the lamin genes coding for the nuclear filament protein, lamin
- mutation occurs at the splicing site and leads to a shortened truncated protein, which no longer has a cleavage site at the Farnesyl tail and leads to the accumulation in the nuclear periphery of the aberrant proteins
What is the Farnesyl tail removal important for?
proper assembly of the malin protein in the nuclear lamina
How can the elimination of damages cells be forced?
reactivaing telomerase
What animal model can be used to study aging?
mice as the age was converted from mice to human years
What can be an animal model that can be used to study premature aging syndromes?
mice with progeroid
What happens to the hematopoietic system during aging?
they proliferate and expand, but they exhaust their functional activity and decrease their homing capacity, which leads to more circulating hematopoietic cells in peripheral blood
*leads to increased platelet production and decrease in lymphoid which leads to the decrease in immune function during aging
What is a non-hematopoietic population that is affecting HSC function and retention?
sympathetic nervous system
stiffness of ECM
bone matrix
What are some major findings from the experimental paper used to study HSC in aging?
most quiescent-aged HSC (LR_HSC) are closer to bone marrow sinusoids
sinusoidal niches are uniquely preserved during aging
endothelial Jag2 protects HSC from aging in the perisinusoidal niches
What were the results from the experimental paper used to study HSC in aging?
HSCs are more distant from the bone
they are also distant from:
arterioles
megakaryocytes
Nestin(high) stromal cells
they remain close to:
sinusoids
Nestin(low) cells
What preserves HSC quiescence in sinusoids?
Jag2, a ligand of Notch
