Cellular Aging Flashcards
Cellular aging is regulated by?
Genes that are evolutionarily conserved from yeast to worms to mammals.
Briefly outline the process behind cellular aging
Genetic abnormalities and accumulation of cellular and molecular damage due to exogenous influences cause a progressive decline in cellular function and viability.
Several mechanisms, some ____ _______ and others _________ _________ are believed to play a role in aging.
Cell intrinsic
Environmentally induced
What 4 mechanisms play a role in cellular aging?
- DNA damage
- Cellular scenescence
- Defective protein homeostasis
- Deregulated nutrient sensing
How many new mutations per year is the average haemopoietic stem cell expected to suffer?
14
Patients with Werner syndrome show premature aging due to a defective DNA ______. This causes rapid _______ of _______ damage that may mimic the injury that normally accumulates during cellular _______.
Helicase
Accumulation
Chromosomal
Aging
Other disorders in which patients display some of the manifestations of aging at an increased rate.
Bloom syndrome
Ataxia-telangiectasia
In Bloom syndrome and Ataxia-Telangiectasia, mutated genes encode proteins involved in?
Repairing double-strand breaks in DNA
All normal cells have a limited capacity for?
Replication
After a _______ number of divisions, cells become __________ in a terminally __-______ state, known as ________ ______.
Fixed
Arrested
Non-dividing
Replicative senesence
Aging is associated with
progressive replicative senescence of cells.
T or F: Cells from children can undergo fewer rounds of replication than cells of older people.
False
What are the 2 mechanisms underlying cellular senescence?
- Telomere attrition
2. Activation of tumour suppressor genes
What are telomeres?
Short repeated sequences of DNA present at the ends of linear chromosomes
What are telomeres important for?
- Ensuring complete replication of chromosome ends
2. Protecting the ends from fusion and degradation
What happens to telomeres as somatic cell replication occurs?
A small section of the telomere is not duplicated each time and telomeres become progressively short.
What is the consequence of telomere shortening?
The ends of the chromosomes are no longer protected and are seen as broken DNA, signalling cell cycle arrest
How is telomere length maintained?
Nucleotide addition mediated by an enzyme called telomerase
What is telomerase?
A specialised RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes.
Telomerase activity is expressed in which cells?
Germ cells Stem cells (low level)
Telomerase activity is absent in which cells?
Most somatic tissues
Therefore, as most somatic cells age, their telomeres become shorter and they exit the cell cycle. This results in?
An inability to generate new cells to replace damaged ones.
In immortalised cancer cells, telomerase is usually _______ and telomere length is __________.
Reactivated
Stabilised
What diseases has premature telomere shortening been associated with?
Pulmonary fibrosis
Aplastic anaemia
Which tumour suppressor genes are correlated with chronologic age?
p16
INK4a
Where are p16 and INK4a located?
CDKNA2A locus
What does p16 do?
Controlling G1 to S phase progression during the cell cycle.
What does p16 protect the cell from?
Uncontrolled mitogenic signales
Protein homeostasis involves 2 mechanisms.
- Maintenance of proteins in their correctly folded conformations
- Degradation of misfolded proteins by the autophagy-lysosome system and ubiquitin-proteasome system
Maintenance of protein conformation is mediated by?
Chaperones eg heat shock protein family
What is rapamycin?
mTOR inhibitor
What role does rapamycin play in cellular aging?
Promotes autophagy that probably prevents accumulation of misfolded proteins which would otherwise trigger apoptosis.
T or F: caloric restriction decreases longevity.
False
2 pathways by which caloric restriction may increase longevity
- Reducing signaling intensity of IGF-1 pathway
2. Increasing sirtuins
What role does IGF-1 play in cellular aging?
IGF-1 informs cells of the availability of glucose, promoting an anabolic state as well as cell growth and replication, via multiple downstream targets, the 2 most pertinent being AKT and its downstream target, mTOR
What is IGF-1?
Produced by many cell types in response to growth hormone secretion by the pituitary, mimics intracellular signaling by insulin.
What are sirtuins?
A family of NAD-dependent protein deacetylases.
How many types of sirtuins are there?
At least 7 type in different cellular compartments with non-redundant functions.
What are the functions of sirtuins?
Adapt bodily functions to environmental stresses including food deprivation and DNA damage.
What role do sirtuins have in cellular aging?
Promote the expression of several genes whose products increase longevity.
What are the actions of proteins produced by sirtuins?
Inhibit metabolic activity
Reduce apoptosis
Stimulate protein folding
Inhibit harmful effects of oxygen free radicals
Increase insulin sensitivity and glucose metabolism
