36. Cellular Aspects of Aging Flashcards
What are some consequences of aging?
Describe cellular ‘aging’ IRT damage/stress.
What is the tumour supression and ageing evolutionary balancing act?
What factors influence life expectancy?
Reduced tissue/physiological function. Decreased resistance to stress (physical and psychological). Increased susceptibility to age-related disease e.g. AD, heart disease, immune system decline, cancer, T2DM.
Apoptosis or senescence (arrested growth).
Tumour supressor genes evolved to protect from cancer by causing damaged cells to undergo apoptosis or senescence, but these are also cellular aging responses.
Disease processes, medical treatment, lifestyle choices, nutrition, heredity.
What are the hallmarks of aging?
What is the programmed senescence theory (Hayflick limit)? How does this lead on to the telomeric theory of senescence?
In normal DNA replication, the end of the chromosome is not copied exactly which leaves an unreplicated gap. What happens to it?
Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondiral dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication.
Certain number of times a normal human cell population will divide until it stops. Telomeres = specialised DNA sequences at end of chromosomes, non-coding repeats of TTAGGG. Telomeres shorten with each division, and when become too short, cell = senescence.
Telomerase fills it by attaching bases to end of chromosomes. It keeps telomeres long enough to prevet loss of important info during replication. Over time telomerase levels decrease and telomeres get shorter and shorter.
What age-related diseases are shortened telomeres found in?
How does the telomeric theory link to cancer?
How does intercellular communication alter with age?
Atherosclerosis, heart disease, hepatitis, cirrhosis.
90% of cancer cells possess telomerase which allows them to reproduce -> tumour growth.
Biological clocks act via hormones to control pace of ageing - affect growth, metabolism, temperature, inflammation and stress. E.g. menopause, immune system decline (programmed decline (i.e. thymus involution withe age) causes increased vulnerability to disease, ageing and death).
What is the mitochondrial free radical theory of ageing?
What defenses does the body have against ROS?
Do all free radicals cause damage?
During ageing, damage produced by free radicals (e.g. O2 FR) causes cells and organs to stop functioning. ROS are produced mainly from e- leak during mitochondrial oxidative phosphorylation. Mit dysfunction that occurs with ageing results in increased ROS production. Cycle! ROS can damage DNA, lipids and protein -> accumulate -> deterioration.
Natural antioxidants e.g. bilirubin, enzymes e.g. superoxide dismutase, catalase and glutathione peroxidase, dietary antioxidants e.g. beta carotene, vit C and E.
No - use as part of immunological response: macrophages engulf bacteria, free radical reactions inside oxidise and kill bacteria.
What is proteostasis and how does loss of it contribute to ageing?
Cross-liked proteins damage cells and tissues - how does non-enzymatic glycosylation damage arteries?
How does somatic mutation occur with age?
Biological paths in cells that control biogenesis, folding, trafficking and degradation of proteins in and out of the cell. Unfolded proteins can either undergo autophagy (intracellular degradation, cytoplasmic constituents -> lysosome), proteasomal degradation via ubiquitin, be refolded via chaperones, or if there is loss of proteostasis, will AGGREGATE -> ageing -> AD etc.
Glucose attaches to proteins causing a chain of chemical reactions resulting in a structural change to the proteins -> loss of flexibility of connective tissue and microvascular changes in arteries -> arteries harden.
Ageing = imbalance between rate of DNA repair and accumulation of DNA damage. When damage>repair, cell malfunctions. At some point normal processes become pathology e.g. carcinoma.
What is deregulated nutrient sensing with age?
What epigenetic alterations does ageing induce?
What intrinsic and extrinsic factors cause stem cell loss and dysfunction with age?
Nutrient sensing: cell’s ability to recognise and respond to fuel substrates e.g. glucose. Homeostatic mechanisms respond to different hormones e.g. insulin to maintain BG. Old age: mechanisms become disrupted and result in reduced insulin sensitivity -> glucose intolence -> diabetes, and an increase in visceral fat.
Don’t change DNA sequence but alter expression: DNA methylation, histone modifications, regulatory RNAs, spatial organisations of chromosomes, chromatin structure. These are reversible, so possible therapeutic targets!
Intrinsic: accumulation of ROS, DNA damage, epigenetic alterations, aggregation of damaged proteins, mitochondrial dysfunction. Extrinsic: exhaustion of SC pool, impaired regeneration. Can target these problems e.g. telomere reactivation, antioxidants and caloric restriction.
What causes stem cell function to decline with age?
What interventions may extend human life span?
What cellular alterations during ageing underpin changes in heart function?
Loss of lineage specificity and self-renewal, senescence and malignant transformation. Results in anemia, myelodysplasia, osteoporosis, decreased repair of muscle fibres and intestinal function decrease.
Clearance of senescent cells, SC-based therapies, anti-inflammatory drugs, elimination of damaged cells, telomerase reactivation, epigenetic drugs, activation of chaperones, dietary restriction.
Vavles of heart thicken and stiffen, number of pacemaker cells decrease and fatty and fibrous tissues increase around SAN = slower HR, heart wall thickens so amount of blood chamber can hold may decrease, heart may fill slower.
