2.4 Cell Ageing and Cell Death Slides

Cellular Senescence

• The process in which cells cease to divide

• An irreversible block in proliferation

• A natural barrier against cancer

Telomere shortening

• Telomeres

  • DNA sequence

  • ‘Caps’ at the ends of a chromosomes, to prevent degradation

  • Shortens with each cell division, contributing to cellular senescence and aging.

• Telomerase

  • An enzyme that adds DNA sequence repeats to the ends of telomeres.

  • Helps maintain telomere length during cell division, counteracting telomere shortening.

  • Plays a critical role in cellular lifespan and is often active in stem cells and cancer cells.

• Shelterin

  • A protein complex that protects telomeres.

  • Comprised of six proteins: TRF1, TRF2, POT1, TPP1, RAP1, and PINX1.

  • Functions to prevent telomere degradation and inappropriate DNA damage responses.

  • Essential for maintaining telomere structure and integrity.

DNA Damage Genomic Instability

• DNA damage is a leading cause of senescence

  • External insults

    • UV, Chemicals, pollutants, infections

  • Internal insults

    • Metabolic bi-products

    • Reactive Oxygen Species (ROS)

  • DNA Replication/Proliferation

    • Rapid proliferation promoting DNA damage causing senescence

• Error Theory of Ageing

  • Accumulation of ROS leads to oxidative stress, which can damage cellular components, including lipids, proteins, and nucleic acids, ultimately contributing to the ageing process.

• Ageing disease

  • Progeroid syndromes

    • Rare genetic disorders

    • Mimic physiological ageing

  • All diseases are monogenic

    • Single gene mutation

    • Mutation affects DNA repair or nuclear structure

  • Examples

    • Werner Syndrome, bloom syndrome, cockyane syndrome, xeroderma pigmentosum, hutchinson gilford progeria syndrome

Epigenetic Drift

• Epigenetics

  • A change in gene expression that is not dependant on DNA sequence

• Epigenetic drift

  • The divergence of the epigenome due to age

  • Global DNA hypomethylation → open chromation → Genetic instability

  • Genetic instatbility → DNA damage

  • DNA damage → senescence, apoptosis, cellular dysfunction

  • Induced by diet, stress, chemicals

Stem Cell Exhaustion

• Stem cells serve as a grow/repir system for the body

• A single stem cell is an uncommitted immature cell with a unique capacity to

  • Produce multiple specialised cells

  • self-renew

  • reconstiture an entire tissue

Stem cells and ageing

• The single major driver of ageing is loss of stem cell number and function

• Reduced potential to differentiate

  • Less specialised cells

• Reduced ability to proliferation (divide)

  • Less stem cells → less specialised cells

• Enhanced abulity to differentiate

  • “stem cell exhaustion”

  • Diminished reservvoir of stem cells

• Causes

  • DNA damage

  • telomere shortening

  • senescence

  • abnormal cellular signalling/metabolism or epigenetic changes

Nurient Sensing

• Metabolism is regulated by a group of hormones that have stimulating effect on the body

• Growth hormone (GH)

  • Release caused by dietary factors

  • Stimulates production of In sulin like growth Factor-1

• Insulin like Growth Factor-1

  • Produced by most cells, mainly hepatocytes

  • informs cells of the presence of glucose

  • Stimulates systemic body growth

  • increased metabolism and proliferation enhances DNA damage

• Dietary restriction

  • reduced GH/IGF-1

  • reduced metabolism and cel growth

  • reduced DNA damage, lipid and protein oxidation

  • increased longevity in any organism studied thus far

Caloric Restriction

• Sirtuins

  • enzymes

  • repair and modify DNA

  • Modfy proteins resulting in genetic stability

  • Increase metabolic efficiency

• Sense nutrient scarcity

  • When food is low

    • sirtuin expression increases

    • genomic stability increases

    • metabolism efficiency increase

Inflammaging

• Inflammation

  • natural defence mechanism

  • can be detrimental when prolonged

  • increased in older organisms

• As we age, there is a

  • Decrease in

    • adaptve immunity

  • Increase in

    • Innate immunity

    • Natural killer cells

    • Pro-inflammatory cytokines

    • Low grade chronic inflammation

  • Compound effect leads to diabetes, cardiovascular disease, cancer, frailty

Mitochondrial Dysfunction

• Mitochondria

  • Bioenergentics

    • ATP production

  • Intracellular signalling

    • Lipid signalling, ROS, Apoptosis

  • Regulation of innate Immunity

    • activation, differentiation and survival of immune cells

  • Chromatin and transcription

    • Metabolites

  • Stem cell activity

• Decline in mitochondrial function results in

  • Decrease in respiration

  • Increase in ROS

  • Increased apoptosis

  • Altered metabolites

    • Change the chromatin landscape

  • Activation of the innate immune system

    • low grade chronic inflammatory response

Cell Death

• Apoptosis

  • Programmed cell death

  • Suicide by coordinated intracellular processes

  • “falling off”

  • No inflammation

• Necrosis

  • Unplanned cell death

  • Homicide by external stressors

  • “death”

  • Inflammation

• Causes

  • cell turnover

  • Development

  • Hormone dependent atrophy

  • Infection

Apoptosis

• Pathways

  • Intrinsic

    • Internal DNA damage/cell stress

    • Mitochondrial-mediated

      • Signal binds to mitochondrial membrane

      • Disrupts the membrance

      • An apoptotic complex (caspase-protease) is formed and destroys organelles , leading to the eventual fragmentation of the cell and triggering the processes associated with programmed cell death.

  • Extrinsic

    • External signals

    • Death-receptor mediated

      • Via surface of cell membrance

    • Activation of apoptotic complex - Death cascade (proteins)

  • Process

    • Cell shrinkage

    • A cascade of enzymatic reactions

    • nuclear condensation

    • ‘blebbing’ — Cell membrance fragments

    • phagocytosis

      • Fragments engulfed by phagocytes

      • Cleared by macrophages

    • No inflammation occurs as the phagocytes efficiently remove cellular debris and pathogens, promoting tissue homeostasis.

Necrosis

• Causes

  • Pathological - Injury/damage

    • Mechanical

    • Chemical

    • Infection

    • Immune response

• Process

  • Swelling of the cell

    • Organelle swelling

    • cytoplasm vacuolation

    • Ions + H2O enter the cell

  • Blebbing

    • Cell speparates into fragments

  • Nuclear shrinkage

    • Condensation of chromatin

  • Nuclear fragmentation

    • Chromatin disperses into the cytoplasm

  • Cell rupture

    • inflammation

    • destructive to surrounding environment , leading to further tissue damage and exacerbating the inflammatory response.