PHYSIOLOGY 364
AGEING
Ageing and senescence
Senescence ⇋ ageing (technical difference)
Ageing = natural, progressive process of physiological changes occurring in an
organism over time
▪ Inability to maintain homeostasis
▪ Increased susceptibility to disease
Senescence = specifically refers to the state of irreversible cell cycle arrest, alive but
not proliferating *dysfunctional
▪ Response to stress and damage
▪ Accumulates in tissue due to ageing contributing to organ dysfunction
Features of ageing
Molecular changes such as telomere shortening, accumulation cellular damage,
decline organ function and reduced homeostatic mechanisms
✓ Genetic factors
✓ Lifestyle choices – diet and exercise
✓ Environmental exposures – UV radiation
✓ Epigenetic factors
Features of senescence
Senescent cells remain metabolically active but no longer proliferate
Exhibit altered gene expression patterns or phenotype – senescence associated
secretory phenotype (SASP) as proinflammatory cytokines, MMPs proteinases and
growth factors (stell cell activation) – influences tissue microenvironments
Mechanism that limits the proliferation of damaged or potentially cancerous cells
Senescence associated secretory phenotype (SASP)
->cell cycle arrest with no proliferation
1. Chromatin remodelling
2. Lysosomal accumulation
3. Metabolic changes
4. Release of cytokines, growth factors and MMPs
, PHYSIOLOGY 364
Implications of senescence
Accumulation of senescent cells in tissues over time contributes to ageing phenotypes
SASP-mediated inflammation and cellular or tissue damage
Senescence – intracellular response contributing to ageing
Ageing – holistic outcoming affecting organism overall
Ageing vs senescence
Ageing
*Macromolecule damage (DNA, proteins and lipids)
*Oxidative stress
*Genomic instability
*Mitochondrial dysfunction
*Cell, tissue, organ, systems and organism affected
*Systemic or consequences of cumulative damage
*Irreversible
Senescence
*DNA damage, oxidative stress, telomere shortening and oncogene activation
*Permanent cell arrest
*SASP
*Affects neighbouring cells and extracellular environment
*Cell
*Cellular response – but senescent cells accumulate over time
*Can be mitigated
Senescence
Senescent cells accumulate in tissues over time
Contributes to tissue degeneration and age-related disease
SASP
Senolytics –> drugs targeting and clearing senescent cells
▪ Dasatinib, Quercetin, Fisetin, Navitoclax (ABT-263), ABT-737, Piperlongumine,
Foxo4-DRI peptide and HSP90 inhibitors
▪ Targets cell survival pathways
Beneficial functions senescence:
1. Tumour suppression
Senescence protective mechanism against oncogene activation
Limiting proliferation and growth
Occurs prior to oncogene activation during cellular stress and damage
, PHYSIOLOGY 364
Mediated by tumour suppressor pathways
Oncogene-mediated senescence
Not just for cancer – but damaged DNA – not want to replicate damaged DNA,
potential for oncogene activation downstream
2. Wound healing
SASP = inflammatory cytokines, chemokines and growth factors aiding in healing
process including VEGF and MMPs (matrix metalloproteinases degrading collagen)
Injury – senescence induced and response contributes to chemotaxis (IL-6, IL-8 and
MCP-1, neutrophils and monocytes), stem cell activation and differentiation,
proliferation, angiogenesis and ECM remodelling
Cleared by immune cells during tissue repair and restoration
3. Embryogenesis
4. Anti-fibrosis
Secretes factors limiting fibroblast activation and proliferation
Inhibition of collage deposition in tissues that require to be distensible
MMPs degrade collagen and prevent excessive collagen deposition (i.e. = fibroblasts)
5. Immune modulation
Chemotaxis
▪ To site of injury
▪ Directly to senescent cell from which the signal originated from to clear
senescent cell for chemotaxis purposes
▪ Immune surveillance to site where senescence is to search for pathogen or
defective cancerous cells; to site where there once was damage significant
enough to induce damage
Theories of ageing – addendum 1
Smoking -> DNA or telomere damage -> cancer or senescence
*Error or damage theory!! [system and mutations]
*Free radical theory i.e. oxidative damage, waste accumulation and DNA + protein
damage (mutations) [collagen crosslinks]
, PHYSIOLOGY 364
Program theories of ageing [not important]:
Inherent mechanism of ageing
Deliberate deterioration with age because a limited life span results in evolutionary
benefits (eliminating post-reproductive individuals)
Damage theories of ageing!!: free radical theory of ageing
Evolutionary biologists argue ageing occurs due to absence of natural selection at post-reproductive life
Age theories are subjectively appealing – accumulation of damage is spontaneous
entropy-driven process – its kinetics genetically and environmentally modulated
resulting in wide range of life spans
Combined theories of ageing:
1. Membrane hypothesis of ageing – cell membranes more rigid during ageing
therefore ageing related to changes in cell ability to transfer chemicals, heat and
electrical processes
2. Dysdifferentiation hypothesis – inability of cells to reach and maintain respective phenotype or
differentiated state (abandoned)
3. Fading electricity hypothesis of ageing – as cells gradually lose ability to produce electricity,
biochemical processes as drivers of ageing into play leading to death by senescence (lacks data
supporting hypothesis)
Mechanisms interact = complex = integrative analysis of quantitative avaliable evidence at
different levels of biological hierarchy to fundamentally understand ageing process
The chemical interplay
Ageing dubbed war raged between chemical processes and biochemical processes
Ageing fundamentally end result of unwanted chemical processes yielding
spontaneous side products of normal metabolism with mutated, less active, toxic
species of lipids, proteins, RNA, DNA and small molecules
Optimisation of biochemical processes?
AGEING
Ageing and senescence
Senescence ⇋ ageing (technical difference)
Ageing = natural, progressive process of physiological changes occurring in an
organism over time
▪ Inability to maintain homeostasis
▪ Increased susceptibility to disease
Senescence = specifically refers to the state of irreversible cell cycle arrest, alive but
not proliferating *dysfunctional
▪ Response to stress and damage
▪ Accumulates in tissue due to ageing contributing to organ dysfunction
Features of ageing
Molecular changes such as telomere shortening, accumulation cellular damage,
decline organ function and reduced homeostatic mechanisms
✓ Genetic factors
✓ Lifestyle choices – diet and exercise
✓ Environmental exposures – UV radiation
✓ Epigenetic factors
Features of senescence
Senescent cells remain metabolically active but no longer proliferate
Exhibit altered gene expression patterns or phenotype – senescence associated
secretory phenotype (SASP) as proinflammatory cytokines, MMPs proteinases and
growth factors (stell cell activation) – influences tissue microenvironments
Mechanism that limits the proliferation of damaged or potentially cancerous cells
Senescence associated secretory phenotype (SASP)
->cell cycle arrest with no proliferation
1. Chromatin remodelling
2. Lysosomal accumulation
3. Metabolic changes
4. Release of cytokines, growth factors and MMPs
, PHYSIOLOGY 364
Implications of senescence
Accumulation of senescent cells in tissues over time contributes to ageing phenotypes
SASP-mediated inflammation and cellular or tissue damage
Senescence – intracellular response contributing to ageing
Ageing – holistic outcoming affecting organism overall
Ageing vs senescence
Ageing
*Macromolecule damage (DNA, proteins and lipids)
*Oxidative stress
*Genomic instability
*Mitochondrial dysfunction
*Cell, tissue, organ, systems and organism affected
*Systemic or consequences of cumulative damage
*Irreversible
Senescence
*DNA damage, oxidative stress, telomere shortening and oncogene activation
*Permanent cell arrest
*SASP
*Affects neighbouring cells and extracellular environment
*Cell
*Cellular response – but senescent cells accumulate over time
*Can be mitigated
Senescence
Senescent cells accumulate in tissues over time
Contributes to tissue degeneration and age-related disease
SASP
Senolytics –> drugs targeting and clearing senescent cells
▪ Dasatinib, Quercetin, Fisetin, Navitoclax (ABT-263), ABT-737, Piperlongumine,
Foxo4-DRI peptide and HSP90 inhibitors
▪ Targets cell survival pathways
Beneficial functions senescence:
1. Tumour suppression
Senescence protective mechanism against oncogene activation
Limiting proliferation and growth
Occurs prior to oncogene activation during cellular stress and damage
, PHYSIOLOGY 364
Mediated by tumour suppressor pathways
Oncogene-mediated senescence
Not just for cancer – but damaged DNA – not want to replicate damaged DNA,
potential for oncogene activation downstream
2. Wound healing
SASP = inflammatory cytokines, chemokines and growth factors aiding in healing
process including VEGF and MMPs (matrix metalloproteinases degrading collagen)
Injury – senescence induced and response contributes to chemotaxis (IL-6, IL-8 and
MCP-1, neutrophils and monocytes), stem cell activation and differentiation,
proliferation, angiogenesis and ECM remodelling
Cleared by immune cells during tissue repair and restoration
3. Embryogenesis
4. Anti-fibrosis
Secretes factors limiting fibroblast activation and proliferation
Inhibition of collage deposition in tissues that require to be distensible
MMPs degrade collagen and prevent excessive collagen deposition (i.e. = fibroblasts)
5. Immune modulation
Chemotaxis
▪ To site of injury
▪ Directly to senescent cell from which the signal originated from to clear
senescent cell for chemotaxis purposes
▪ Immune surveillance to site where senescence is to search for pathogen or
defective cancerous cells; to site where there once was damage significant
enough to induce damage
Theories of ageing – addendum 1
Smoking -> DNA or telomere damage -> cancer or senescence
*Error or damage theory!! [system and mutations]
*Free radical theory i.e. oxidative damage, waste accumulation and DNA + protein
damage (mutations) [collagen crosslinks]
, PHYSIOLOGY 364
Program theories of ageing [not important]:
Inherent mechanism of ageing
Deliberate deterioration with age because a limited life span results in evolutionary
benefits (eliminating post-reproductive individuals)
Damage theories of ageing!!: free radical theory of ageing
Evolutionary biologists argue ageing occurs due to absence of natural selection at post-reproductive life
Age theories are subjectively appealing – accumulation of damage is spontaneous
entropy-driven process – its kinetics genetically and environmentally modulated
resulting in wide range of life spans
Combined theories of ageing:
1. Membrane hypothesis of ageing – cell membranes more rigid during ageing
therefore ageing related to changes in cell ability to transfer chemicals, heat and
electrical processes
2. Dysdifferentiation hypothesis – inability of cells to reach and maintain respective phenotype or
differentiated state (abandoned)
3. Fading electricity hypothesis of ageing – as cells gradually lose ability to produce electricity,
biochemical processes as drivers of ageing into play leading to death by senescence (lacks data
supporting hypothesis)
Mechanisms interact = complex = integrative analysis of quantitative avaliable evidence at
different levels of biological hierarchy to fundamentally understand ageing process
The chemical interplay
Ageing dubbed war raged between chemical processes and biochemical processes
Ageing fundamentally end result of unwanted chemical processes yielding
spontaneous side products of normal metabolism with mutated, less active, toxic
species of lipids, proteins, RNA, DNA and small molecules
Optimisation of biochemical processes?
