Biology of ageing Flashcards
What is ageing
No central definition
the time-related deterioration of the physiological functions necessary for survival and reproduction
What is longevity
the length of the lifespan independent of aging
Evolved to maximise reproductive fitness
Weissman theory of ageing
removing older members of the population to reduce competition for resources between younger members of a species, thus improving reproductive fitness.
What are the two major groups of aging theories
damage theories of aging
program theories of aging
Environmental assaults experienced throughout an organisms lifespan
External impacts (eg UV exposure),
Intrinsic physiological processes (eg Reactive Oxygen Species (ROS) generated from biochemical processes.)
What is meant by the damage theories of ageing
Cumulative impact of environmental assaults causes ageing
What are some examples of the damage theories of ageing
Wear and tear theory – cell organelles wear over time
Rate of living theory – basal metabolism determines lifespan, ^ basal metabolism = short lifespan (eg rodents vs humans)
Cross-linking theory – accum cross-linked proteins over time impairs cellular function
Free-Radical Theory – reactive oxygen species (ROS) damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function.
Somatic DNA damage theory – genetic mutations acquired faster than they can be repaired -> breakdown of genetic integrity
What is meant by the program theories of ageing
suggest that aging follows a biological timetable.
some single gene mutations with characteristics of accelerated ageing
What are some examples of the program theories of ageing
Programmed longevity – time-dependent changes in expression of key genes involved in growth or development.
Endocrine theory – hormonal influences (eg GH-IGFI signalling) constitutes a biological clock
Immunological theory– progressive loss of immune system activity with increasing age -> cellular stress and eventual death from impact of disease
Driver of biological ageing
no single thing - combo of accumulating damage and (epi?)genetic dysregulation
Criteria for hallmarks of ageing
i) manifests during normal aging;
(ii) experimental aggravation accelerates aging
(iii) experimental amelioration (dampening) should retard the normal aging process
What are the genomic hallmarks of ageing
Genetic instability
Epigenetic changes
Telomere attrition
What is genomic instability
Changes in copy no. + chromosome instability
Changes to nuclear architecture + mitochondrial DNA
cause cellular dysfunction
How do epigenetic changes cause ageing
Loss of DNA methylation
Histone modification
Changes in expression of enzymes regulating DNA packaging and chromatin remodelling
cause impaired DNA repair
How does telomere attrition cause ageing
Progressive loss of telomeres causes cellular senescence and inability to maintain homeostasis
What are telomeres
Repeated DNA sq on the end of chromosomes
shorten with each round of cell division
once too short, cells enter senescence
What is the enzyme telomerase
Maintain telomere length
mainly expressed by stem cells
What are the cellular hallmarks of ageing
Stem cell exhaustion
Changes in cell signalling
Cellular senescence
How can stem cell exhaustion cause ageing
Aged stem cells divide less frequently due to red. cell cycle activity.
May accum mutations leading to neoplasia formation
Impact on stem cell exhaustion on dif stem cell types
Haematopoietic (HSC) - Anemia, Myelodysplasia
Mesenchymal (MSC) - Osteoporosis, red. fracture repair
Satellite cells - red. muscle fibre repair
Intestinal Epithelial (IESC) - red. intestinal function
How can changes in cell signalling cause ageing
inflammation, hormonal changes, and reduced immune system activity characterise ageing
senescent cells cause senescence in neighbouring cells via gap jct communication
What is senescence
Stable arrest of the cell cycle in response to dna damage. Blocks proliferation of damaged cells to prevent cancer
How can cell senescence cause ageing
Secrete pro-inflammatory cytokines
Increase demand for replacement cells causes stem cell exhaustion
What are the biochemical hallmarks of ageing
Impaired mitochondrial function
Impaired proteostasis
Impaired nutrient sensing
How can impaired mitochondrial function cause ageing
Respiration becomes less effective -> less energy available
mitochondrial dysfunction ^ ROS prod
mtDNA mutations -> red bioenergetics
mitochondria becomes leaky triggering apoptosis/inflammation
How can impaired proteostasis cause ageing
Unfolded proteins are a target for autophagy
If they remain -> aggregation which disrupts normal cell function
What is proteostasis
controls the normal folding and maintenance of proteins in their folded state through chaperone (heat shock protein) activity)
How does impaired nutrient sensing cause ageing
Mutations affecting GH-IGF1 function can extend lifespan
What is the information theory of ageing
accumulation of epigenetic mutations over time underpins ageing - can be reversible
What are the Yamanaka factors
4 transcription factors (OCT4, SOX2, KLF4 and MYC) when artificially-expressed together in mature cells can reprogram them to an embryonic, pluripotent state
How to treat biological ageing
Develop therapeutics that target one of the 9 hallmarks of ageing
Therapeutics targeting the biochemical hallmarks
- Mitohormetics, mitophagy to fix impaired mitochondria
- Activation of chaperones and proteolytics
- Dietary restrictions
Therapeutics targeting the genomic hallmarks
- elimination of damaged cells
- epigenetic drugs
- telomerase reactivation
Therapeutics targeting the cellular hallmarks
- stem cell therapies
- anti-inflamm drugs w/ blood-borne rejuvenation factors
- Clearing senescent cells
