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Dev/Age > Biology of ageing > Flashcards

Biology of ageing Flashcards

1
Q

What is ageing

A

No central definition
the time-related deterioration of the physiological functions necessary for survival and reproduction

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2
Q

What is longevity

A

the length of the lifespan independent of aging
Evolved to maximise reproductive fitness

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3
Q

Weissman theory of ageing

A

removing older members of the population to reduce competition for resources between younger members of a species, thus improving reproductive fitness.

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4
Q

What are the two major groups of aging theories

A

damage theories of aging
program theories of aging

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5
Q

Environmental assaults experienced throughout an organisms lifespan

A

External impacts (eg UV exposure),
Intrinsic physiological processes (eg Reactive Oxygen Species (ROS) generated from biochemical processes.)

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6
Q

What is meant by the damage theories of ageing

A

Cumulative impact of environmental assaults causes ageing

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7
Q

What are some examples of the damage theories of ageing

A

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

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8
Q

What is meant by the program theories of ageing

A

suggest that aging follows a biological timetable.
some single gene mutations with characteristics of accelerated ageing

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9
Q

What are some examples of the program theories of ageing

A

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

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10
Q

Driver of biological ageing

A

no single thing - combo of accumulating damage and (epi?)genetic dysregulation

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11
Q

Criteria for hallmarks of ageing

A

i) manifests during normal aging;
(ii) experimental aggravation accelerates aging
(iii) experimental amelioration (dampening) should retard the normal aging process

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12
Q

What are the genomic hallmarks of ageing

A

Genetic instability
Epigenetic changes
Telomere attrition

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13
Q

What is genomic instability

A

Changes in copy no. + chromosome instability
Changes to nuclear architecture + mitochondrial DNA
cause cellular dysfunction

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14
Q

How do epigenetic changes cause ageing

A

Loss of DNA methylation
Histone modification
Changes in expression of enzymes regulating DNA packaging and chromatin remodelling
cause impaired DNA repair

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15
Q

How does telomere attrition cause ageing

A

Progressive loss of telomeres causes cellular senescence and inability to maintain homeostasis

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16
Q

What are telomeres

A

Repeated DNA sq on the end of chromosomes
shorten with each round of cell division
once too short, cells enter senescence

17
Q

What is the enzyme telomerase

A

Maintain telomere length
mainly expressed by stem cells

18
Q

What are the cellular hallmarks of ageing

A

Stem cell exhaustion
Changes in cell signalling
Cellular senescence

19
Q

How can stem cell exhaustion cause ageing

A

Aged stem cells divide less frequently due to red. cell cycle activity.
May accum mutations leading to neoplasia formation

20
Q

Impact on stem cell exhaustion on dif stem cell types

A

Haematopoietic (HSC) - Anemia, Myelodysplasia
Mesenchymal (MSC) - Osteoporosis, red. fracture repair
Satellite cells - red. muscle fibre repair
Intestinal Epithelial (IESC) - red. intestinal function

21
Q

How can changes in cell signalling cause ageing

A

inflammation, hormonal changes, and reduced immune system activity characterise ageing
senescent cells cause senescence in neighbouring cells via gap jct communication

22
Q

What is senescence

A

Stable arrest of the cell cycle in response to dna damage. Blocks proliferation of damaged cells to prevent cancer

23
Q

How can cell senescence cause ageing

A

Secrete pro-inflammatory cytokines
Increase demand for replacement cells causes stem cell exhaustion

24
Q

What are the biochemical hallmarks of ageing

A

Impaired mitochondrial function
Impaired proteostasis
Impaired nutrient sensing

25
Q

How can impaired mitochondrial function cause ageing

A

Respiration becomes less effective -> less energy available
mitochondrial dysfunction ^ ROS prod
mtDNA mutations -> red bioenergetics
mitochondria becomes leaky triggering apoptosis/inflammation

26
Q

How can impaired proteostasis cause ageing

A

Unfolded proteins are a target for autophagy
If they remain -> aggregation which disrupts normal cell function

27
Q

What is proteostasis

A

controls the normal folding and maintenance of proteins in their folded state through chaperone (heat shock protein) activity)

28
Q

How does impaired nutrient sensing cause ageing

A

Mutations affecting GH-IGF1 function can extend lifespan

29
Q

What is the information theory of ageing

A

accumulation of epigenetic mutations over time underpins ageing - can be reversible

30
Q

What are the Yamanaka factors

A

4 transcription factors (OCT4, SOX2, KLF4 and MYC) when artificially-expressed together in mature cells can reprogram them to an embryonic, pluripotent state

31
Q

How to treat biological ageing

A

Develop therapeutics that target one of the 9 hallmarks of ageing

32
Q

Therapeutics targeting the biochemical hallmarks

A
  • Mitohormetics, mitophagy to fix impaired mitochondria
  • Activation of chaperones and proteolytics
  • Dietary restrictions
33
Q

Therapeutics targeting the genomic hallmarks

A
  • elimination of damaged cells
  • epigenetic drugs
  • telomerase reactivation
34
Q

Therapeutics targeting the cellular hallmarks

A
  • stem cell therapies
  • anti-inflamm drugs w/ blood-borne rejuvenation factors
  • Clearing senescent cells

Dev/Age (4 decks)

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