Theories Of Ageing Flashcards
Accumulated mutation theory
Progressive accumulation of DNA damage and mutation of genes encoding DNA repair enzymes
•Most organisms (in the wild) die before reaching old age, so little benefit to the number of offspring (reproductive fitness) by living beyond reproductive years
•Therefore – natural selection will act on harmful mutations early in life, but have power to select out the accumulation of mutations that are detrimental in older organisms
Antagonistic pleiotropy
Some genes have more than one unconnected role or effect (pleiotropy)
•Genes that promote a beneficial effect early in age (and boost number of offspring) but have negative effects in old age will be selected for by evolution
Disposable soma theory
Organisms have limited resources, and must balance these between investing in reproduction and maintaining and repairing the body
•Resources spent early in live promoting development and reproduction are ‘lost’ to old age and can’t be used to support repair
Programme theories
Suggest ageing follows biological timetable
Programmed longevity – aging arises due to time-dependent changes in expression of key genes involved in growth or development
Endocrine theory – hormonal influences (eg GH-IGFI) constitute a biological clock that determines the rate of aging of an organism
Immunological theory– progressive loss of immune system activity with increasing age leads to cellular str
Damage theories
Organisms experience environmental assaults throughout their lifespan
Wear and tear theory – components of cells and tissues eventually wear out, leading to the aging of the organism
Rate of living theory – an organisms rate of basal metabolism determines its lifespan
Free-Radical Theory – reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function
Cross-linking Theory – accumulation of cross-linked proteins impairs cellular function, slowing down bodily processes and leading to
Genomic instability
DNA damage is accumulated throughout life
•This damage arises from exposure to external sources (eg UV radiation) or body processes (eg free radicals)
•Changes in DNA copy number and chromosome stability are observed with increasing age
Telomere attrition
The ends of chromosomes contain repeated DNA sequences known as telomeres
•In most cells, telomeres cannot be replicated fully by the DNA replication machinery, so shorten with each round of cell division
•Once the telomere reaches a critical shortness, cells enter senescence
•Some cells (mostly stem cells) express an enzyme called telomerase, which can maintain telomere length
•Experimental manipulation of telomere length or telomerase expression can modulate mammalian lifespan
Impaired proteostasis
Proteostasis controls the normal folding and maintenance of proteins in their folded state through chaperone (heat shock protein) activity)
•Unfolded proteins are normally targeted for autophagy, or breakdown by the proteosome
•Persistence of unfolded proteins leads to their aggregation, a situation associated with numerous age-related disorders (eg Alzheimers, Parkinsons)
Deregulated nutrient
•Mutations that impair the function of the activity of the Growth Hormone (GH) – Insulin-Like Growth Factor I (IGFI) pathway are associated with increased lifespan and healthy aging
•Dietary (caloric) restriction is thought to work through this pathway
•Very low levels of GH-IGFI are incompatible with life, so it’s not possible to block this pathway completely to inhibit aging
•mTOR regulates many aspects of cell metabolism, and contributes
Mitochondrial dysfunction
Mitochondrial defects are closely associated with aging and longevity
•There is a loss of efficacy of the respiratory train with increasing age»_space; less energy for cellular processes
•Age-related mitochondrial dysfunction leads to increased reactive oxygen species (ROS) which can damage cellular macromolecules
•Accumulation of mtDNA mutations may lead to reduced bioenergetics, contributing to a decrease in cellular processes and aging
Cellular senescence
Senescence is the stable arrest of the cell cycle.
•This occurs in response to DNA damage, and prevents the ongoing proliferation of these dysfunctional cells.
•These cells are efficiently removed by the immune system, preventing progression to cancer or aging
•Removed cells are replaced by stem cell activity
In older cells stem cell activity is less efficient
Primary vs antagonistic hallmarks
Primary hallmarks are those which are the causes of damage which underpin aging
Antagonistic hallmarks are those which are cell or tissue responses to the damage caused by primary hallmarks
Integrative hallmarks are those which occur as a result of the above two categories
Altered intercellular communication
Senescent cells influence cells around them to enter sensecenntoo called bystander effect via communication to neighboring cells through gap junctions
