Intro+Theories of Aging Flashcards
Give the a general definition of aging
Progressive accumulation of changes in the body which occur with the passing of time and which cause the increase in the probability of disease and death of the individual
What is the difference between aging and longevity?
Longevity is the length of the lifespan independent from the biological aging process
Why may have longevity and aging arisen?
- Longevity may have evolved to increase the time an organism can reproduce
- Aging may be a bit more random, arising from the impacts that have happened over the lifecourse
Give a few physiological changes that occur when we age
Reduced epithelial barrier function
Reduction in brain volume/mass
Reduction in bone marrow volume
Decreased lung capacity
Decreased cardiac output and increased blood pressure
Give a few pathological changes that occur when we age
Increased incidence of cancer
Increased incidence of coronary heart disease
Increased incidence of obstructive lung diseases and asthma
Increased incidence of rheumatoid disorders
Give a few psychological changes that occur when we age
Altered sleep patterns
Cognitive decline
Memory impairment (recall and formation of new memories)
Reduced speech and rate of speech
Increased risk of depression
Outline Medawars’ 1952 theory of aging
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
Outline Williams’ 1957 theory of aging
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
Outline Kirkwoods’ 1970s’ theory of aging
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
Outline what a program aging theory suggest?
Program theories of aging suggest that aging follows a biological timetable
This might be a continuation of the growth and development programmes of fetal life and childhood
What kind of aging theory is programmed longevity and what does it mean?
Program theory
Aging arises due to time-dependent changes in expression of key genes involved in growth or development
What kind of aging theory is endocrine theory and what does it mean?
Program theory
Hormonal influences (eg GH-IGFI) constitute a biological clock that determines the rate of aging of an organism
What kind of aging theory is immunological theory and what does it mean?
Program theory
Progressive loss of immune system activity with increasing age leads to cellular stress and eventual death from impact of disease
What do damage theories stipulate?
Organisms experience environmental assaults throughout their lifespan
These can arise from external insults (eg UV), or from intrinsic physiological processes (eg ROS)
Damage theories postulate that the cumulative impact of these assaults causes aging
What kind of theory is wear and tear theory and what does it mean?
Damage theory
Components of cells and tissues eventually wear out, leading to the aging of the organism
What kind of theory is rate of living theory and what does it mean?
Damage theory
The basal metabolic rate of an organism determines its lifespan
What kind of theory is cross-linking theory and what does it mean?
Damage theory
Accumulation of cross-linked proteins impairs cellular function, slowing down bodily processes and leading to aging
What kind of theory is free-radical theory and what does it mean?
Damage theory
Reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function
What kind of theory is somatic DNA damage theory and what does it mean?
Damage theory
Mutations are acquired faster than they can be repaired, so accumulate over time leading to a breakdown of genetic integrity
What 3 criteria must all hallmarks of aging fulfill?
1) Manifests during normal aging
2) Its experimental aggravation will accelerate aging
3) Its experimental amelioration should retard aging, leading to a longer, healthier lifespan
Give the 9 hallmarks of aging
- Genomic instability
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Deregulated nutrient sensing
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
Outline 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
Some premature aging syndromes (Werner, Blooms) arise from mutations in DNA repair enzymes – indicating a link between aging and genetic integrity
As well as damage to nuclear DNA, there is also mitochondrial DNA damage, and changes to nuclear architecture (how the DNA is arranged and packaged within the nucleus) with advancing age
Outline 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
Outline epigenetic alterations
Aging is associated with distinct epigenetic changes, including loss of DNA methylation, age-specific patterns of histone modification, and changes in the expression of enzymes that regulate DNA packaging and chromatin remodelling.
Genetic modification of these processes in model organisms indicates significant contributions to aging and lifespan (eg SIRT6)
Outline 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)
Outline deregulated nutrient sensing
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
AMPK activated by low energy states, and promotes healthy aging by inhibiting mTOR
Outline 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
Mitochondria may become permeabilized (‘leaky’) with age, triggering apoptosis and inflammation
Outline stem cell exhaustion
Decline in the regenerative potential of tissues is a key hallmark of aging
Cell cycle activity in aged stem cells is reduced»_space; divide less frequently
Loss of haematopoietic stem cell activity leads to reduced production of adaptive immune cells, and contributes to anaemia and myeloid cancers
May occur due accumulation of DNA damage and telomere shortening
Outline 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, senescence still occurs, but stem cell activity is less efficient, so removed cells do not get replaced as effectively
The demand for replacement cells may increase, thus exhausting the capacity of the stem cells
Senescent cells also secrete pro-inflammatory cytokines, which may contribute to aging
Outline altered intercellular communication
Aging is associated with age-related changes in inflammation, hormonal changes, and reduced immune system activity, along with resultant changes in microbiome (eg gut)
Senescent cells can influence those around them to enter senescence too (so called bystander effect) through communication to neighbouring cells via gap junctions
Manipulation of signalling pathways, or prevention of chronic inflammation, may present attractive strategies for inhibiting aging
What are primary hallmarks of aging and which ones are they?
Primary hallmarks are the causes of damage which underpin aging
-Genomic instability
-Telomere attrition
-Epigenetic alterations
-Loss of proteostasis
GELT
What are antagonistic hallmarks of aging and which ones are they?
Antagonistic hallmarks are tissue and cell responses to the damage caused by primary hallmarks
-Deregulated nutrient sensing
-Mitochondrial dysfunction
-Cellular senescence
What are integrative hallmarks of aging and which ones are they?
Integrative hallmarks are those which occur as a result of the above two categories
-Stem cell exhaustion
-Altered intercellular communication
AS
What is the best method to avoid aging?
Target the hallmarks of aging and therapeutically reverse them
