Intro to aging Flashcards
What are 5 physiological changes that occur with aging?
1.Reduced epithelial barrier function
2.Reduction in brain volume/mass
3.Reduction in bone marrow volume
4.Decreased lung capacity
5.Decreased cardiac output and increased blood pressure
What are 4 pathological changes that occur with aging?
1.Increased incidence of cancer
2.Increased incidence of coronary heart disease
3.Increased incidence of obstructive lung diseases and asthma
4.Increased incidence of rheumatoid disorders
What are 5 psychological changes that occur with aging?
- Altered sleep patterns
- Cognitive decline
- Memory impairment
- Reduced speech and rate of speech
- Increased risk of depression
Theories of aging: Weissmann (1890s)
Aging evolved to benefit species rather than individual, to remove older members to reduce competition for resources with younger members
Theories of aging: Medawar (1952)
- 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
Theories of aging: Williams (1957)
- 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
Theories of aging: Kirkwood (1970s)
- 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
What do program theories suggest?
aging follows a biological timetable
Program theories: What is programmed longevity?
aging arises due to time-dependent changes in expression of key genes involved in growth or development
Program theories: What is endocrine theory?
hormonal influences (eg GH-IGFI) constitute a biological clock that determines the rate of aging of an organism
Program theories: What is immunological theory ?
progressive loss of immune system activity with increasing age leads to cellular stress and eventual death from impact of disease
What are damage theories?
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
Damage theories: What is wear and tear theory?
components of cells and tissues eventually wear out, leading to the aging of the organism
Damage theories: What is rate of living theory?
an organisms rate of basal metabolism determines its lifespan
Damage theories: What is cross-linking theory?
accumulation of cross-linked proteins impairs cellular function, slowing down bodily processes and leading to aging
Damage theories: What is free-radical theory?
reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function
Damage theories: What is somatic DNA damage theory?
mutations are acquired faster than they can be repaired, so accumulate over time leading to a breakdown of genetic integrity
What criteria do hallmarks of aging need to meet?
(i) it should manifest during normal aging;
(ii) its experimental aggravation should accelerate aging; and
(iii) its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan
Hallmarks of aging: 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
Hallmarks of aging: 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
Hallmarks of aging: 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
Hallmarks of aging: 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)
Hallmarks of aging: 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
Hallmarks of aging: 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
Hallmarks of aging: 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
Hallmarks of 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, 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
Hallmarks of aging: altered intracellular 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?
Causes of damage which underpin aging
What are antagonistic hallmarks of aging?
cell or tissue responses to the damage caused by primary hallmarks
What are integrative hallmarks of aging?
occur as a result of causes and responses
