1B biology of ageing Flashcards
What is aging?
Aging is not very well defined – as it stands, there is no universally-agreed definition of what aging is, although there are a number of proposals:
- a 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.
- the wearing out of the structures and functions that reach a peak or plateau during development and maturations of the individuals of a given species
- the time-related deterioration of the physiological functions necessary for survival and reproduction
What is longevity?
The length of the lifespan independent of aging
How is aging distinct from longevity?
Two individuals with similar lifespans are unlikely to ‘age’ at the same rate.
Longevity may have evolved to maximise opportunities to reproduce (i.e. to maximise ‘reproductive fitness’ in evolutionary terms), whereas aging may be a more random process arising from the impact of events over the life-course.
What are the two major groups of aging theories?
- Damage theories of aging
- Program theories of aging
What are the damage (or error) theories of aging?
Organisms experience environmental assaults throughout their lifespan. These insults can arise from external impacts (e.g. UV exposure), or from intrinsic physiological processes (e.g. Reactive Oxygen Species (ROS) generated from biochemical processes.
The cumulative impact of these assaults over the life course causes aging.
List some examples of damage theories
- Wear and tear theory
- Rate of living theory
- Cross-linking theory
- Free-radical theory
- Somatic DNA damage theory
What is the wear and tear theory?
Over time the components of cells and tissues eventually wear out, leading to the aging of the organism.
What is the rate of living theory?
An organisms rate of basal metabolism determines its lifespan - the higher the basal metabolism, the shorter the lifespan (eg rodents vs humans)
What is the cross-linking theory?
Accumulation of cross-linked proteins over time impairs cellular function, slowing down bodily processes and leading to aging
What is the free-radical theory?
Reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function. Accumulation of this damage over time results in aging.
What is the somatic DNA damage theory?
Genetics mutations are acquired faster than they can be repaired. These accumulate over time leading to a breakdown of genetic integrity, resulting in aging.
What is the drawback of damage theories?
While the damage theories of aging is generally widely accepted, the precise nature of the damage that causes aging, and how this manifests as aging, remains unclear.
What are program theories of aging?
Program theories of aging suggest that aging follows a biological timetable. This programme might be a continuation of the growth and development programmes of foetal life and childhood.
Give an example of a single-gene mutation disorder that have many characteristics of accelerated or pre-mature aging, to suggest that aging might be pre-programmed genetically.
Hutchinson-Gilford Progeria syndrome
List some examples of program theories
- Programmed longevity
- Endocrine theory
- Immunological theory
What is genomic instability?
- DNA damage accumulates over time from external sources (e.g., UV radiation) and internal processes (e.g., free radicals).
- Premature aging syndromes (e.g., Werner, Bloom) stem from mutations in DNA repair enzymes, highlighting the connection between aging and genetic integrity.
- Changes in copy number and chromosome stability occur in nuclear DNA as individuals age.
- Alterations in nuclear architecture and mitochondrial DNA are also observed with aging.
- Failure to repair these changes results in cellular dysfunction, contributing to the aging process.
How are epigenetic changes linked to aging?
- Aging is linked to specific epigenetic alterations, such as:
- Loss of DNA methylation.
- Age-specific patterns of histone modification.
- Changes in the expression of enzymes regulating DNA packaging and chromatin remodelling.
- These alterations result in:
- Inappropriate gene expression (transcriptional noise).
- Changes in DNA packaging and accessibility to proteins.
- Consequently, impaired DNA repair and chromosome instability may occur.
What is telomere attrition?
- Telomeres, repeated DNA sequences at chromosome ends, shorten with each cell division due to incomplete replication by DNA machinery.
- When telomeres become critically short, cells enter senescence (stop dividing).
- Telomerase, expressed in some cells (mostly stem cells), can maintain telomere length.
- Experimental manipulation of telomere length or telomerase expression can affect mammalian lifespan.
- Progressive telomere loss throughout life leads to cellular senescence and disrupts tissue homeostasis, contributing to aging.
What is stem cell exhaustion?
- Decline in tissue regeneration is a significant feature of aging.
- Aged stem cells exhibit reduced cell cycle activity, leading to less frequent division and diminished contribution to tissue repair and maintenance.
- Accumulation of mutations in aged stem cells may lead to the development of neoplasias.
- Changes in Haematopoietic Stem Cells (HSCs), Mesenchymal Stem Cells (MSCs), Satellite Cells, and Intestinal Epithelial Stem Cells (IESCs) with age contribute to organ dysfunction and aging.
- See diagram for visualization of age-related changes in stem cells and their impact on tissue function.
What is cellular senescence?
- Senescence involves a permanent halt in the cell cycle in response to DNA damage, preventing the proliferation of dysfunctional cells.
- The immune system efficiently eliminates senescent cells, preventing cancer or aging progression, and stem cells replace removed cells.
- In aging, senescence still occurs, but reduced stem cell activity hinders effective replacement of removed cells.
- This increased demand for replacement cells may overwhelm stem cell capacity.
- Senescent cells also secrete pro-inflammatory cytokines, potentially contributing to aging processes.
How is impaired proteostasis linked to aging?
- Proteostasis controls the normal folding and maintenance of proteins in their folded state through chaperone (heat shock protein) activity).
- Normally, unfolded proteins are targeted for autophagy, or breakdown by the proteosome.
- However, persistence of unfolded proteins leads to their aggregation, disrupting normal cell function, a situation associated with numerous age-related disorders (e.g. Alzheimers, Parkinsons).
Why is identifying the hallmarks of aging useful?
Identifying the hallmarks of aging provides targets for anti-aging research. If the hallmarks of aging are causative, then developing therapeutics that target one or multiple hallmarks may help slow the aging process/increase longevity.
