1B biology of ageing

Question 1

What is aging?

Answer 1

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

Question 2

What is longevity?

Answer 2

The length of the lifespan independent of aging

Question 3

How is aging distinct from longevity?

Answer 3

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.

Question 4

What are the two major groups of aging theories?

Answer 4

• Damage theories of aging
• Program theories of aging

Question 5

What are the damage (or error) theories of aging?

Answer 5

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.

Question 6

List some examples of damage theories

Answer 6

• Wear and tear theory
• Rate of living theory
• Cross-linking theory
• Free-radical theory
• Somatic DNA damage theory

Question 7

What is the wear and tear theory?

Answer 7

Over time the components of cells and tissues eventually wear out, leading to the aging of the organism.

Question 8

What is the rate of living theory?

Answer 8

An organisms rate of basal metabolism determines its lifespan - the higher the basal metabolism, the shorter the lifespan (eg rodents vs humans)

Question 9

What is the cross-linking theory?

Answer 9

Accumulation of cross-linked proteins over time impairs cellular function, slowing down bodily processes and leading to aging

Question 10

What is the free-radical theory?

Answer 10

Reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function. Accumulation of this damage over time results in aging.

Question 11

What is the somatic DNA damage theory?

Answer 11

Genetics mutations are acquired faster than they can be repaired. These accumulate over time leading to a breakdown of genetic integrity, resulting in aging.

Question 12

What is the drawback of damage theories?

Answer 12

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.

Question 13

What are program theories of aging?

Answer 13

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.

Question 14

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.

Answer 14

Hutchinson-Gilford Progeria syndrome

Question 15

List some examples of program theories

Answer 15

• Programmed longevity
• Endocrine theory
• Immunological theory

Question 16

What is programmed longevity?

Answer 16

This suggests that aging arises due to time-dependent changes in expression of key genes involved in growth or development.

Question 17

What is endocrine theory?

Answer 17

This suggests that hormonal influences (e.g. GH-IGFI signalling) constitutes a biological clock that determines the rate of aging of an organism

Question 18

What is immunological theory?

Answer 18

This suggests that progressive loss of immune system activity with increasing age leads to cellular stress and eventual death from impact of disease

Question 19

Why are program theories less widely accepted?

Answer 19

They are less well supported by evidence.

In reality, it is likely that there is no single thing which drives biological aging, but instead a combination of accumulating damage and (epi?)genetic dysregulation may underpin biological aging.

Question 20

What is a ‘hallmark of aging’?

Answer 20

Common characteristics of aging across multiple species

Question 21

What criteria does each hallmark of aging have to meet?

Answer 21

1. It should manifest during normal aging
2. Its experimental aggravation should accelerate aging
3. Its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan

Question 22

What are the three domains of the hallmarks of aging in its original form?

Answer 22

• Genomic hallmarks
• Cellular hallmarks
• Biochemical hallmarks

Question 23

What are genomic hallmarks concerned with?

Answer 23

Changes in gene, chromosome or genome structure or expression, changes in the epigenome, that result in cellular dysfunction, leading to aging.

Question 24

What are the genetic hallmarks?

Answer 24

• Genomic Instability
• Epigenetic changes
• Telomere attrition

Question 25

What is genomic instability?

Answer 25

- 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.

Question 26

How are epigenetic changes linked to aging?

Answer 26

- 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.

Question 27

What is telomere attrition?

Answer 27

- 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.

Question 28

What are cellular hallmarks?

Answer 28

Cellular hallmarks of aging relate to changes in cell behaviour or function over the life course, that might contribute to aging through failure to maintain or repair tissues or organs.

Question 29

What are the cellular hallmarks?

Answer 29

- Stem cell exhaustion - Changes in cell signally - Cellular senescence

Question 30

What is stem cell exhaustion?

Answer 30

- 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.

Question 31

How do changes in cell signalling contribute to aging?

Answer 31

- Aging is linked to changes in inflammation, hormonal levels, and decreased immune system function. - Senescent cells, which cease dividing at the end of their lifespan, can induce neighbouring cells to undergo senescence through a process known as the bystander effect. - Communication between senescent cells and neighbouring cells occurs via gap junctions. - Modulation of signalling pathways or mitigation of chronic inflammation may offer promising approaches to slow down the aging process.

Question 32

What is cellular senescence?

Answer 32

- 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.

Question 33

What are biochemical hallmarks?

Answer 33

Biochemical hallmarks relate to cellular changes in metabolism or biochemistry, which over time may contribute to cell damage and dysfunction, leading to aging.

Question 34

What are the biochemical hallmarks?

Answer 34

- Impaired mitochondrial function - Impaired proteostasis - Impaired nutrient sensing

Question 35

What is impaired mitochondrial function?

Answer 35

- Aging is associated with reduced efficiency of the respiratory chain, resulting in decreased energy availability for cellular processes. - Age-related mitochondrial dysfunction leads to increased production of reactive oxygen species (ROS), which can damage cellular macromolecules. - Accumulation of mutations in mitochondrial DNA (mtDNA) may impair bioenergetics, further decreasing cellular processes and contributing to aging. - With age, mitochondria may become permeabilized ("leaky"), triggering apoptosis (cell death) and inflammation.

Question 36

How is impaired proteostasis linked to aging?

Answer 36

- 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).

Question 37

How is impaired nutrient sensing related to aging?

Answer 37

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 in model organisms, although very low levels of GH-IGFI signalling are incompatible with life. In parallel, dietary restriction has been shown to extend lifespan in model organisms, through the AMPK pathway.

Question 38

What is the information theory of aging?

Answer 38

New theory that suggests that acquisition of epimutations (harmful epigenetic changes) over the life-course leads to aging through loss of 'youthful epigenetic information'.

Question 39

Why is identifying the hallmarks of aging useful?

Answer 39

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.