10.5 - Biology of aging

Question 1

What are some proposals for the definition of aging? (3)

Answer 1

• 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

How is aging distinct from longevity?

Answer 2

• longevity - the length of the lifespan independent of aging
  
  • two individuals with similar lifespans are unlikely to ‘age’ at the same rate
• longevity may have evolved to maximise reproduction opportunities, whereas aging may be a more random process arising from the impact of events over the life course

Question 3

What are the two major groups of aging theories?

Answer 3

• damage (/error) theories of aging
• program theories of aging

Question 4

What are damage theories of aging?

Answer 4

• organisms experience environmental assaults throughout their lifespan - can arise from external impacts (e.g. UV exposure) or from intrinsic physiological processes (e.g. ROS generation)
• damage (or error) theories of aging postulate that the cumulative impact of these assaults over the lifecourse causes aging
• 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 5

What are some examples of damage theories of aging? (5)

Answer 5

• wear and tear theory - over time the components of cells and tissues eventually wear out, leading to aging
• rate of living theory - an organisms rate of basal metabolism determines its lifespan: higher the rate, the shorter the lifespan (e.g. rodents vs humans)
• cross-linking theory - accumulation of cross-linked proteins over time impairs cellular function, slowing down bodily processes and leading to aging
• free radical theory - ROS cause damage to cellular macromolecules (DNA and proteins) and organelles, impairing function and accumulating as aging
• somatic DNA damage theory - genetic mutations are acquired faster than they can be repaired, accumulate over time leading to breakdown of genetic integrity, resulting in aging

Question 6

What are program theories of aging?

Answer 6

• 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
• some single-gene disorders (e.g. Hutchinson-Gilford Progeria syndrome) may have many characteristics of accelerated or premature aging, and suggest that aging might be pre-programmed genetically
• program theories of aging are less widely accepted and less well supported by evidence

Question 7

What are some examples of program theories of aging? (3)

Answer 7

• programmed longevity - this suggests that aging arises due to time-dependent changes in expression of key genes involved in growth or development
• endocrine theory - this suggests that hormonal influences (e.g. GH-IGF1 signalling) constitutes a biological clock that determines the rate of aging of an organism
• immunological theory - this suggests that progressive loss of immune system activity with increasing age leads to cellular stress and eventual death from impact of disease

Question 8

In reality, a combination of what two things drive biological aging?

Answer 8

Combination of accumulating damage and (epi)genetic dysregulation may underpin biological aging

Question 9

What do the ‘hallmarks of aging’ mean?

Answer 9

They sought to identify common characteristics of aging across multiple species, in an attempt to identify biological pathways that drive or contribute to aging

Question 10

What criteria do each of the hallmarks of aging need meet for inclusion? (3)

Answer 10

• it should manifest during normal aging
• its experimental aggravation should accelerate aging
• its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan

Question 11

What are the three functional domains of the hallmarks of aging?

Answer 11

• genomic hallmarks - concern changes in gene, chromosome or genome structure or expression, changes in the epigenome, that result in cellular dysfunction, leading to aging
• cellular hallmarks - relate to changes in cell behaviour or function over the lifecourse, that might contribute to aging through failure to maintain or repair tissues or organs
• biochemical hallmarks - relate to cellular changes in metabolism or biochemistry, which over time may contribute to cell damage and dysfunction, leading to aging

Question 12

What are the hallmarks of aging (9) and their functional domains (3)?

Answer 12

• genomic hallmarks
  
  • genomic instability
  • epigenetic changes
  • telomere attrition
• cellular hallmarks
  
  • stem cell exhaustion
  • changes in cell signalling
  • cellular senescence
• biochemical hallmarks
  
  • impaired mitochondrial function
  • impaired proteostasis
  • impaired nutrient sensing

Question 13

Describe genomic instability as a hallmark of aging.

Answer 13

• DNA damage is accumulated throughout life from exposure to external sources (e.g. UV radiation) or body processes (e.g. free radicals)
• some premature aging syndromes (Werner, Blooms) arise from mutations in DNA repair enzymes – indicating a link between aging and genetic integrity
• within nuclear DNA, changes in copy number and chromosome stability are observed with increasing age, but there are also changes to nuclear architecture (how the DNA is arranged and packaged within the nucleus) and to the mitochondrial DNA
• failure to remedy these changes leads to cellular dysfunction, which accumulates, leading to aging

Question 14

Describe epigenetic changes as a hallmark of aging.

Answer 14

• 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
• together, these lead to inappropriate expression of genes (transcriptional noise) and changes in the packaging and accessibility of DNA to proteins, which in turn can lead to impaired DNA repair and chromosome instability

Question 15

Describe telomere attrition as a hallmark of aging.

Answer 15

• 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, and once the telomere reaches a critical shortness, cells enter senescence (stop dividing)
• some cells (mostly stem cells) express an enzyme called telomerase, which can maintain telomere length, and experimental manipulation of telomere length or telomerase expression can modulate mammalian lifespan
• progressive loss of telomeres over the lifecourse of the organism is thought to lead to cellular senescence and an inability to maintain homeostasis in tissues, resulting in aging

Question 16

Describe stem cell exhaustion as a hallmark of aging.

Answer 16

• decline in the regenerative potential of tissues is a key hallmark of aging
• cell cycle activity in aged stem cells is reduced, leading them divide less frequently, and thus contribute less to repair and maintenance of tissues, resulting in aging
• the stem cells may also accumulate mutations, leading to the formation of neoplasias
• changes in Haematopoietic Stem Cells (HSCs), Mesenchymal Stem Cells (MSCs), Satellite Cells, and Intestinal Epithelial Stem Cells (IESCs) with age could contribute to organ dysfunction and ageing

Question 17

Describe changes in cell signalling as a hallmark of aging.

Answer 17

• aging is associated with age-related changes in inflammation, hormonal changes, and reduced immune system activity
• senescent cells (i.e. non-dividing cells at the end of their lifespan) can influence the cells 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

Question 18

Describe cellular senescence as a hallmark of aging.

Answer 18

• senescence is the stable arrest of the cell cycle, and 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, with removed cells are replaced by stem cell activity
• in aged cells, senescence still occurs, but stem cell activity is less efficient, so removed cells do not get replaced as effectively, thus 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
• improving the mechanisms by which the body can clear senescent cells has been a focus of anti-aging research

Question 19

Describe impaired mitochondrial function as a hallmark of aging.

Answer 19

• there is a loss of efficacy of the respiratory train with increasing age, which in turn results in less energy being available for cellular processes
• in parallel, 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 also become permeabilized (‘leaky’) with age, triggering apoptosis and inflammation

Question 20

Describe impaired proteostasis as a hallmark of aging.

Answer 20

• 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 (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 (eg Alzheimers, Parkinsons).

Question 21

Describe impaired nutrient sensing as a hallmark of aging.

Answer 21

• mutations that impair the function of the activity of the Growth Hormone (GH)–Insulin-Like Growth Factor I (IGF1) 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 22

What is the information theory of aging?

Answer 22

• new theory that suggests that acquisition of epimutations (harmful epigenetic changes) over the lifecourse leads to aging through loss of ‘youthful epigenetic information’
• testable theory - Yamanaka factors (collection of 4 transcription factors: OCT4, SOX2, KLF4, MYC that when artificially-expressed together in mature cells can reprogram them to an embryonic pluripotent state) to ‘reset’ the epigenome of cells in aging tissues and animals

Question 23

Can we ‘treat’ biological aging?

Answer 23

• identifying 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

Question 24

What strategies can be used to target each of the hallmarks of aging? (9 - just be aware)

Answer 24

• elimination of damaged cells
• epigenetic drugs
• telomerase reactivation
• stem cell-based therapies
• anti-inflammatory drugs, blood-borne rejuvenation factors
• clearance of senescent cells
• mitohormetics, mitophagy
• activation of chaperones and proteolytic systems
• dietary restriction: IIS and mTOR inhibition, AMPK and sirtuin activation