Biology of Ageing complete notes with Tutorial work and extra reading.
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Course
BIOL0022 Biology of Ageing (BIOL0022)
Institution
University College London (UCL)
In-depth description of all content covered in the course, with added critically analysed studies and extra reading. Everything you need to know for the exam.
Wear and Tear Theory
Hypothesis:
o Ageing is a result of the progressive accumulation of damage to cells, tissues, and
organs over time due to normal metabolic processes and environmental insults. This
theory posits that organisms "wear out" similarly to mechanical systems (e.g., cars,
machines).
o The damage is often attributed to reactive oxygen species (ROS), DNA replication
errors, protein misfolding, and other by-products of metabolism, leading to a
gradual decline in physiological function.
Supporting Evidence:
o Oxidative Stress: Studies in diverse species, including mice and fruit flies, have
linked oxidative damage (produced by ROS during metabolism) to ageing
phenotypes. ROS are known to damage lipids, proteins, and DNA, leading to cellular
dysfunction.
o Caloric Restriction: Evidence from caloric restriction (CR) experiments across
various taxa (mice, yeast, worms) suggests that reduced caloric intake lowers
metabolic rate and oxidative damage, leading to an extended lifespan, supporting
the view that less metabolic activity results in slower wear and tear.
Challenges and Counter-Evidence:
o Hydra Studies (Martínez, 1998; Schaible et al., 2015): Hydra, a small freshwater
organism, shows no signs of senescence or ageing over extended periods. Mortality
rates in Hydra remain constant over time, and their ability to regenerate
continuously suggests that some organisms do not "wear out," which contradicts the
wear and tear theory.
o Variability Across Species: Organisms like turtles and whales exhibit long lifespans despite
high metabolic rates, implying that there are protective mechanisms beyond simply reducing
damage from metabolic activity.
Mutation Accumulation Theory (Medawar, 1952)
Hypothesis:
o Ageing is the result of the accumulation of deleterious mutations that exert their effects late
in life, after the reproductive period. Since natural selection acts more strongly on traits that
affect early-life reproductive success, mutations with deleterious effects that manifest post-
reproductively accumulate in populations because selection cannot effectively remove them.
Supporting Evidence:
o Medawar’s Model: Peter Medawar developed theoretical models suggesting that organisms
experience a decline in the force of natural selection after their reproductive peak. As a
result, late-acting deleterious mutations accumulate, as their effects are not strongly
selected against.
o Huntington’s Disease (Haldane, 1942): J.B.S. Haldane noted that Huntington’s Disease, a
neurodegenerative disorder with a late onset (mean age of 35.5 years), persists in
populations despite its lethal effects because natural selection is weak against mutations
with late-life effects.
, o Human Age-Related Disease Clusters (Donertas et al., 2021): Genome-wide association
studies (GWAS) have identified clusters of age-related diseases that appear later in life.
These diseases show weak selection against their genetic variants, supporting the mutation
accumulation model.
Challenges and Counter-Evidence:
o No "Wall of Death": Mutation accumulation theory predicts a sharp increase in
mortality (a “wall of death”) at post-reproductive ages, but this is rarely observed in
nature. Instead, mortality rates typically increase gradually, as seen in species such
as birds and mammals (e.g., baboons).
o High Genetic Variability in Late-Life: Experimental populations of Drosophila have
shown substantial genetic variability in ageing-related traits, suggesting that
selection continues to operate on these traits even after reproduction, which
contradicts the strict predictions of mutation accumulation.
Group Selection Theories (Weismann, Wallace)
Hypothesis:
o Early group selection theories suggested that ageing evolved for the benefit of the
group or species rather than the individual. Weismann proposed that ageing serves
to remove old and less fit individuals from the population, allowing for the more
efficient reproduction and survival of younger individuals. Wallace argued that
ageing reduces competition for resources, benefiting the reproductive success of
offspring and descendants.
Supporting Evidence:
o Post-Reproductive Lifespan in Mammals (Nattrass et al., 2019): In species such as
killer whales, post-reproductive females provide benefits to their kin by transmitting
cultural knowledge (e.g., food location), which enhances the survival of their
grandchildren. This suggests a possible group-level benefit of longevity in species
with strong familial structures.
o Social Species: In some eusocial insects, like ants and termites, sterile worker castes
live long lives while serving the reproductive individuals, providing some support for
group-level selection.
Challenges and Counter-Evidence:
o Kin Selection vs. Group Selection: Group selection theories have largely been
replaced by kin selection and individual selection models, as group selection is a
weaker force in evolution. In most organisms, natural selection acts on individuals,
not groups.
o Limited Generalizability: Theories based on group selection fail to explain ageing in
species that do not live in family groups or exhibit strong kinship structures, limiting
the theory’s applicability.
Cultural Transmission and Extended Lifespan in Humans and
Cetaceans
Hypothesis:
o In species with advanced social structures, such as humans and killer whales, post-
reproductive individuals provide significant advantages to their offspring and
grandchildren by transmitting cultural knowledge and survival strategies. This
extended lifespan may have evolved to allow older individuals to enhance the
survival of their kin, even after they are no longer directly reproducing.
Supporting Evidence:
, o Killer Whale Grandmother Effect (Nattrass et al., 2019): Research on killer whales
has shown that post-reproductive females increase the survival of their
grandchildren by guiding them to food sources during periods of scarcity. This
suggests that longevity beyond reproductive years may be selected for in species
with complex social behaviors and cultural transmission.
Programmed Aging and Phenoptosis (Galimov et al., 2019)
Hypothesis:
o Programmed aging, or phenoptosis, refers to the theory that aging and death might
be adaptations that promote group fitness by benefiting younger generations, a
controversial concept in mainstream evolutionary theory.
o It proposes that aging could have evolved as a mechanism to eliminate older, less fit
individuals to allow more resources for the younger population. This may only apply
in certain organisms where kin selection or group selection is stronger.
Supporting Evidence:
o Unicellular Organisms: Programmed cell death (apoptosis) in unicellular organisms
such as yeast (Saccharomyces cerevisiae) is well-documented. Apoptosis in yeast
promotes colony fitness by redistributing resources from older cells to younger
ones, suggesting a model for biomass sacrifice or phenoptosis(Galimov_2019).
o C. elegans: In certain conditions where populations are clonal and resources are
limited, programmed death may enhance the fitness of related individuals. For
instance, C. elegans exhibits behaviors where death could be adaptive by increasing
kin survival(Galimov_2019).
Challenges:
o Mainstream Evolutionary Theory: Mainstream theory predicts that non-aging
individuals (i.e., cheaters) would outcompete aging individuals, making group
selection for aging a weak evolutionary strategy.
o Human Relevance: The concept of adaptive death may apply to specific organisms
(e.g., unicellular or colonial species) but lacks strong empirical support for
multicellular animals like mammals.
Insulin/IGF-1 Signaling Pathway (Kenyon, 2010) - supports
pleiotropy
Hypothesis:
o The Insulin/IGF-1 pathway is central to lifespan regulation in many organisms,
including C. elegans, Drosophila, and mammals. Mutations in this pathway can more
than double the lifespan by modulating genes involved in stress response and
metabolism.
o Reduced Insulin/IGF-1 signaling shifts physiology towards maintenance and stress
resistance rather than growth, extending lifespan and delaying age-related diseases.
Supporting Evidence:
o C. elegans: Mutations in the daf-2 gene (encoding a receptor homologous to
insulin/IGF-1 receptors) lead to significant lifespan extension by activating the DAF-
16/FOXO transcription factor, which upregulates stress response genes like
catalases and heat shock proteins(Kenyon 2010).
o Mice and Flies: Similar effects are observed in mice and flies, where reduced IGF-1
signaling extends lifespan and enhances stress resistance, indicating the pathway is
conserved across species(Kenyon 2010).
, o Human Studies: Variants of FOXO genes have been linked to exceptional longevity in
human populations (e.g., Ashkenazi Jews and Hawaiians), showing the relevance of
this pathway to human aging(Kenyon 2010).
Challenges:
Trade-offs: In some models, reducing Insulin/IGF-1 signaling can lead to insulin
resistance, which is a hallmark of diabetes, highlighting the need for a balance
between pathway modulation and metabolic health(Kenyon 2010).
Antagonistic Pleiotropy Theory (Williams, 1957)
What is pleiotropy
-> one gene can affect various biological processes or characteristics that may seem unrelated. This
phenomenon occurs because a single gene can have multiple roles in an organism’s physiology,
often because it is expressed in different tissues or at different stages of development, or because its
product (protein or RNA) interacts with multiple cellular pathways.
Types of pleiotropy
Molecular Pleiotropy:
A gene might produce a protein that has multiple functions in different tissues or
under different conditions. For example, the same enzyme might be involved in
metabolism in one tissue and in a signaling pathway in another.
Developmental Pleiotropy:
A gene may be involved in more than one aspect of an organism’s development. For
example, genes that control early cell division might also be important in later
differentiation processes.
Antagonistic Pleiotropy:
o This specific form of pleiotropy occurs when a gene has a beneficial effect on one
trait but a detrimental effect on another. In the context of ageing, antagonistic
pleiotropy is particularly important because it describes how a gene that enhances
early-life fitness (such as promoting rapid growth or early reproduction) might have
negative effects later in life, contributing to ageing or age-related diseases.
Hypothesis:
o Antagonistic pleiotropy occurs when a single gene influences multiple traits, where
one of these traits provides a fitness benefit early in life (e.g., enhanced
reproduction or survival) but has detrimental effects later (e.g., accelerated ageing).
This trade-off arises because selection favors early-life reproductive success, even at
the cost of late-life survival or health.
o Ageing, according to this theory, evolves because of the evolutionary benefits of
early-life traits that are selected for, despite their harmful effects in later life.
Supporting Evidence:
o Drosophila Studies (Sgrò & Partridge, 1999): Experimental selection on age at
reproduction in Drosophila (fruit flies) has demonstrated trade-offs between early
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