Ageing 2: Cancer
Review:
The force of natural selection declines
with ageing due to increase in extrinsic
mortality (= weakening of natural
selection) and reduction in
reproduction with age (selection acts at
reproduction)
Review
• Selection acts on genetic variation in a
population (culling different individuals that
have different genotypes)
• This variation is caused by mutations
• What are mutations?
Mutations
The Raw Material
for Evolution
Mistakes: Any change in the genetic code,
including changes caused by errors in DNA
replication or errors in DNA repair
Mutations
The Double Edged
Sword
Cause of many diseases, ageing, cancer
Cause of evolutionary novelty, upon which
natural selection could act
Hierarchical processes that are affected by Mutations
STRUCTURAL
• Amino Acid composition (nucleotide substitutions,
Amino Acid substitutions)
• Gene duplications, deletions; Chromosome
duplications, deletions
• Secondary, Tertiary, Quaternary structure
REGULATORY
• Gene/Protein expression (transcription, RNA
processing, translation, etc)
• Protein activity (allosteric control, conformational
changes, receptors)
Amino Acid
Substitutions
• Synonymous substitutions:
Mutations that do not cause amino
acid change (usually 3rd position)
• Nonsynonymous substitutions:
Mutations that cause amino acid
change (usually 1st, 2nd position)
REGULATORY
Gene/Protein expression
• Transcription: Mutations at promoters, enhancers,
transcription factors, Histones/acetylation, etc.
•
RNA Processing: Mutations at splice sites, sites of
polyadenylation, sites controlling RNA export
•
Translation: Mutations in ribosomes, regulatory regions,
etc
Protein activity (allosteric control, conformational
changes, receptors)
Central Dogma
(gene expression)
Transcription
•
•
•
•
Could have mutations in promoter or enhancer
Could have mutation in transcription factor
Mutation in repressor
Mutations in factors that alter chromatin structure (histone
acetylation)
A hallmark of ageing and cancer is the increase
of genomic instability with age
Selection that acts to preserve genomic
stability would diminish with age
Somatic mutations (mutations in the body)
accumulate with age
≠ mutational accumulation from previous
lecture (heritable deleterious mutations that get
expressed later in life  diseases expressed later in life)
Cancer is very common
• Lifetime risk of cancer in human
populations is around 1 out of 3
• Each year 10 million cases are diagnosed
• We have no global cure for cancer
What is Cancer?
HeLa cells
A problem of multicellular organisms
Multicellularity requires social cohesion of cells:
All cells must die at some point in multicellular
organisms (apoptosis, programmed cell death)
Cancer cells revert to unicellular selfishness, and
are immortal, and fail to die  tumor
Tumor Progression by Clonal
Evolution
•
Cancer cells have a short term evolutionary advantage
over wild type cells, because they grow and proliferate at a
greater rate
•
Thus, selection leads to a preponderance of cancer cells
over healthy cells
•
As more mutations accumulate in cancer cells, the greater
the competitive edge
•
In other words, cancer cells evolve towards higher
virulence within the body
•
However, at the whole organismal level there is a cost
Cancer Stem Cells?
• Unresolved issue: to what extent is cancer (tumor
growth) due to proliferation of all cells or a few
special cells (cancer stem cells)?
• Hypothesis 1: all tumor cells are immortal- every
cell in a tumor is the same
• Hypothesis 2: only some cells immortal- special
lineage of cells (cancer stem cells) in a tumor is
really responsible for tumor growth and metastasis
• To what extent should treatment focus on
targeting cancer stem cells?
Ageing and Cancer
• Cancer Cells
– Cancer is considered a disease of ageing
because the somatic mutations that accumulate
during ageing can sometimes disrupt normal
genetic control of cell proliferation and cell
death (apoptosis)
– Ironically, these mutations make cancer cells
immortal, such that they fail to age and die
The Irony of Cancer
Environmental assaults (oxidative stress, smoking,
pesticides, radiation, etc.) cause DNA damage
This is considered a symptom of “ageing” because
as you age the DNA repair and genomic stability
mechanisms decline with age
Mutations by chance at genes that affect cell
growth, proliferation, DNA repair; some of the
mutations might have been inherited
Cancer (immortal) cells that fail to age and die
(tend to be expressed in older individuals)
Types of Mutations that lead to Cancer
• Mutations to proto-oncogenes --> leading to
oncogenes, or insertions of oncogenes (genes
involved in cell growth and development; growth factors,
growth factor receptors etc)
• Mutations to tumor suppressor genes (e.g. Trp53;
Genes whose products block abnormal growth)
• Mutations to DNA repair genes (mismatch repair
etc)
• Telomere shortening leading to chromosome
instability and gene deletions
Treatment for Cancer can age
you further
• Once cells have become immortal, there is a
tradeoff between killing the cancer cells and
accelerating ageing in normal cells
• Radiation and chemotherapy kills cancer cells but
will age normal cells (and induce mutations)
• Cancer is a byproduct of ageing; yet, cancer
protection/treatment could accelerate ageing
Targets for
Cancer Suppression
• Reduction in cell proliferation and apoptosis
(programmed cell death)
• Tyrosine kinase inhibitors: target signal
transduction (block signal pathways that cause cells to
proliferate; upregulate pathways that cause apoptosis)
• Histone deacetylase inhibitors
• Angiogenesis inhibitors (choking cells, by cutting off
blood supply)
Example: p53
• Transcription factor -- regulates expression of other genes
In humans is encoded by the TP53 gene
• One of the most commonly mutated genes in human
cancers; Regulates the cell cycle; reduce cell proliferation,
increases apoptosis; thus, functions as a tumor suppressor that
is involved in preventing cancer
• Activate DNA repair proteins when DNA has sustained
damage
• Regulates genes involved in metabolism (glucose utilization
and mitochondrial respiration)-- recall that increased
metabolism could lead to faster ageing, as escaped
electrons during respiration (e-transport chain) could cause
cellular and DNA damage)
Sirtuins
• In recent years, the increasing interest in Sirtuin
protein biology has been astounding
• Mechanism of action poorly understood
• Important function in maintaining genomic stability,
in some cases DNA repair
Sirtuins
Sirtuins perform NAD+
dependent ADPribosylation of histones
to interfere with histone
acetylation (they are
histone deacetylases)
Histone Deacetylases/
Histone Acetyltransferase
• Plays important role in regulation of gene expression
• The ability of a particular transcription factor to bind to its
target gene is, in part, dependent on modifications that are
made to the histone proteins.
• Abnormal activity of HDACs has been observed in acute
promyelocytic leukemia, acute myelogenous leukemia, nonHodgkin lymphoma, and some types of colorectal and gastric
carcinoma
Histone Deacetylases/
Histone Acetyltransferase
• Plays an important role in the regulation of gene expression
• Histone acetyl transferases (HATs): Acetylate Histones,
enhance transcription; acetylation neutralizes positive charges
on the histone by changing amines into amides and
decreases the ability of the histones to bind to DNA, allowing
gene expression
• Histone Deacetylases (HDACs): Deactylate Histones,
repress transcription; remove acetyl groups from an ε-N-acetyl
lysine amino acid on a histone
• Different classes have different effects that either promote or
suppress cancer depending on which histones they are
affecting (and which genes are expressed or repressed)
• Defects in acetylation machinery appears to
lead to alterations in acetylation and perhaps
the development of cancer
• An imbalance in histone acetylation may lead
to changes in chromatin structure and
transcriptional dysregulation of genes
involved in the control of cell cycle
progression, differentiation, and apoptosis
Histone
Deacetylases
• Certain classes of Histone deacetylases (which affect
gene expression) affect insulin regulation (glucose, insulin
production, fat metabolism, cell survival)
• Such HDACs have the same effects of DR without
starving
• One class of Histone Deacetylases: Sirtuins are a family
of NAD+ dependent histone deacetylases that play
important roles in gene silencing, DNA repair, rDNA
recombination, and aging
SIR2
• The deacetylation of histones by SIR2 interferes with
recombination in the repeated array of ribosomal DNA
genes
• Such rDNA recombination could result in a type of
mutation (extrachromosomal rDNA circles), which cause
ageing in yeast (Sinclair & Guarente, 1997)
• Extra copies of or greater expression of SIR2 increases
lifespan in yeast, C. elegans, Drosophila, Metazoans
(multicellular animals)
Mammalian
Sirtuins
SIRT1
• The most prominent mammalian sirtuin,
SIRT1, has received considerable
attention because of its link with human
metabolism, aging and cancer
• SIRT1 has many targets for histone
deacetylation, including lysine residues
at positions 9 and 26 of histone H1, 14
of H3, and 16 of H4 (next figure)
SIRT1 regulates
many functions
involving apoptosis
and cell survival
• For example,
cooperates with
HIC1 to regulate
activity of p53
(tumor suppressor
gene) and apoptosis
Ageing 3: Mechanisms,
Mitigation
• Well, ageing and cancer are difficult
issues to resolve because so many
potential targets are involved (as
mutations are happening all across the
genome)
Current treatment
• Ageing: the tendency is to treat the symptoms, and not
the mechanistic root causes
• For example with cancer: the treatments are very
crude and involve a brute force approach
• Let’s just kill off the cells with radiation or chemotherapy:
kill both normal and cancer cells; hope that the cancer
will die and the patient will survive
• It might be more effective to take a
targeted approach in treating ageing
and diseases of ageing, like cancer
• This is difficult because there are so
many potential targets
• Where are the mutations occurring?
• What impacts are they having?
Related topics that I’ll discuss
Next:
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Caloric Restriction
Nutrient Signaling
Sirtuins
Resveratrol
Caloric Restriction
Much research is devoted to
understanding why caloric restriction
extends lifespan, as such insights
would help reveal what genetic
mechanisms cause ageing
Role of Diet
• Dietary restriction (DR) has been found to
increase life span in many organisms
• Caloric Reduction by 30% greatly increases
lifespan
• Mechanism is not fully understood
Lifespan varies
among populations
While there are genetic differences
among populations, environment (diet)
also plays a big role
It has been established that certain diets
lead to longer lifespan
For example, the Japanese live the
longest. However, Japanese-Americans
on an American diet have shorter (=
American) life spans
Americans tend to eat large portions
(large caloric intake), and have higher
animal fat intake, less vegetables
Evolutionary Hypothesis: tradeoff between
reproduction and maintenance (longer
lifespan)
Why should caloric restriction slow
aging and increase lifespan?
During years of famine, it may be evolutionarily
favorable for an organism to halt reproduction and to
upregulate protective and repair enzyme mechanisms to
try to extend lifespan to allow for reproduction in future
years.
Mechanism?
Physiological mechanisms are poorly understood
Hypotheses (some examples):
1. Energy: Decreased oxidative damage: less food
consumption, less metabolic damage
2. Nutrient Signaling: Altered glucose utilization,
Reduction of IGF/insulin signaling activity
3. Enhanced stress responsiveness
4. Changes in gene expression; Increased levels of sirtuins
Bishop, N.A. & L. Guarente. 2007. Genetic links between diet and
lifespan: shared mechanisms from yeast to humans. Nature
Reviews Genetics 8:835-844.
Mechanisms of life span
extension might differ
between moderate vs
severe caloric restriction
Severe Caloric Restriction
(famine)
Upregulate AMPK and
downregulate TOR genes
Severe Caloric
Restriction
• Under severe caloric restriction, downregulating TOR1 and
SCH9 (genes encoding two protein kinases involved in
nutrient sensing), as well as other genes of these nutrientsensing pathways, extend the life span of yeast (not know yet
if important in mammals)
• Sirtuin independent extension of lifespan
• mTOR (downregulated with severe DR) is a
serine/threonine protein kinase that regulates cell
growth, cell proliferation, cell motility, cell survival,
protein synthesis, and transcription
• AMPK (upregulated with severe DR) suppresses
mTOR; acts as a metabolic master switch
regulating several intracellular systems, including
cellular uptake of glucose, β-oxidation of fatty
acids and the biogenesis of glucose transporter 4
(GLUT4) and mitochondria.
It has been argued that reduced insulin
signaling and DR increase lifespan by a
common mechanism
• Insulin-like signaling accelerates ageing
• Reduction of IGF/insulin signaling activity is
associated with increased longevity
• With caloric restriction, there is an increase in
insulin sensitivity and decrease in blood glucose
• Some think that there is a link between insulinsignaling and caloric restriction, but the link is not
yet clear
Moderate Caloric Restriction
(~30% decrease)
Activate Sirtuins
Moderate
Caloric
Restriction
• Reduced glycolysis and increased
respiration during moderate DR raises the
cellular NAD+/NADH ratio
• This elevated ratio activates Sir2 and its
homologues, which drive increased lifespan
Resveratrol (3,5,4’-trihydroxystilbene)
mimics the effects of dietary restriction
• Mechanism not well understood
• Hypothesized to activate Sir2, or SIRT1 in mammals
• Alternatively, hypothesized to upregulate AMPK,
downregulate mTOR (Mammalian target of rapamycin)
Resveratrol (3,5,4’-trihydroxystilbene)
• Increases lifespan in yeast, C. elegans, Drosophila,
vertebrate fish, and mice; reduce obesity, increase
mitochondria
• There might be no cost to reproduction
Effects of resveratrol on mouse survival and
performance
Baur et al. 2006
Nature