Ageing and Age-related Diseases
Juan Ponce de Léon
searches for the
of Youth in Florida
(Frank Harper, 1908)
What is Ageing (Senescence)?
Ageing refers to the increased impairment of physiological
function with age (i.e. a deterioration in age-specific components
At a certain threshold the survival
capacity of the organism is
Accumulated random damage causes a
reduction in the efficiency of the overall
function of an organism resulting in
Ageing is characterised by an exponential rise in age-specific
death rate (Gompertz’s Law, 1825) and a concomitant decline
in reproductive output.
Gompertz’s Law, illustrated using 1999 US mortality data,
underpins many life insurance valuations.
Species-specific Lifespan Species Age (y)
Aldabra tortoise 170
Gompertz’s Law implies that as an Lake sturgeon 152
individual gets older the chances of Rockfish 140
dying in the next time interval increase. Halibut 90
Asian elephant 80
Thus an age will be reached after which African gray parrot 73
Wood turtle 60
it would be unlikely to find any more American white pelican 54
surviving individuals. Red-breasted parrot 33.4
Little brown bat 30
Pacific ocean perch 26
Lifespan (the maximum number of Eastern gray squirrel 23.5
House canary 22
years an individual can live) appears to American crow 14.6
be species-specific (Helfand and Rogina, American robin 12.8
2003 BioEsssays 25: 134-141). Sockeye salmon 8
White-winged crossbill 4
Laxmann’s shrew 2
The great diversity in lifespan suggests Highland desert mouse 0.8
Pygmy goby fish 0.17
longevity may be easily evolvable.
The maximum lifespan of the
human species is about 122
years, the age at death of Jeanne
Life expectancy (the length of time an
individual can expect to live) is
characteristic of specific populations.
Life Expectancy in New Zealand
Life Expectancy and HIV/AIDS in African Countries
The lifespan of humans (c. 122
years) has probably not
changed in 100,000 years.
Life expectancy, however, has
almost doubled in the last
Life expectancy: England/Wales, Sweden
Largely due to efficacious
treatment of infectious
Further increases in life
expectancy in the western
world require significant
reductions in total mortality
at every age (Olshansky et al.
(2001) Science 291:
1491-1492). Life expectancy (projected) in Japan
Causes of Death (2003)
The 15 leading causes of death (US):
1. Heart disease
3. Stroke and cerebrovascular disease
4. Chronic lower respiratory disease
e.g. bronchitis, emphysema and asthma
7. Flu and pneumonia
8. Alzheimer's disease
9. Kidney disease
10. Blood disease
12. Chronic liver disease and cirrhosis
13. High blood pressure and hypertensive kidney disease
14. Parkinson's disease
15. Choking on solids and liquids
Mechanisms of Ageing
Two major theories:
1. Program theories argue that genetic or ageing programs (possibly
regulated by one or more intrinsic developmental clocks)
determine the maximum life span for each species.
However, there is little evidence that ageing is a significant cause
of death in natural populations and genes for ageing are not
2. Error theories emphasize that ageing is an outcome of the
random accumulation of somatic damage, owing to limited
investment in maintenance and repair.
Longevity (the distribution of lifespans within a population) is
thus regulated by genes controlling activities such as DNA repair
and antioxidant defence.
Genes and Ageing
Each species has a typical range of average and maximal life
spans, indicating some contribution from genetic determinants
i.e. genes influence longevity.
So are there “genes for ageing”?
According to evolutionary theory (natural selection) there are
probably no “ageing genes” (i.e. ageing is not genetically
programmed and it is not selected for).
Thus there are no genes that direct the body down a death
Although many genes alter lifespan, none abolishes ageing.
These genes can be considered as “longevity genes”, the opposite
of “ageing genes”.
Evolutionary Theory and Ageing
Natural selection acts to increase fitness.
Therefore natural selection should oppose ageing.
Despite its obvious disadvantages, ageing nevertheless occurs.
However, it is not universal (Hydra, for example, may not age).
How did Ageing Evolve?
Aging may have evolved because of the increasingly smaller
probability of an organism still being alive at an older age, due
to predation and accidents.
Higher lifetime reproductive success could thus be achieved by
investing more in an increased reproduction rate at a younger
age, and less in longevity (i.e. shorter overall lifespan).
How can Ageing be Reconciled with
There are three theories of ageing based on evolutionary
1. Mutation Accumulation Theory (Medawar, 1952)
2. Antagonistic Pleiotropy Theory (Williams, 1957)
3. Disposable Soma Theory (Kirkwood, 1977)
These three theories are not mutually exclusive.
1. Mutation Accumulation Theory
(Medawar, 1952: An Unsolved Problem of Biology,
HK Lewis, London).
“The human mind treats a new idea the way the
body treats a strange protein -- it rejects it.” Sir Peter Medawar
Young cohorts, not yet depleted in numbers by extrinsic mortality
(predation; disease; accidents), contribute far more to the next
generation than the few surviving older cohorts.
The force of selection against late-acting deleterious mutations,
which only affect these few older individuals, is thus very weak.
These deleterious mutations (e.g. leading to ageing) may not be
selected against and may spread over time within the population.
2. Antagonistic Pleiotropy Theory
(Williams, 1957 Evolution 11: 398-411)
Williams recognised that genes which confer
advantages early in life, but which are deleterious
later, may evolve through natural selection if the
early benefits outweigh the late harmful effects. If
the later effects are post-reproductive, they cannot
be selected against. George C Williams
Pleiotropic genes (genes with multiple effects) trade benefit at an
early age against harm at older ages (“life-history trade-off”).
For example, p53 protects against cancer (and death) by
interrupting the abnormal proliferation of cells, but increases the
risk of ageing.
Thus mice with a p53 gain of function show increased tumour
suppression and decreased longevity.
3. Disposable Soma Theory.
(Kirkwood and Austad, 2000 Nature 408:
Ageing is the result of investing resources in reproduction, rather
than maintenance of the body.
Natural selection tunes the life history of an organism so that
sufficient resources are invested in maintenance and repair to
prevent ageing, at least until the organism has reproduced.
Damage accumulates within cells because the energy required for
somatic maintenance and repair is unnecessary after reproduction.
The optimal course is to invest fewer resources into somatic
maintenance than are necessary for indefinite survival, and more
into reproductive success.
Once the division of labour between germ-line and somatic cells
evolved, the soma became disposable.
According to the Disposable Soma Theory:
1. Ageing is due to the lifelong, progressive accumulation of
unrepaired molecular and cellular defects.
2. Multiple types of damage accumulate (somatic damage;
oxidative damage; aberrant proteins; defective
3. The primary genetic determinants of the rate of ageing are
those that regulate somatic maintenance and repair systems.
Selection works not on “genes for ageing”, but on “genes for
somatic maintenance”, which act as “longevity assurance”.
Ageing in the Nematode Caenorhabditis elegans.
(Houthoofd and Vanfleteren, 2007 Mol Genet Genom 277: 601-617).
When threatened with overcrowding, the larval worm responds to
pheromones (ascarosides) by diverting development into a long-
living, dispersal form (the dauer larva) more resistant to stress.
The gene daf-2 (which encodes the
insulin/IGF-1 receptor) controls the
switch into the dauer form.
Mutations in daf-2 cause worms to
enter the dauer state more frequently,
or produce animals that have double
the lifespan and show increased
resistance to a variety of stresses
(oxidative; heat; UV; heavy metals)
mediated in part by reactive oxygen
Insulin/IGF-1 Binds to DAF-2 and negatively regulates DAF-16
Ligands (e.g. the insulin-like
DAF-28) bind to the DAF-2
insulin/IGF-1 receptor and (PI-3)
activate PI-3 (phosphatidyl
inositol) kinase (AGE-1).
PI-3 kinase signals via a
cascade to phosphorylate the Phosphorylated
DAF-16 is inactive
factor DAF-16 (FOXO) by
the AKT protein kinase.
Phosphorylated DAF-16 is
AGE-1: PI3 kinase catalytic subunit
then sequestered in the PDK-1: phosphoinositide dependent kinase 1 (phosphorylates AKT)
AKT: S/T kinase (phosphorylates and inhibits DAF-16)
Adults in this state mature reproductively and are not long-lived.
Mutations in the receptor daf-2
or the presence of the antagonist
INS-1 yield dephosphorylated
This enters the nucleus, promotes
transcription (multiple targets)
and induces long life.
DAF-16 is active
Mutations in daf-16 reduce the Catalase
increased life span of daf-2 Mn-SOD
mutants to wild type (i.e. daf-2
effects are daf-16 dependent).
Since daf-2 expression is affected in only a few cell types, a
secondary hormone is probably involved in regulating ageing.
The daf-2 signalling pathway also regulates lipid metabolism
(increased fat in mutants) and reproduction.
How does DAF-16 Influence Ageing in the Worm?
(Murphy et al., 2003 Nature 424: 277-284).
DAF-16 is a FOXO-family (forkhead) transcription factor
Some genes upregulated under daf-2- conditions (longevity)
Peroxisomal Cytochrome P450 family
Metallothionein-related cadmium-binding protein
Manganese superoxide dismutase
Ins-18 Insulin-like protein (antagonizes DAF-2 receptor)
Some genes downregulated under daf-2- conditions (longevity)
Vitellogenin (170 kDa yolk protein)
Ins-7 Insulin-like protein (agonist for DAF-2 receptor)
Sirtuins in Aging
In C. elegans, DAF-16 is activated by SIR2 (Silent information
regulator 2) via deacetylation.
The activities of FOXO proteins seemingly shift from cell death
towards survival on deacetylation (presence of SIR2), elevating
levels of ROS inhibitors.
Extra copies of SIR2 thus extend lifespan and increase stress
SIR2 is a (nicotinamide adenine dinucleotide) NAD-dependent
It acts as a transcriptional silencer by deacetylation of histones H3
and H4, thus setting up a repressive chromatin structure.
• histone acetylation increases
transcription (characteristic of
• histone deacetylation represses
transcription (characteristic of
However, many non-histone proteins have now been identified as
acetylation targets (e.g. DAF-16).
Can perturbation of insulin/IGF-1 activity increase
lifespan in humans?
• Mutations that impair IGF-1 receptor function are
overrepresented in a cohort of centenarian Ashkenazi Jews.
• DNA variants in the insulin receptor gene are linked to
longevity in a Japanese cohort.
• Variants of AKT (a S/T kinase that phosphorylates
and inhibits DAF-16) and FOXO3A (upregulates
antioxidants; downregulated in tumorigenisis) have
been linked to longevity in numerous cohorts.
The Effects of Dietary Restriction (DR)
Reduction of nutrient intake to 25-60% of voluntary levels
increases lifespan in organisms from yeast to mammals
(Koubova and Guarente, 2003: Genes Develop 17: 313-321).
Could DR extend lifespan by slowing down metabolism (and
hence reducing the rate of damage accumulation over time)?
In Drosophila, DR produces a rapid decrease in mortality rate
suggesting an acute effect. The effects of DR are not related to the
caloric content of the food, but works in part by increasing
Could DR act as a stressor that induces a defensive response to
boost survival chances?
Sublethal stressors increase lifespan (“hormesis effect” i.e. benefits
of low doses).
In rodent models, DR postpones or prevents a wide spectrum of
diseases and age-associated neuronal loss without causing
irreversible developmental or reproductive defects.
DR, for example, extends the lifespan of mice strains that
normally die early from cancer and it extends the lifespan of
Fischer rats that normally die of kidney disease (Guarente and
Picard, 2005 Cell 120: 473).
Ongoing studies in Rhesus monkeys show many changes that
occur in DR rodents e.g lowered risk factors for
cardiometabolic disease (such as blood pressure; serum lipids;
Restriction in C.
Different modes of DR
extend lifespan via
• eat-2 mutations inhibit feeding throughout life.
• the TOR kinase (Target of Rapamycin) is a nutrient sensor
• the sirtuins are NAD+ dependent deacetylases
• AMP kinase is a nutrient sensor that activates catabolism and
represses anabolism when the AMP/ATP ratio increases.
• PHA-4 (required for autophagy), Daf-16 and SKN-1 (in neurons;
increases respiration) are transcription factors.
Chronic Dietary Restriction
DR elevates respiration and promotes longevity (Although
decreased respiration extends lifespan under normal feeding
regimens. Could this explain longevity of large mammals?).
TOR (Target of Rapamycin) Links DR and the Insulin/
(Fingar and Blenis 2004 Oncogene 23: 3151-3171).
TOR is an evolutionary conserved S/T kinase that regulates cell,
organ and organismal size through effects on cell growth and cell
TOR senses and integrates nutrient availability and growth factor
signals to regulate cell growth and division through altered protein
synthesis (upregulates translation via ribosomal S6 kinase).
Inhibition of TOR by rapamycin mimics nutrient and growth factor
deprivation (ie DR), downregulates S6 kinase, limits translation and
TOR deficiency in C. elegans doubles the lifespan independently of
Daf-16 and is not further increased by DR.
TOR inhibition also stimulates autophagy (rejuvenates the cell;
associated with longevity).
Integration of nutrient (amino acids) and growth factor (e.g. insulin)
signaling indicates crosstalk between the insulin/IGF receptor PI-3
kinase cascade and TOR function.
This indirectly links two aspects of ageing control (DR and growth
Rheb is aRas-
Harman, 1956. J Gerontol 11: 298–300.
Bokov et al., 2004 Mech Ageing Dev 125: 811-826.
Reactive oxygen species (ROS) are generated during metabolism
and these damage proteins, lipid and DNA.
The ability to
prevent or repair
such damage is not
The rate of accumulation of oxidative damage may thus determine
the rate of ageing.
Mutations in the primary anti-oxidant systems including Cu, Zn
superoxide dismutase (SOD), Mn superoxide dismutase (SOD2),
and catalase appear to shorten the life span (Sun et al., 1999 Mol
Cell Biol 19: 216-228).
The converse (overexpression and longlife) does not necessarily
follow (Helfand and Rogina, 2003 BioEsssays 25: 134-141).
However, the expression of human SOD in a subset of adult
Drosophila cells (motorneurons) caused a 40% increase in life
span (Phillips et al., 2000 Exp Gerontol 35: 1157-1164).
The fact that only a subset of cells can influence ageing
suggests a hormonal response may be involved.
Mitochondria have their own circular genome, which contains
13 protein-coding genes.
A single cell can have hundreds of mitochondria, each with as
many as 10 copies of the mitochondrial genome.
Each time the mtDNA replicates, there is a mutational risk.
In the aged human, virtually every mitochondrial genome has a
Cells can tolerate a high proportion of mutant mitochondrial
genomes, but once a threshold is passed energy production falls
Mutations in mt DNA can potentiate the ageing process by energy-
mtDNA polymerase-γ is the only DNA polymerase that is targeted
to and resides in mitochondria.
In the absence of other mtDNA polymerases it is assumed to be
responsible for both replication and repair of the mt genome.
Mice with mutations in the proof-reading capacity of mtDNA
polymerase-γ have reduced lifespan and display typical ageing
signs such as weight loss, alopecia and anaemia (Trifunovic et al.
2004 Nature 429: 417).
These mice show respiratory dysfunction, but no enhanced ROS
production (Trifunovic et al. 2005 PNAS 102: 17993-17998).
Perhaps the alterations act downstream of mechanisms that
It is easy to make mice die young, but does reduced mtDNA
damage allow mice to liver longer?
Effects of Stress
According to the mitochondrial
permeability transition (PT) theory,
oxidative stress opens pores in the
mitochondria (Crompton, 1999.
Biochem J 341: 233-249).
Cytosolic pro-apoptotic bcl-2
proteins (e.g. Bad) sense cellular
damage or stress and relocate to
the surface of the mitochondria.
Here they interact with anti-apoptotic proteins (e.g. Bcl-2) leading to
the formation of pores and the release of cytochrome C.
This leads to the formation of the apoptosome, activation of the
caspase cascade and apoptosis.
When cells start dying quicker than they are replaced, ageing
Mitochondria are a major site for the production of free radicals
Transgenic mice overexpressing
human catalase localized to the
mitochondria (but not the nucleus or
peroxisome) live an average 5
months longer and signs of ageing
(Schriner et al., 2005 Science 308:
Survival curve against wild type
Cardiac pathology and cataract development were delayed,
oxidative damage was reduced, and the development of
mitchondrial deletions was reduced.
The results support the free radical theory of ageing and the
importance of the mitochondria as a source of these radicals.
Telomeres and Ageing
What are telomeres?
Telomeres are repetitive DNA sequences and specific associated
proteins at the ends of chromosomes.
They have three major roles:
1. They serve a capping function to protect DNA ends from fusing
and from being processed in the same way as broken DNA
2. They attach chromosomes to the nuclear envelope during
3. They preserve chromosome integrity by ensuring complete
replication of chromosome ends without loss of
Human telomeres are composed of a repetitive hexameric
sequence [TTAGGG]n about 10-15,000 bp in length.
The bulk of telomeric DNA is double-stranded [TTAGGG/
CCCTAA]n, but the end consists of a 3’ overhang of single-
stranded repeats [TTAGGG]n.
What happens to telomeres during division?
Telomeres shorten by about 50-150 base pairs at each division
because conventional DNA polymerases cannot replicate the ends of
This end replication problem occurs on the lagging strand during
DNA synthesis, leaving a gap between the final priming event and
the end of the chromosome.
How is the end replication problem overcome?
Germ cells (along with certain immortal cells e.g. cancer cells)
have an enzyme, telomerase, which repairs shortened telomeres.
In humans, telomerase is a complex of proteins including a cellular
reverse transcriptase (hTERT) and an RNA (hTR), which acts as a
template for catalyzing DNA addition at the telomere.
Extending the Telomere
1. The RNA (hTR) binds to the 3’ overhang of the telomeric
DNA to generate a base-paired primer for reverse
transcriptase (hTERT) activity.
2. A new telomeric sequence is synthesized in the 5’→3’ direction.
3. This elongation is followed by a translocation event that
repositions the RNA template so that the process can be
4. The gap in the lagging strand is then filled in using DNA
Telomeres and Cell Senescence
In the absence of telomerase to offset telomere shortening, cells
proliferate for a certain number of divisions and then senesce.
Somatic cells (but not germ cells and many tumour cells) lack
telomerase, and thus telomere shortening could be a “clock”
that eventually stops somatic cell division.
1. There is no correlation between telomere length and the
lifespan of an animal (e.g. humans have shorter telomeres than
2. There is no correlation between telomere length and a person’s
3. Telomeres do not shorten in post-mitotic tissue, but the cells
undergo senescent changes.
Nonetheless, mice engineered to have longer telomeres can live
However, to live longer these mice must be genetically
modified to resist cancer.
(A Tomas-Loba et al. (2008): Cell 135: 609-622)
How do Telomeres Signal to the Cell?
In normal cells the telomere signal is transduced via the p53
tumour suppressor protein, which is activated by acetylation.
This activates p21CIP1/WAF1, a cyclin-dependent kinase inhibitor
that shuts down the cell cycle and leads to senescence.
Cells with inactive p53
become immortal and
can progress to a
cancerous state. The Breakage-Fusion-Bridge
cycle generates genome
Replicative (or Cellular) Senescence is a
Block to Tumour Formation
Fibroblasts in culture undergo a limited
number of cell divisions depending on
the species and the age of the donor.
This is known as the Hayflick Limit or
Mortality Stage M1.
Len Hayflick 1988
Cells from a human fetus go through ~60 doublings, whereas those
from an 80 year old go through ~30 (replicative senescence).
Cells from an adult mouse go through about 12-15 doublings.
The Hayflick Limit (M1)
The Hayflick limit (or Mortality Stage 1), in which cells stop
dividing and become senescent, is triggered by a variety of
i. loss of telomeres
ii. DNA damage and activation of DNA damage response (DDR)
iii. de-repression of cyclin dependent kinase inhibitor (CDKN2a)
Senescence is executed by pathways involving the tumour
suppressor proteins retinoblastoma (RB) and p53.
Disruption of this tumour surveillance pathway predisposes to
Thus tumour suppression is at the expense of senescence
Cells can pass through the Hayflick Limit (M1).
Inactivation of the tumour suppressors p53 and RB by viral
oncoproteins such as:
• human papillomavirus type 16 E6 (inactivates p53) and E7
• SV40 Large T antigen (inactivates both)
allows cells to pass through the Hayflick Limit (M1).
This leads to an extended life span until critically shortened
telomeres signal crisis or Mortality Stage M2.
Genetic instability is a hallmark of crisis, highlighted by
chromosomal fusions and aneuploidy.
Secondary genetic change leads to death or immortalisation.
For cells to become immortal (tumour cells) they must:
1. Overcome the M1 block (generally by inactivating tumour
They then continue telomere erosion and acquire additional
mutations in the life span phase.
2. Bypass M2 (generally by reactivating endogenous telomerase).
Expression of hTERT (human telomerase reverse transcriptase)
halts telomere shortening and immortalises human fibroblasts
(Bodnar et al., 1998 Science 278: 349-352).
Note that hTR (human telomerase RNA) is ubiquitously
expressed in normal cells.
Immortalization always requires the reactivation of telomerase to
preserve genomic stability by maintaining chromosome ends.
The progerias are characterised by the early onset of complex
Werner Syndrome (WS) is an autosomal recessive disease of genomic
instability characterised by premature onset of age-related diseases,
including greying of hair and hair-loss, atherosclerosis, osteoporosis,
type II diabetes mellitus, cataracts and cancer (Shen and Loeb, 2000
Trends in Genetics 16: 213-220) .
Average age at diagnosis is late-
thirties (i.e. adult onset) and the mean
age of death is 47 (mostly due to
cancer or atherosclerosis).
Affected individuals develop
normally initially, but lack the
pubertal growth spurt. They usually
do not develop Alzheimer-type
Hutchinson-Gilford Progeria Syndrome (HGPS) is a very rare (1
in 4 million) premature ageing disorder.
(Eriksson et al., 2003 Nature 423: 293-298).
• growth retardation
• loss of hair
• receding mandible
• protruding ears
• prominent eyes
• absence of subcutaneous fat
• parchment-like skin Ashley
• skeletal abnormalities
• aged appearance. Photo links via
Show no significant neurodegeneration or cancer predisposition.
Life expectancy of HGPS individuals is short
(c. 13 years i.e. childhood onset).
Death almost invariably from atherosclerosis. Photo links via
Majority of HGPS cases due to a de novo mutation in the lamin A
Lamins (type V intermediate filament proteins) are the main
structural components of the nuclear lamina (Goldman et al., 2002
Genes Dev 16: 533-547).
They exist as A and B types and are required for:
• nuclear shape, mechanical stability, assembly and positioning
• chromatin organization
• transcription regulation
• DNA replication
LMNA gene (12 exons) encoding lamin A and lamin C proteins.
C-terminus of pre-lamin A bears a CaaX motif (C is cysteine, a is
any aliphatic (non-polar, hydrophobic) aa, and X is any aa).
The cysteine is the site of post-translational farnesylation allowing it
to be included into the nuclear membrane.
The C-terminal region is then removed by proteolysis, yielding the
mature form of lamin A.
The shorter C-terminus of
lamin C does not undergo
farnesylation (no CaaX
box), and its nuclear
membrane integration is
association with lamin A.
Exons affected in the “laminopathies” including dilated
cardiomyopathy, limb-girdle muscular dystrophy 1B, familial
Dunnigan-type partial lipodystrophy, Emery–Dreifuss muscular
dystrophy and Charcot–Marie–Tooth disorder type 2 are shown
(Gotzmann et al., 2006 Histochem Cell Biol 125: 33-41).
In HGPS, a mutation in exon 11 creates a novel splice donor site
yielding progerin (LAΔ50), which lacks 50 aa near the C
terminus (Eriksson et al., 2003 Nature 423: 293-298).
This results in the loss of the proteolytic site so that progerin is
Predicted to yield
membrane complex that
alters nuclear structure
Prelamin A and C
knockout mice show no
symptoms. It is misplaced
prelamin A, rather than
the loss of the function of
lamin A, that causes the
disease. Aberrant nuclear shape in HGPS
Farnesyl transferase inhibitors (FTIs) inhibit farnesylation and
may be useful in the treatment of HGPS, since they could
inhibit the permanent farnesylation of progerin.
Commercially available FTI
The nuclear shape of cells expressing progerin returns to
normal following FTI treatment (Glynn and Glover 2005 Hum
Molec Genet 14: 2959-2969).
But what do the progerias tell us about “normal” ageing?
Disorganised Development as a Clue to Ageing
(Walker et al. 2009 Mech Age Develop 130: 350-356)
At 15 years Brooke Greenberg (b 8
January 1993) weighed about 7.3
kg and was 72 cm tall.
She has not developed significantly
(physically or cognitively) since
measurements (height age)
equate to that of an 11 month old.
MOD 130: 352 (2009)
Human growth hormone
replacement proved ineffective. Brooke Greenberg (15 )
Brooke’s body is not developing as a coordinated unit.
Although a teenager, her brain is no more mature than that of a
newborn, she still has her deciduous teeth (est age 8 years), while
her bones are equivalent to that of a 10 year old (although short).
Short telomere length and telomerase inactivity suggest a cellular
age at least comparable to her chronological age (and possibly
She has no known genetic syndrome or chromosomal abnormality
to explain her condition.
Walker and colleagues propose that Brooke carries a
mutation in a putative central regulator of development that
may also orchestrate ageing (Bidder 1932 Brit Med J 2:
They argue that ageing results from the continued expression
of the developmental program after maturity.
Indeterminate survival requires organismal stability not change.
The continued (post-reproductive) expression of previously
adaptive genes for change (when selection pressure is lost) would
eventually become maladaptive.