Ageing and Age-related Diseases

Juan Ponce de Léon searches for the legendary Fountain of Youth in Florida (1513).

(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 of fitness).

At a certain threshold the survival capacity of the organism is compromised.

Accumulated random damage causes a reduction in the efficiency of the overall function of an organism resulting in death.

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.

Lifespan (the maximum number of years an individual can live) appears to be species-specific (Helfand and Rogina, 2003 BioEsssays 25: 134-141).

Species-specific Lifespan Gompertz’s Law implies that as an individual gets older the chances of dying in the next time interval increase.

Thus an age will be reached after which it would be unlikely to find any more surviving individuals.

Species Age (y) Aldabra tortoise 170 Lake sturgeon 152 Rockfish 140 Halibut 90 Asian elephant 80 African gray parrot 73 Wood turtle 60 American white pelican 54 Red-breasted parrot 33.4 Little brown bat 30 Pacific ocean perch 26 Eastern gray squirrel 23.5 House canary 22 American crow 14.6 American robin 12.8 Sockeye salmon 8 White-winged crossbill 4 Laxmann’s shrew 2 Highland desert mouse 0.8 Pygmy goby fish 0.17

The great diversity in lifespan suggests longevity may be easily evolvable.

The maximum lifespan of the human species is about 122 years, the age at death of Jeanne Calment.

Life Expectancy Life expectancy (the length of time an individual can expect to live) is characteristic of specific populations.

Life Expectancy in New Zealand

Males Females

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: England/Wales, Sweden

Life expectancy, however, has almost doubled in the last century.

Largely due to efficacious treatment of infectious diseases. 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 2.  Cancer 3.  Stroke and cerebrovascular disease 4.  Chronic lower respiratory disease e.g. bronchitis, emphysema and asthma 5.  Accidents 6.  Diabetes 7.  Flu and pneumonia 8.  Alzheimer's disease 9.  Kidney disease 10.  Blood disease 11.  Suicide 12.  Chronic liver disease and cirrhosis 13.  High blood pressure and hypertensive kidney disease 14.  Parkinson's disease 15.  Choking on solids and liquids

2. Error theories emphasize that ageing is an outcome of the random accumulation of somatic damage, owing to limited investment in maintenance and repair.

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.

Mechanisms of Ageing Two major theories:

However, there is little evidence that ageing is a significant cause of death in natural populations and genes for ageing are not selected for.

Longevity (the distribution of lifespans within a population) is thus regulated by genes controlling activities such as DNA repair and antioxidant defence.

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 programme.

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.

Although many genes alter lifespan, none abolishes ageing.

These genes can be considered as “longevity genes”, the opposite of “ageing genes”.

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).

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 can Ageing be Reconciled with Evolutionary Theory? There are three theories of ageing based on evolutionary concepts:

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.”

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.

Sir Peter Medawar

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)

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.

George C Williams

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.

Pleiotropic genes (genes with multiple effects) trade benefit at an early age against harm at older ages (“life-history trade-off”).

Ageing is the result of investing resources in reproduction, rather than maintenance of the body.

Tom Kirkwood

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.

3. Disposable Soma Theory. (Kirkwood and Austad, 2000 Nature 408: 233-238).

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 mitochondria).

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 species (ROS).

AGE-1: PI3 kinase catalytic subunit PDK-1: phosphoinositide dependent kinase 1 (phosphorylates AKT) AKT: S/T kinase (phosphorylates and inhibits DAF-16)

Ligands (e.g. the insulin-like DAF-28) bind to the DAF-2 insulin/IGF-1 receptor and activate PI-3 (phosphatidyl inositol) kinase (AGE-1).

Adults in this state mature reproductively and are not long-lived.

PI-3 kinase signals via a cascade to phosphorylate the forkhead transcription factor DAF-16 (FOXO) by the AKT protein kinase.

Insulin/IGF-1 Binds to DAF-2 and negatively regulates DAF-16 (FOXO)

Phosphorylated DAF-16 is then sequestered in the cytoplasm (inhibited).

(PI-3)

Phosphorylated DAF-16 is inactive

Mutations in the receptor daf-2 or the presence of the antagonist INS-1 yield dephosphorylated DAF-16.

This enters the nucleus, promotes transcription (multiple targets) and induces long life.

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.

Catalase Mn-SOD

Mutations in daf-16 reduce the increased life span of daf-2 mutants to wild type (i.e. daf-2 effects are daf-16 dependent).

Non-phosphorylated DAF-16 is active

Some genes downregulated under daf-2- conditions (longevity) Vitellogenin (170 kDa yolk protein) Ins-7 Insulin-like protein (agonist for DAF-2 receptor)

Some genes upregulated under daf-2- conditions (longevity) Daf-16 Peroxisomal Cytochrome P450 family Hsp-16 family Metallothionein-related cadmium-binding protein Aquaporin AQP Cytosolic catalase Manganese superoxide dismutase Ins-18 Insulin-like protein (antagonizes DAF-2 receptor)

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

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 resistance.

In general:

• histone acetylation increases transcription (characteristic of euchromatin)

• histone deacetylation represses transcription (characteristic of heterochromatin).

Acetylation SIR2 is a (nicotinamide adenine dinucleotide) NAD-dependent histone deacetylase.

It acts as a transcriptional silencer by deacetylation of histones H3 and H4, thus setting up a repressive chromatin structure.

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 respiration.

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; insulin levels).

Dietary Restriction in C. elegans.

• 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.

Different modes of DR extend lifespan via different pathways.

DR elevates respiration and promotes longevity (Although decreased respiration extends lifespan under normal feeding regimens. Could this explain longevity of large mammals?).

respiration

Chronic Dietary Restriction

TOR (Target of Rapamycin) Links DR and the Insulin/IGF-1 Pathway (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 cycle progression.

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 promotes longevity.

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 factor responsiveness).

Rheb is aRas-related GTPase

Oxidative Stress

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 perfect and damage accumulates with age.

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.

Mitochondrial Ageing

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 mutation.

Cells can tolerate a high proportion of mutant mitochondrial genomes, but once a threshold is passed energy production falls dramatically.

Mutations in mt DNA can potentiate the ageing process by energy-generation defects.

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 generate ROS?

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).

When cells start dying quicker than they are replaced, ageing results.

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.

Cytosolic pro-apoptotic bcl-2 proteins (e.g. Bad) sense cellular damage or stress and relocate to the surface of the mitochondria.

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.

Mitochondria are a major site for the production of free radicals and ROS.

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 arise later.

(Schriner et al., 2005 Science 308: 1909-1911). Survival curve against wild type

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 ends.

2.  They attach chromosomes to the nuclear envelope during meiosis.

3.  They preserve chromosome integrity by ensuring complete replication of chromosome ends without loss of informational DNA.

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 linear DNA.

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.

4.  The gap in the lagging strand is then filled in using DNA polymerase.

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 repeated.

Translocation

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.

However,

1.  There is no correlation between telomere length and the lifespan of an animal (e.g. humans have shorter telomeres than mice).

2.  There is no correlation between telomere length and a person’s age.

3.  Telomeres do not shorten in post-mitotic tissue, but the cells undergo senescent changes.

Nonetheless, mice engineered to have longer telomeres can live longer.

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 (e.g. deacetylation) become immortal and can progress to a cancerous state.

Alternative lengthening of telomeres

The Breakage-Fusion-Bridge cycle generates genome instability

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.

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.

Len Hayflick 1988

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 stresses: 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 cancer.

Thus tumour suppression is at the expense of senescence (antagonistic pleiotropy).

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 (inactivates RB) or • 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 suppressors).

They then continue telomere erosion and acquire additional mutations in the life span phase.

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.

2.  Bypass M2 (generally by reactivating endogenous telomerase).

The Progerias The progerias are characterised by the early onset of complex senescent phenotypes.

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 dementia.

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) .

Symptoms include: • growth retardation • loss of hair • receding mandible • protruding ears • prominent eyes • absence of subcutaneous fat • parchment-like skin • atherosclerosis • skeletal abnormalities • aged appearance.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a very rare (1 in 4 million) premature ageing disorder. (Eriksson et al., 2003 Nature 423: 293-298).

Ashley

Hayley Photo links via www.progeriaresearch.org

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.

Majority of HGPS cases due to a de novo mutation in the lamin A gene (LMNA).

Photo links via www.progeriaresearch.org

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).

Farnesol

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.

Pre-laminA

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).

The shorter C-terminus of lamin C does not undergo farnesylation (no CaaX box), and its nuclear membrane integration is dependent upon association with lamin A.

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 permanently farnesylated.

Predicted to yield mislocalized nuclear membrane complex that alters nuclear structure and function.

Aberrant nuclear shape in HGPS

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.

Farnesyl transferase inhibitors (FTIs) inhibit farnesylation and may be useful in the treatment of HGPS, since they could inhibit the permanent farnesylation of progerin.

The nuclear shape of cells expressing progerin returns to normal following FTI treatment (Glynn and Glover 2005 Hum Molec Genet 14: 2959-2969).

Commercially available FTI

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 early infancy.

Brooke Greenberg (15 ) MOD 130: 352 (2009)

Her anthropometric measurements (height age) equate to that of an 11 month old.

Human growth hormone replacement proved ineffective.

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 enhanced). 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: 583-585).

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.