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Ageing: Biological Events

Tom Kirkwood
Newcastle University Institute for Ageing
The Continuing Increase in Life Expectancy

UN estimate 2000

UN estimate 1990

UN estimate 1980

Oeppen & Vaupel Science 2002

Declining early/mid-life mortality Declining later-life mortality


Age and Sex Specific Mortality Rates for Humans
What Is Normal Ageing?

Why is the Aged Cell (or Organ)


More Vulnerable to Pathology?
Ageing or Disease?

Osteoporosis

Osteoarthritis

Dementia
What Drives Intrinsic Ageing?

Is intrinsic ageing programmed?

When does intrinsic ageing begin?

Is intrinsic ageing amenable to change?


Survival Under Wild or Protected Conditions

Protected
Survival

Wild

Age
Selection Weakens With Age

Selection
shadow
Survival

Age
DISPOSABLE SOMA THEORY

Protected
Survival

Period of longevity assured by


maintenance and repair

Wild

Age

Kirkwood Nature 1977


Ageing – Historically a Rarity, Now Routine

1900

20 40 60 80 Age

2000

Differences in survival using death rates from


Registrar-General of England & Wales for
1900 (blue) and 2000 (pink)
Implications of the Evolutionary Theories of Ageing

There is no genetic program for ageing. We age


because in our evolutionary past it would have been
too expensive to build a body that might last for ever.

 Aging is caused primarily by damage.


 Longevity is regulated by resistance/repair.

 Multiple mechanisms.
 Inherently stochastic (influenced by chance).
The Ageing Process
Functional Impairments in Organs and Tissues leading to
Age-related Frailty, Disability, and Disease

Accumulation of Cellular
Defects

Random Molecular Damage


Damage Accumulates From Day One
Each cell division is accompanied by
inevitable somatic mutation

SAM

Age-Related Increase in
Frequency of Hprt
WT
Mutations in Mice
Odagiri et al Nat Genet 1998
Oxygen as a Potent Source of
Molecular Damage
 Reactive oxygen species (‘free radicals’) are
formed as by-products of energy generation
within the mitochondria.

 Free radicals damage multiple targets within


the cell, including the DNA within the cell
nucleus and mitochondria.

 Mutant mitochondria impair the cell’s ability to


make the energy it needs in order to function.
Mitochondrial Mutations in Ageing Tissue

Taylor et al J Clin Invest 2003


Greaves et al Aging Cell 2011
Abnormal Protein Aggregation in Aging Brain
Telomere Erosion, Stress and Health

•Telomeres protect chromosome ends – they shorten with


cell division and this is accelerated by biochemical stress.
• Prematurely short telomeres are linked with increased risk
of age-related disease and diminished survival.
•People suffering severe chronic stress (eg carers of those
with dementia and other conditions) have shorter telomeres.
Senescent Cell (human fibroblast)

●DNA damage foci


●Telomeres
●Overlap of damage foci
with telomeres
●Mitochondria with high
membrane potential
●Mitochondria with low
membrane potential
Ageing and Age-Related Disease
Accumulation of Molecular and Cellular Damage

Disease B

Intrinsic Ageing

End-Stage Pathology
Initiating Processes

Disease A

Disease C

Likely Effectiveness of Interventions


Risk Factors for Age-Related Diseases
Alzheimer’s Disease Heart Disease Cancer
600 100 100

500
Percent Increase

80 80

Percent Increase

Percent Increase
400
60 60
300

40 40
200

100 20 20

0
0 0
x s c t E g
Se e n Hypertension Smoking Cholesterol Diabetes
b et Ina Apo o ki Tobacco Alcohol Diet Infection

D
ia ys Sm
Ph

Alzheimer’s Disease Heart Disease Cancer


100000 6000

80000 6000 5000


Percent Increase

Percent Increase

Percent Increase
4000
60000
4000
3000
40000
2000
2000
20000
1000

0 0 0
Hypertension Smoking Cholesterol Diabetes Aging
x

oE
t

g
g
s

Tobacco Alcohol Diet Infection Aging


ac
Se

te

in
in
Ap

Ag
be

In

ok
Sm
ia

ys
D

Ph
What Accounts for the
Individuality of Human Ageing?
Heritability of Human Longevity

Twin Studies Coefficient of heritability


McGue et al (1993) 0.22
Herskind et al (1996) 0.25
Ljungquist et al (1998) <0.33

►Genes account for about 25% of what determines


human longevity
Factors Influencing Longevity and Health Span

 Genes
 Nutrition
Nutrition and Survival: The EPIC-Ageing Study

76,707 men and women aged 60+


Followed for 7.5 years
Adherence to Mediterranean diet
assessed on 10-point scale:
0 (poor)…9 (high)

2 unit increase in ‘Mediterranean-


ness’ of diet results in 8%
reduction of overall mortality

Trichopoulou A et al. (2005) BMJ 330, 991-997


Factors Influencing Longevity and Health Span

 Genes
 Nutrition
 Socioeconomic status
A few minutes on the Newcastle metro
(or the Tube) can take years off your life
Ponteland South

66.1 68.0
74.8 71.5

70.1

63.8
Age of expected onset of limiting long-term condition for 55 yr old person

Courtesy Prof Peter Gore/Prof Carol Jagger/ONS


Factors Influencing Longevity and Health Span

 Genes
 Nutrition
 Socioeconomic status
 Lifestyle
Sitting on a
bus is bad for
you too!

Morris JN, et al. Lancet 265:1053–1057, 1953


P = 0.001 P = 0.005

per 10,000 person years


160

All Cause Mortality


Lower 3rd
120

80 Middle 3rd
40
Upper 3rd

<60 >60 Tertiles of


per 10,000 person years

P = 0.02 P = 0.007
muscular
Cancer Mortality

60
strength
40

20

<60 >60

8762 men
Ruiz J, et al. BMJ 19: 150-151 (2008)
Complex Factors Influence Individual Ageing Trajectories

 Genes
 Nutrition
 Lifestyle
 Environment
 Socioeconomic status
 Attitude

Newcastle 85+ Study; a prospective study in 1041


individuals all born in 1921 of the biological, clinical and
psychosocial factors associated with healthy aging.
Multi-Morbidity is the Norm

No one has perfect medical health at age 85.


Yet, 78% rated their health compared with others of the same age as “good”
(34%), “very good” (32%) or “excellent” (12%).
Collerton et al British Medical Journal 2009
Extreme Diversity in Capability/Disability at
Advanced Old Age

Distribution of Individual Disability Scores with Respect to


17 Activities of Daily Living

A quarter of men and a sixth of women have no important functional limitation


at age 85.
Collerton et al British Medical Journal 2009
AGEING PROCESS AND ITS MALLEABILITY
Kirkwood Cell 2005

Age-related Frailty, Disability, and Disease

INFLAMMATION ANTI-INFLAMM.

Accumulation of Cellular Defects

GOOD GOOD
LIFESTYLE NUTRITION

Random Molecular Damage

STRESS BAD
ENVIRONMENT NUTRITION
Beating the Biological Clock

Biological ‘Wrong’ lifestyle


Ageing •Excess calorie intake
•High saturated fats
•Low micro-nutrients
•Too little exercise
•Poor glucose tolerance
•Stress
•Smoking

‘Right’ lifestyle
•Energy balance
•Maintain glucose sensitivity
•Low saturated fats
•Rich micro-nutrient diet
•High exercise level
•Low to moderate stress

Chronological Ageing
The Traditional View of Ageing A New View of Age

 The ageing process is biologically determined (we are


programmed to die) with an inbuilt limit to lifespan
We are programmed for survival not death.
 The ageing process is one of progressive, irreversible
loss of functional capacity and of quality of life
Ageing is intrinsically malleable
 Ageing is a distinct, degenerative phase of the life
cycle
Youth and age are a continuum
 Diseases of ageing are distinct from the intrinsic
underlying processes of ‘healthy’ ageing.
Intrinsic ageing and many age-related diseases
share common underlying mechanisms.
Waking up to the 29-hour day!
• Each day we have 24 hours for
now, and 5 hours for later.

• How good will those 5 hours be


when we come to use them?

• Can we make them better?