The future of the Whitehall II study
1. How do we separate risk and bias in
the epidemiology of ageing?
2. Can we reverse the ageing process?
3. Well-being in old age
Maximising the use of Whitehall II data to advance scientific knowledge
High-power research
consortia
High-throughput
discovery substudies
1985-88
N = 10,308
1991-94
N =1997-99
8,815
N = 7,870
IPD-Work
Psychosocial
Atheroscler
osis cIMT
2002-04
N = 2007-09
6,967
N =2012-13
6,761
UCLEB genetics
N = 6,318
2015-16
In progress
2019-20
METABOCHIP
Emerging
Risk Factor
Collaboration
LIFEPATH
(immunity)
Scan
Brain
MRI
Heart
Scan
Planned
2023
Planned
2027
Planned
GIANT
EULIFEPATH
Sharing of anonymised data to high-quality bona fide research
-
Data
sharing
policy
-
Europe
USA
Japan
Australia
1. How do we separate risk and bias in
the aetiology of ageing
Randomised controlled trials represent the gold standard, but most trials
offer only a relatively short period of surveillance
The results based on ‘Big Data’ (e.g., electronic medical records) are
precise, although not necessarily free of bias.
Highly phenotyped cohort studies with long follow-ups, such Whitehall II,
have a crucial role to obtain reliable evidence on disease
•
Antidepressants a risk factor for type 2 diabetes?
•
Healthy obesity a harmless condition?
•
Obesity and hypertension protecting against dementia?
Nested case-­‐control study: Selection of cases and controls UK GPRD
Andersohn et al. Am J Psychiatry 2009
The General Practice Research Database, UK
Rate ratio for incident diabetes
2
1.75
1.5
1.25
1
Nonuse
<12 m
12-24 m
Exposure to antidepressants
Andersohn et al. Am J Psychiatry 2009
>24 m
Antidepressants taken by hundreds
of thousands of people may
increase the chances of developing
diabetes, researchers warn
Diabetes
Prediabetes
Diabetes
Prediabetes
Tabak et al. Lancet 2009
Antidepressant use and risk diabetes in cohort studies with serial phenotyping
10
Risk ratio for incident diabetes
Diagnosed diabetes
2.34
Undiagnosed diabetes
2.13
1
0.91
0.88
Nonuse
Antidepressant use
0.1
Whitehall II
NHANES
Whitehall II
NHANES
Kivimaki et al. Biol Psychiatry 2011 Mezuk et al. Health Psychol 2013
Cu
1
The Whitehall II study, UK D.E.S.I.R, France (N = 5978) (N = 4700)
9 year change
Time (15 years)
Kivimäki et al. Biol Psychiatry 2011 Da Silva et al. Int J Epidemiol 2015 The Natural Course of “Metabolically Healthy Obesity”
The clinical value of “healthy obesity” rests on the
assumption that it is a stable physiological state.
Metabolic health refers to the absence of
•
•
•
•
•
hypertension
low HDL-cholesterol
high triglycerides
insulin resistance
high glucose
The Natural Course of “Metabolically Healthy Obesity”
60
Becoming unhealthy obese, %
Healthy normal weight
Healthy obese
45
30
15
0
0
5
10
Follow-up period, years
Bell et al. JACC 2015
15
Whitehall II shows “healthy obesity” is a transient
phase of obesity-associated metabolic deterioration
Age- and sex-standardised rates of dementia per 1000
person-years by body mass index in 1.9 million UK adults
Electronic medical records
Underweight
Normal Overweight Obese
Qizilbash et al. Lancet DE 2015
NEWS
Being overweight 'can cut risk of dementia’
10 April 2015 Last updated at 16:20 BST
Being overweight cuts the risk of dementia, according to the
largest and most precise investigation into the relationship.
The researchers admit they were surprised by the findings, which
run contrary to current health advice.
The analysis of nearly two million British people, in the Lancet
Diabetes & Endocrinology, showed underweight people had the
highest risk.
17,008 individuals with AD
37,154 cognitively normal controls
2. Can we reverse the ageing process?
The shared aetiology of common agerelated diseases
•
For several adult-onset diseases, age is the
strongest risk factor
•
Blood - a circulating global regulator
(plausible plus open to therapeutics)?
Oeppen et al. Science 2002
•
Animal models suggest there may be blood-related modulators of ageing
(loss of homeostasis; defective repair after injury; dysfunctions affecting
multiple distinct tissues semisynchronously)
•
Repeat clinical examinations will enable testing blood-based ageing in
humans
Heterochronic parabiosis reverses age-related cardiac
hypertrophy
Loffredo et al. Cell 2013
Parabiosis: a class of techniques in which two
living organisms are joined together surgically and
develop single, shared physiological systems, such
as a shared circulatory system
Growth differentiation factor 11
The heart weight-to-tibia length ratio was significantly lower in old mice exposed to a young circulation (O-HP) compared to
old mice exposed to an old circulation (O-IP) for 4 weeks and to old unpaired mice (O). No significant difference was
observed when comparing old isochronic to old unpaired mice or when comparing any of the young groups.
Heterochronic parabiosis enhances neurogenesis and
cognitive functions in the ageing mouse
Quantification of neurogenesis in the olfactory bulbs of old (B) and young (C) parabionts. (n=4, *p<0.05). (D) Measurement of
the exploratory time during the olfactory sensitivity assay (n=3). Data shown as mean±S.E.M
Katsimpardi et al. Science 2014
Improved kinetics of healing of dorsal wounds in diabetic
(db) mice exposed to a wild-type (wt) systemic milieu
(a) Open wound area decreased over time in all animals; however, wound healing in db control pairs (db-control) was
generally slower than in wt pairs (wt-control). On day 7, db animals joined to wt partners exhibited significantly increased
wound closure when compared with db-controls (n=12 per group). Results are shown as meanSD, *=P<0.05 for db
chimera compared with db control group. (b) Granulation tissue area increased 3.9-fold under chimeric parabiotic
conditions in db animals (db-chimera) compared with db controls (db-controls, n=6 per group). * P<0.05 for comparison
indicated.
Pietramaggiori et al. JID 2009
Blood parameters from age 35 into old age
1985-88
N = 10,308
35-55
1991-94
N = 8,815
1997-99
N = 7,870
2002-04
N = 6,967
Blood samples
-
Standard blood parameters
-
Immune markers
-
200 metabolites covering amino acid
metabolism, gluconeogenesis,
ketogenesis, kidney and liver metabolism,
and detailed lipid and lipoprotein
metabolism
Follow-up of age-related morbidity and
functional impairment
2007-09
N = 6,761
2012-13
N = 6,318
2015-16
In progress
2019-20
Planned
2023
Planned
2027
Planned
77-97
3. Well-being in old age
Study of social and psychological resources from across the life
course that contribute to well-being at older ages.
Midlife and old-age determinants of functional abilities that are
essential if older people are to continue to do things they value
and enjoy, despite disease or reduced longevity.
Identify age-friendly environments that provide older people with
opportunities for personal growth and to make contributions to
their communities while retaining autonomy