The Dutch famine birth cohort study: consequences of a
suboptimal start in life

The Dutch population, as most of the populations worldwide, is *greying*: the
proportion of people aged over 60 years is growing faster than any other age
group. At the individual level, there is increased ageing across diverse body
systems. Alzheimer*s disease, cardiovascular disease, metabolic disorders and
osteoporosis are just a few examples of many age-related conditions where the
prevalences are expected to rise even further in the coming decades. This not
only puts a major burden on our social and health care systems, it also greatly
affects the independence and quality of life of older people, their families
and caregivers.

Although ageing is an inevitable biological process, the health with which old
age is reached can be optimised. Healthy lifestyles are known to increase life
expectancy. An important lifestyle factor influencing the ageing process is
nutrition. Dietary restriction is one of the most extensively studied ways to
elongate lifespan. However, when diet is restricted in early life, the effects
seem to be reversed completely. Early life malnutrition may even be more
important for the ageing process than later life over nutrition. This was
elegantly shown by studies in which mice received either a normal or a 20%
protein restricted diet during gestation and/ or lactation followed by either a
normal or a high fat cafeteria diet (1). A normal diet during the whole period
resulted in a lifespan of on average 765 days, a postnatal cafeteria diet
resulted in a lifespan of 715 days, while a prenatally restricted diet resulted
in a lifespan of 568 days which was even lowered to 517 days when combined with
a postnatal cafeteria diet. Evidence for an effect of suboptimal nutritional
circumstance in utero on the ageing process in humans does not exist.

Previous studies in the Dutch famine birth cohort suggest that prenatal
exposure to undernutrition may lead to accelerated ageing. We have shown that
exposure to famine during early gestation is associated with age-related
disorders including a more atherogenic lipid profile, decreased glucose
tolerance and a doubled prevalence of coronary artery disease (CAD) (2).
However, of particular interest for the proposed study is our finding that
people conceived during the famine were on average 3 years younger at the time
of CAD diagnosis (3). Another indication that prenatal famine exposure may lead
to accelerated ageing is our finding that those exposed to famine in early
gestation performed worse on a selective attention task, a cognitive ability
that usually declines with age (4). Results of- as yet unpublished- analyses in
the cohort also seem to suggest a shorter lifespan: analyses on mortality up to
the age of 63 years show that women conceived during the famine have an
increased risk of all cause mortality, cancer related mortality and
cardiovascular related mortality (van Abeelen et al., under revision). Other
evidence that prenatal undernutrition may lead to accelerated ageing mainly
comes from animal experiments. A restriction of the pre or perinatal diet in
rats and mice has been shown to lead to several age-related changes and a
decreased lifespan (1;5-11). There is also some indirect evidence based on
studies investigating surrogate indirect measures for a suboptimal nutritional
early environment. Low birth weight and low weight at one year of age have been
associated with markers of ageing in a number of different body systems,
including the eye, ear, muscle and bone (12;13). We propose to use the unique
opportunity provided by the Dutch famine birth cohort to investigate whether
the ageing process is affected by a suboptimal early environment and how this
may come about.

With the proposed study we intend to investigate in humans whether the ageing
process is affected by nutritional environmental factors operating in the very
earliest stages of life. We will use the Dutch famine birth cohort to study the
effects of prenatal exposure to undernutrition on ageing across body systems,
mortality and on possible underlying mechanisms. Based on animal experiments
and on the previous findings in the Dutch famine birth cohort, we expect to
find increased markers of ageing in the group of people who experienced a
suboptimal environment in prenatal life. Those who have been exposed to famine
during gestation will show more cognitive decline, decreased vascular function,
increased incidence of fracture, decreased grip strength and physical
performance, and decreased vision, hearing and physical performance.
Furthermore, those exposed to undernutrition in utero will show increased
mortality up to the age of 67 years. In studying underlying mechanisms, we
expect to find that those exposed to famine during gestation will have
increased cerebrovacular tone, a decreased telomere length, increased oxidative
stress and increased basal inflammation.

The proposed study will be the first to establish in humans whether ageing
across systems is affected by prenatal undernutrition and what the underlying
biological ageing processes may be. These findings will shed light on the
pathophysiology of the ageing process. Furthermore, the findings may also be of
importance from a future public health point of view. Data of the proposed
study may provide evidence that suboptimal circumstances during early life can
affect the ageing process. Although severe malnutrition such as the shortages
that occurred during the famine are uncommon in the Western world today, still
many babies have a suboptimal nutritional start in life due to factors such as
dieting of the mother (1 in 4 women of reproductive age diet at any given
moment in time) and complication of the pregnancy by placental insufficiency.
Also, worrying data from the UK suggest that only 3% of the women who get
pregnant abide with the healthy diet guideline of less than 7 units of alcohol
a week and taking enough folic acid, let alone taking fruits and vegetables
daily (14). Placed in a broader perspective, a poor start in life may also be
experienced by those whose mothers suffer from pre-eclampsia or hyperemesis
gravidarum, those who are born pre-term and possibly those who are conceived by
in vitro fertilization. There is potentially a lot to be gained by improving
the prenatal environment.

Primary Objective: To assess whether ageing across body systems is accelerated
by sub-optimal early life circumstances.

Secondary Objective: To asses underlying mechanisms of the potential
association between sub-optimal early life circumstances and ageing.

We hypothesize that a suboptimal start in life as quantified by prenatal
exposure to the Dutch famine is associated with accelerated ageing across body
systems including the brain, the vascular system, bone, muscle, the eye and the
ear. Increased cerebrovascular tone, cellular ageing, oxidative stress and
basal inflammation are biological mechanisms underlying these associations.

We will investigate this research question in the Dutch famine birth cohort.
Ageing markers as well as possible underlying mechanisms will be compared
between cohort members who have been exposed to famine during early, mid or
late gestation and cohort members who have not been exposed to the famine
during pregnancy.

Cohort study

all measurements are minimally invasive and safe. Participation in the study
will not be of benefit nor be of harm to participants