The effect of a combined caloric restriction and exercise intervention on phenotypic profiles of offspring of families with exceptional longevity and their partners

In animals caloric restriction (CR) is the most effective intervention known to
extend lifespan and to delay the onset or reduce the incidence of many
age-related diseases. A similar effect is seen in multiple nutrient signaling
pathways that have been connected to CR and longevity regulation, implying that
aging is a regulated process and that certain genes govern the rate of aging.
This has been shown in a variety of species including mammals and is also an
interesting observation from the perspective of human aging. However, the
evidence on the effectiveness of caloric restriction on biomarkers of healthy
aging in humans is limited and lacking in middle-aged individuals. It can also
be questioned in the genetic heterogeneous human population, whether dietary
restriction improves the metabolism of all individuals. In the Leiden Longevity
Study we have two groups of individuals to compare in this sense: a healthy
ageing group (members of long-lived families) that display a beneficial profile
of many metabolic markers and a normative ageing group (the partners of these
members) with an average metabolic profile. The longevity families were
included by selecting for living nonagenarian sibships (sibpairs or larger
sibships) and recruiting these individuals, their offspring and the partners of
that offspring (The Leiden Longevity Study). The existing contrast of healthy
and normative ageing, the fact that we have numerous metabolic baseline
phenotypes of these study participants and the fact that they are middle aged
(the group of individuals that are likely to improve life expectancy by healthy
behavior) prompted us to initiate a study into the health effects of dietary
restriction and physical exercise specifically in these contrasting groups of
middle aged individuals.

The main objective of this study is to examine whether an intervention of
dietary restriction and exercise can bring the phenotypic profiles (with
respect to biomarkers of metabolic health) of the normative ageing controls
(*partners*) towards those of their healthy aging spouses (*offspring* of
families with exceptional longevity). We also examine if such an intervention
could still improve the phenotypic profile of the offspring and which
(clinical, biochemical, molecular) baseline mediators determine response to
treatment. Additional objectives are to assess compliance (and its
determinants) to the intervention, to determine implementation possibilities to
stimulate healthy aging in middle-aged couples and to assess if possible health
benefits last by reassessing the biomarkers of metabolic health 1 year after
the intervention (for this aim budget still has to be raised).

Intervention study.

3 months (13 weeks) intervention with 25% lowered energy expenditure by 12.5%
caloric restriction and a 12.5% increase in physical activity.

Main study:
Eligible participants will first undergo a screening to determine fulfilment to
in- and exclusion criteria. Prior to the baseline measurements habitual dietary
intake (online FFQ) and habitual physical activity (accelerometer and physical
activity questionnaire) will be assessed. In total participants will be visited
at home twice (screening and pre-baseline assessment) and visit the study
centre twice (baseline and after 13 weeks) after an overnight fast. At baseline
and after 13 weeks of intervention the following biomaterials will be
collected: blood, a fat biopsy and a muscle biopsy. Furthermore, at baseline
and after 13 weeks of intervention, anthropometrics, body composition, blood
pressure, 24-hour glucose, energy metabolism, and psychological factors will be
assessed. Home visits will take about 45 minutes and visits to the study centre
will take about 3 hours each time. Except the pre-baseline measurement, all
visits will include collection of blood samples, which may cause a small
hematoma. Furthermore, for the biopsies a small incision has to be made, which
will be done by an experienced physician and which will heal completely. All
other tests and measurements performed are non-invasive. During the 13 weeks of
intervention participants will follow a dietary regime of 12.5% caloric
restriction and 12.5% increased physical activity. To fulfil this program
participants have to adhere to previously determined individual guidelines,
will record their dietary behaviour and physical activity in a diary and will
weekly be in contact with a dietician and/or physiotherapist.

Validation study:
Eligible participants will first undergo a screening to determine fulfilment to
in- and exclusion criteria.
Participants are asked to fill out at home a questionnaire on their daily
physical activity, taking around 15 minutes. At the LUMC, participants will
fill out their age and sex on a form, and will have their weight assessed by
means of a weighing scale. After attaching the activity sensors to the
participant, a calibration of the COSMED K4b2 will be performed, as well as a
sensor synchronisation by lightly jumping up and down for 20 seconds, and a
step test in which the participant steps up and down a small step 20 times at a
self-selected pace.
Subsequently, participants are to perform a series of daily-life activities:
sitting, standing, lying down, performing household chores, walking and
cycling. Activities will be performed both inside and outside of the LUMC. The
DirectLife Activity monitor, Activ8, Polar Electro, experimental Philips
activity monitor and GENEActiv are small and lightweight, and only burden
participants minimally. The Equivital belt and COSMED K4b2 do not hinder
participants* freedom of movement. The COSMED K4b2 is lightweight (<1kg) and
the participant can remove its facemask at any time during the trial. All
activities, both indoors as well as outdoors, are monitored and supervised at
all times by a researcher. The entire trial at and around the LUMC will take
approximately two hours.