Maintaining health in old age through homeostasis

Although life expectancy is increasing, very few people achieve healthy
longevity, making the identification of biological and homeostatic mechanisms
that regulate the rate of ageing, and therewith contribute to the onset or
prevention of age-related disease, of extreme importance. All aspects of mental
and physical health are critically dependent upon appropriate reception,
processing and integration of internal and external signals and the capacity to
mount adaptive responses. This critical Homeostatic (the ability to dynamically
adapt to environmental challenge whilst maintaining the composition of the
*milieu intérieur* within certain limits) role is played by the hypothalamus.
Thus, an understanding of the hypothalamic control of homeostasis is a key to
understanding the mechanisms that drive healthy ageing.

Switchbox will study the diffrences in hypothalamic control of homeostasis in
offspring of long-lived sibling of Leiden Longevity study, who have been shown
to age in better health compared to their partners who show *regular* aging.

The central hypothesis of Switchbox is that control of homeostasis by the
hypothalamus will be better preserved in the offspring of long-lived sibling
who age in better health compared to their partners that show *regular* ageing.
This, we hypothesize, will be reflected in differences in brain function,
neuro-endocrine output and peripheral metabolism. To achieve the central
objective, the study will be conducted in three phases (see Protocol ID
P11.116, pages 12 &13). Below are the objectives specific for phase I.

Phase I objectives:
1. To compare brain function in offspring of long-lived siblings (cases) and
their partners (controls) via brain fMRI measurements; cognition and mood as
well as assessment of sleep and feeding patterns.

2. To compare neuro-endocrine output and rhythms (hypothalamo-pituitary-adrenal
axis, hypothalamo-pituitary-thyroid axis and insulin-IGF- signalling pathway)
of offspring of long-lived siblings (cases) and their partners (controls) over
a 24h period.
3. To compare peripheral metabolism in offspring of long-lived siblings (cases)
and their partners (controls) by assessing glucose metabolism, oxygen
consumption, CO2 production and Physical activity.

Phase 1 of Switchbox is a single-blind case-control observational study. We
will include 60 couples, consisting of an offspring of long-lived siblings
(case) and his/her current partner (control). The couples shall be divided into
2 groups: A and B.

For subjects in group A (20 couples), we will measure brain function (BF,),
neuro-endocrine output (NEo), and peripheral metabolism (PM) over 10 study days
In group B (40 couples), we will measure brain function and peripheral
metabolism over 8 study days. The study will be carried out at the research
center of Leiden University Medical Center (LUMC). {See protocol ID11.116,
pages 13-16}

The total study will be carried out in 60 couples, which will be divided into
two groups (groups A and B).
Group A (20 couples) will undergo the full spectrum of tests to elicit the main
study parameters in10 days, encompassing two and half intensive study days (2
nights at the hotel and 24 hour admittance to the hospital).
* Day 1 (morning only): fMRI (resting state, after stress (TSST) using 3T),
measurement of cognition and insertion of a continuous glucose monitor (CGM).
* Day 2: 24 hour hormone sampling (maximum of 432 ml blood over 24 hours in 10
minutes intervals).
* Day 3 (morning only): Indirect calorimery using a ventilated hood (fasted and
after ingestion of glucose).
The ensuing 7 days (non- intensive phase) involve keeping a simple 7-day sleep,
food and activity diary, accelerometry, and removal and return (by post) of the
CGM on study day 5.
Group B (40 couples) will undergo a selection of tests in 8 days, encompassing
fMRI testing, CGM, accelerometry and diaries, but not 24 hour hormone sampling
or calorimetry. They will come to the study centre once (day 1), without having
to stay overnight.
* Day 1: fMRI (resting state, after stress (Triers social stress test) using
3T), measurement of cognition and insertion of a continuous glucose monitor
(CGM).
The ensuing 7 days (non- intensive phase) involve keeping a simple 7-day sleep,
food and activity diary, accelerometry, and removal and return (by post) of the
CGM on study day 5.
The fMRI, CGM, accelerometry and indirect calorimetry are procedures that are
minimally invasive. 24-hour blood sampling, though invasive, does not exceed
the amount of blood drawn during blood transfusion. There are no direct
benefits to the subjects, and so subjects will be financially compensated for
their time and burden.