MAINTAINING HEALTH IN OLD AGE THROUGH HOMEOSTASIS Phase II

Very few people achieve healthy longevity, making the identification of
biological and homeostatic mechanisms that regulate the rate of ageing, and
there with contribute to the onset or prevention of age-related disease, of
extreme importance.
Homeostasis, the ability to dynamically adapt to environmental challenges while
maintaining the composition of the *milieu intérieur* within certain limits, is
central to healthy lifespan. With ageing, loss of homeostatic control is
thought to contribute to both metabolic and cognitive decline. Homeostasis is
centrally coordinated by the hypothalamus. The hypothalamus plays a central
role in the homeostatic regulation of energy homeostasis and in the regulation
of carbohydrate and lipid metabolism.
The central hypothesis of Switchbox is that sub-optimal ageing results from
drifts in one or more, hierarchically organized, signal generator and/or signal
detection mechanisms in the brain-periphery dialogue. 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.

Insulin plays a critical role in the central regulation of pituitary hormone
release, energy homeostasis and cognitive functions. In humans, intranasal
application of small peptides has been demonstrated to be a safe and effective
way to elevate brain/CSF levels of the peptide without affecting circulating
concentrations. Intranasal application (INA) of insulin has been described to
improve mood and (declarative) memory and to reduce activity of the HPA axis
and (in healthy but not in obese men) to reduce food intake and body weight.
INA of insulin leads to a reduction in anxiety and improvement of memory in
mice on a regular chow diet, but not in insulin resistant mice on a high fat
diet. Moreover, insulin resistance of the brain most likely impacts on the
ability of insulin to affect pituitary hormone release and metabolism.

Imaging analysis in distinct brain regions with key roles in the maintenance of
homeostasis (hypothalamus) will generate novel information with respect to
connectivity between a given brain area responsible for endocrine/metabolic
integration. Emphasis will be placed on examining changes in hypothalamic
activation and function under basal conditions, this will offer insight into
the adaptability of the homeostatic mechanisms.

To identify which brain regions are activated after intranasal application of
insulin and how this affects peripheral metabolism.

Phase II of Switchbox is a, double-blind fully randomised clinical trial with a
cross-over design with a wash-out period of one week. The participants will be
randomised into two groups (half per group) with half of the participants
having INA placebo first and the other half insulin first. They will all follow
exactly the same protocol, except that the intranasal insulin will be replaced
by intranasal placebo.

Intranasal insulin versus intranasal placebo

fMRI is a minimally invasive procedure.
Studies involving the use of intranasal insulin (INA) at dose up to 160IU
insulin have been extensively done and published. We however plan to use a low
dose (40IU) which has been proven to be adequate and effective. The subjects
will be monitored throughout the study period by the experimenter at the
research setting.

After insertion of a iv canula, we will withdraw a total of 104 ml blood over
2.5 hours (at a sampling frequency of 10 minutes). This amount is less than the
amount of blood drawn during regular blood donation (500 ml).

There are no direct benefits to the subjects.