The aim of “Neuroendocrinology and Aging” Group is to investigate the hypothalamus as an underlying mediator and a target for interventional strategies in counteracting aging and related diseases. In this context the group will focus its research on the following scientific questions and strategies: i) Does caloric restriction (CR) delay aging and age-related diseases through hypothalamus-related mechanisms? ii) To delay premature aging of Hutchinson Gilford progeria syndrome (HGPS) rodent models, and normal aging, by targeting the hypothalamus. iii) Hypothalamic changes related to obesity and ageing.
Following are some examples of ongoing projects and future projects in the group and the strategies being employed to address them:
1. Targeting the hypothalamus as a new strategy to rescue the premature aging phenotype of Hutchinson-Gilford Progeria Syndrome (HGPS)
HGPS is an extremely rare genetic disease with premature and accelerated aging. In this line of research we are focusing on the hypothalamus, and related neuropeptides, using different strategies and targets to rescue the premature aging phenotype of HGPS models: a) Gene delivery approach to overexpress NPY in the hypothalamus; b) intranasal administration of NPY; c) Peripheral administration of ghrelin or the ghrelin receptor agonist (MK-0677); d) hypothalamic ataxin-2 modulation; e) Targeting microglia activation; f) Hypothalamic microRNAs changes and respective modulation; g) Modulation of hypothalamic sirtuin-2;h) blood-brain barrier modulation.
In this line of research we will develop new strategies to prevent/delay deteriorations, premature aging of HGPS in vitro and in vivo models. Moreover, the results of this project will also contribute to emphasize the crucial role of hypothalamus as a key brain region involved in whole-body normal aging.
2. Searching for the microRNA maestro in the central regulation of food intake, obesity and aging
Obesity causes alterations in metabolic peripheral organs including deregulation of microRNAs pathway. However, it has never been investigated whether obesity and high-fat diet consumption cause alterations in the microRNAs pathway in the hypothalamus. The main goal of this project is to identify the microRNA maestro in the central regulation of feeding and investigate the alterations in hypothalamic microRNAs associated to obesity and aging. This project will elucidate the alterations in hypothalamic microRNAs induced by obesity and identify the candidate microRNA for a possible innovative and effective anti-obesity and/or anti-ageing therapy.
3. Unraveling the role of intermittent hypoxia induced by sleep apnea on two regulator systems of energy balance: the hypothalamus and the white adipose tissue.
It is known that sleep apnea prevalence is very high in obese patients, and that sleep apnea promotes obesity – a risk factor of aging progression. In this project we will study the changes induced by intermittent hypoxia on rodent hypothalamus and white adipose tissue, using in vitro and in vivo models.
4. Delaying neurodegeneration by caloric restriction approaches: from mechanisms to gene therapy.
We will continue investigating the neuroprotection, and underlying mechanisms, induced by CR, CR mimetics, and hypothalamus manipulation in rodent models of the aged related neurodegenerative disease Machado-Joseph disease (MJD). This project opens new approaches to delay and/or prevent MJD progression. This is a join project with Luis Pereira de Almeida – Gene Therapy Group).