Abstract: One of the major factors affecting lifespan is the environment. Therefore, biological mechanisms exist to interpret environmental information and translate it into changes in lifespan. Food, for example, is one environmental factor that when scarce can result in an extension of lifespan. The strategy I am presenting aims to exploit the mechanisms by which the environment influences lifespan to treat age-related disease. At its core lies the observation that the environment influences lifespan indirectly through perception. It is the nervous system that responds to environmental information by inducing physiological changes that affect lifespan. Therefore small molecules that modulate the flow of environmental information create the perception of a lifespan extending environment which is sufficient to extend lifespan. To support the feasibility of this strategy I present a proof of principle. In C. elegans, the serotonin antagonist Mianserin blocks the perception of food, causes behaviors that are reminiscent of starvation and extends lifespan by mechanisms similar to those of dietary restriction. However, at the same time, Mianserin causes a dramatic increase in food intake. Therefore it is the perceived starvation, caused by Mianserin by blocking food signals, rather than the lack of nutrients, that extends lifespan. Instead of extending lifespan by """"""""""""""""dietary restriction"""""""""""""""", Mianserin extends lifespan by """"""""""""""""food-information restriction."""""""""""""""" Using Mianserin and other lifespan extending molecules as tools, I will identify neural circuits that process and regulate lifespan in response to perceived starvation. Furthermore, I will test the effect of perceived starvation on models of age-related disease. I will then ask what role lifespan-regulating-neurons play in the pathopysiology of neurodegenerative disease. Some of the great successes in medicine were achieved by exploiting existing biological functions to gain medical advantages (e.g. vaccination). Modulation of perception by small molecules to activate mechanisms of longevity exploits an existing biological function to treat age-related disease. Public Health Relevance: The strategy I am presenting aims to exploit the mechanisms by which the environment influences lifespan to treat age-related disease. At its core lies the observation that the environment influences lifespan indirectly through perception which triggers physiological changes that affect lifespan. Therefore, it should be possible to treat age-related diseases by small molecules that modulate perception in ways that activate mechanisms of longevity.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD008398-01
Application #
8145486
Study Section
Special Emphasis Panel (ZGM1-NDIA-S (01))
Program Officer
Basavappa, Ravi
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2011-09-30
Budget End
2016-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$2,842,500
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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