Remarkable extension of lifespan has been achieved in the model organisms (yeast, fly, worm and mouse) by modulation of nutrient intake and/or sensing, via calorie restriction (CR) or via inhibition of mammalian target of rapamycin (mTOR) pathway signaling. These manipulations are being considered for potential increase of lifespan in humans. Inasmuch as any increase in longevity must be accompanied by improved quality of life, it is critical to understand the effects of these interventions upon physiological function o older organisms. While CR appears to improve immune function and homeostasis in old animals, the preciously few infectious challenge experiments suggest increased susceptibility to infection in old CR rodents. Rapamycin (Rapa), which inhibits the mTOR complex 1 (mTORC1), is a potent immunosuppressant in its own right, and the effects of chronic low-dose Rapa-mediated immune suppression on resistance to infection remain unknown. This exploratory proposal aims to test the hypothesis that CR and mTOR inhibition exert negative effects upon protective immunity, specifically by curtailing full development of effector T and B cell responses. We will test this hypothesis in two Aims.
Aim 1 : To establish survival and immune response outcome of various types of infection in CR and Rapa-treated A and O mice. CR and low-dose Rapa-fed mice will be infected with the West Nile virus or Listeria monocytogenes, as prototypes of an arbovirus and a food-borne bacterium that impart high mortality upon older adults, and will be examined for survival and for generation of a protective T cell and antibody response.
Aim 2 : To define molecular correlates of the altered immune response in CR and Rapa-treated old mice. To dissect signaling mechanism(s) by which mTORC1/AMPK pathway manipulation leads to beneficial effects in healthy aging across different tissues and provide preclinical data for direct translation using approved and/or new drugs.
It is expected that people over 65 years of age will make one quarter of the US population by 2040, and ensuring healthy and productive lives of that very large segment of population is becoming an urgent priority. Manipulation of nutrient intake and sensing has been shown to consistently extend lifespan in lower organisms and rodents, and there are ongoing clinical studies in humans. Our experiments will test whether nutrient sensing manipulation may impair survival from, and immunity to, infection, allowing us to evaluate whether manipulations of nutrient pathways may be safe and desirable to achieve optimal healthy longevity.
|Goldberg, Emily L; Smithey, Megan J; Lutes, Lydia K et al. (2014) Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J Immunol 193:757-63|