PgmNr Y3194: Omics approaches for discovery of aging-delaying and anti-tumor compounds and defining mechanisms of their action.

Authors:
V. Titorenko; A. Leonov; A. Arlia-Ciommo; Y. Medkour; V. Svistkova


Institutes
Concordia Univ, Montreal, PQ, CA.


Keyword: Proteomics

Abstract:

Caloric restriction (CR) and dietary restriction (DR) extend lifespan across species and improve health by delaying the onset of age-related diseases. All currently known aging-delaying chemical compounds 1) mimic lifespan-extending and health-improving effects of CR and DR without restricting caloric and nutrient intake; and 2) target signaling pathways that are under the stringent control of calorie and/or nutrient availability. It was believed therefore that all longevity pathways are “adaptable” by nature because they modulate longevity only in response to certain changes in the extracellular and intracellular nutrient and energy status of an organism. However, it is possible that that some longevity pathways could be “constitutive” or “housekeeping” because they control longevity irrespective of calorie and/or nutrient availability. We designed a high-throughput chemical genetic screen for compounds that increase the chronological lifespan of yeast under CR by modulating such housekeeping pathways. Our screen identified lithocholic bile acid (LCA) as a geroprotector which significantly delays the onset and reduces the rate of yeast chronological aging. Using proteomics, lipidomics, metabolomics, and cell biological approaches, we found that LCA delays yeast chronological aging by: 1) remodeling lipid metabolism in the endoplasmic reticulum, lipid droplets, and peroxisomes - thereby preventing liponecrotic programmed cell death caused by the age-related accumulation of fatty acids; 2) remodeling the repertoire of mitochondrial membrane lipids - thereby reducing the number of mitochondria, increasing their size, expanding their cristae, elevating the abundance of respiratory supercomplexes in the inner mitochondrial membrane, and altering the age-related dynamics of changes in mitochondrial respiration, membrane potential, and reactive oxygen species; 3) attenuating age-related mitochondrial fragmentation - thereby suppressing mitochondria-controlled apoptosis; and 4) promoting “mitohormesis” through the activation of several stress response-related processes in mitochondria. Our findings also imply that, in addition to its robust aging-delaying effect, LCA exhibits a potent and selective anti-tumor effect in cultured human neuroblastoma, glioma, breast cancer, and prostate cancer cells by activating both the intrinsic and extrinsic pathways of apoptotic death.