Andrey A. Parkhitko, Ph.D.

Metabolism plays a significant role in the regulation of aging and neurodegeneration at different levels. Studies in different model organisms revealed age- and neurodegeneration-dependent changes in various metabolic pathways. Although the flux via major metabolic pathways is relatively well studied in normal (young) cells, we have a very limited knowledge of how aging and/or neurodegeneration affect metabolic fluxes in old cells representing a significant knowledge gap. The central goal of my lab is to understand the mechanisms underlying age- and neurodegeneration-dependent metabolic reprogramming.

In the next few years, we will focus on answering critical questions:

What is the fate of various important age-dependent metabolites? We previously applied 13C5-Methionine labeling in Drosophila to analyze how the activity of methionine metabolism flux is altered with aging or by overexpression of human Tau and demonstrated decreased activity of the methionine salvage pathway and methionine cycle, and significant redirection of methionine into the transsulfuration pathway. We will expand our tracing analysis on other age- and neurodegeneration-dependent metabolites.

How do different metabolic pathways interact in the regulation of health- and lifespan?

Targeting a single pathway usually results in a moderate effect. I hypothesize that combined targeting of several pro-longevity pathways will result in an additive/synergistic effect on health and lifespan. To test this hypothesis, Drosophila will be used as a model system along with novel state-of-the-art multiplex CRISPRa technology for the simultaneous targeting of multiple pathways.

What is the role of methyltransferases in age-related processes?  We demonstrated that aging and neurodegeneration are characterized by delayed processing of the one of methionine metabolism intermediates, S-adenosyl-L-homocysteine, that functions as a competitive inhibitor of a broad spectrum of methyltransferases. We will screen an RNAi library against all Drosophila methyltransferases using age- and neurodegeneration-dependent phenotypes (climbing, egg-laying, loss of gut integrity, eye phenotypes) to identify methyltransferases that are linked to age-dependent alterations of methionine metabolism.

Is targeting of age-reprogrammed metabolic pathways conserved in mammals? We will use frailty index, epigenetic clocks, and extensive behavior/pathological phenotyping to estimate whether targeting of age- and neurodegeneration-reprogrammed metabolic pathways can improve composite measures of health in mice.