Andrey A. Parkhitko, PhD

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 affects 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 these 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 in a model relevant to AD. This demonstrated decreased activity of the methionine salvage pathway and methionine cycle in addition to a significant redirection of methionine into the transsulfuration pathway. We will expand our tracing analysis on other 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 and will more effectively prevent neurodegeneration. 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 is characterized by delayed processing of one of the 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-dependent phenotypes (climbing, egg-laying, loss of gut integrity) or different models of neurodegeneration to identify methyltransferases that are linked to the alterations of methionine metabolism.

Is targeting of age- or neurodegeneration-reprogrammed metabolic pathways conserved in mammals? We will use the frailty index and epigenetic clocks to estimate whether targeting of age-reprogrammed metabolic pathways can improve the composite measure of health in mice. We are also currently testing whether methionine restriction may improve some phenotypes associated with AD.

What is the role of tyrosine metabolism in the regulation of catecholamine-regulated behavior? We demonstrated that levels of tyrosine decrease with age, due to the activation of the tyrosine degradation pathway, and the downregulation of enzymes in the tyrosine degradation pathway significantly extended Drosophila lifespan. We discovered a new mechanism of how mitochondrial dysfunction serves as an age-dependent stimulus that redirects tyrosine from neuromediator production into mitochondrial metabolism. We are currently studying how reprogramming of trysoine metabolism and mitochondrial function affects the production of tyrosine-derived neurotransmitters and their effects on Drosophila activity, sleep, and other behavior traits.