Loss of metabolic homeostasis is a hallmark of aging. Using Drosophila as a model system, we demonstrated that aging is characterized by extensive reprogramming of methionine metabolism and delayed processing of SAH, a competitive inhibitor of a broad spectrum of methyltransferases. Moreover, we introduced into flies the bacterial enzyme Methioninase, which is capable of degrading methionine and has been safely tested in several cancer clinical trials. Methioninase dramatically extended fly lifespan. In addition, we demonstrated that tyrosine metabolism is altered with age due to the activation of the tyrosine degradation pathway. We found that suppression of mETC complex I drives upregulation of enzymes in the tyrosine degradation pathway and depletes tyrosine, which is required for the production tyrosine-derived neuromediators.
The immediate goals of our laboratory are to determine whether ‘resetting’ the methionine and tyrosine metabolic pathways back to normal is evolutionary conserved and can be translated to delay aging of higher organisms and improve phenotypes related to Alzheimer’s disease.
In the longer term, we will expand our studies by implementing carbon isotope-labeled nutrients coupled with mass spectrometry analysis to determine age-dependent changes in fates of nutrients at the whole-organism and tissue-specific levels; introduce bacterial enzymes similar to Methioninase that can potentially provide novel metabolic routes/functions to eukaryotic cells and help ‘reset’ age-dependent metabolic changes; and repurpose currently existing CRISPR/Cas9 multiplex systems for simultaneous targeting of different metabolic pathways to achieve additive/synergistic effects on lifespan.
- MS, Russian State Medical University, Russia; Partially Carried Out at Fox Chase Cancer Center, 2007
- PhD, Russian State Medical University, Russia; Partially Carried Out at Brigham & Women's Hospital, Harvard Medical School, 2013
- Postdoctoral Fellowship, Department of Genetics, Harvard Medical School, 2020
Education & Training
Parkhitko AA, Singh A, Hsieh S, Hu Y, Binari R, Lord CJ, Hannenhalli S, Ryan CJ, Perrimon N. Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells. PLoS Genet. 2021 Feb 16;17(2):e1009354. PMID: 33591981.
Parkhitko AA, Ramesh D, Wang L, Leshchiner D, Filine E, Binari R, Olsen AL, Asara JM, Cracan V, Rabinowitz JD, Brockmann A, Perrimon N. Downregulation of the tyrosine degradation pathway extends Drosophila lifespan. Elife. 2020 Dec 15;9:e58053. PMID: 33319750.
Parkhitko AA, Filine E, Mohr SE, Moskalev A, Perrimon N. Targeting metabolic pathways for extension of lifespan and healthspan across multiple species. Ageing Res Rev. 2020 Dec;64:101188. PMID: 33031925.
Parkhitko AA, Jouandin P, Mohr SE, Perrimon N. Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species. Aging Cell. 2019 Dec;18(6):e13034. PMID: 31460700.
Rodriguez-Muela N, Parkhitko A, Grass T, Gibbs RM, Norabuena EM, Perrimon N, Singh R, Rubin LL. Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J Clin Invest. 2018 Jul 2;128(7):3008-3023. PMID: 29672276.
Parkhitko AA, Binari R, Zhang N, Asara JM, Demontis F, Perrimon N. Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila. Genes Dev. 2016 Jun 15;30(12):1409-22. PMID: 27313316.
Parkhitko AA, Priolo C, Coloff JL, Yun J, Wu JJ, Mizumura K, Xu W, Malinowska IA, Yu J, Kwiatkowski DJ, Locasale JW, Asara JM, Choi AM, Finkel T, Henske EP. Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol Cancer Res. 2014 Jan;12(1):48-57. PMID: 24296756.
Li C, Lee PS, Sun Y, Gu X, Zhang E, Guo Y, Wu CL, Auricchio N, Priolo C, Li J, Csibi A, Parkhitko A, Morrison T, Planaguma A, Kazani S, Israel E, Xu KF, Henske EP, Blenis J, Levy BD, Kwiatkowski D, Yu JJ. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med. 2014 Jan 13;211(1):15-28. PMID: 24395886.
Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2021 Apr 15;184(8):2256. PMID: 33861966.
Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ, Henske EP. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12455-60. PMID: 21746920.
- Charles A. King Foundation Award, 2017
- NIH Pathway to Independence K99/R00 Award, 2018
