Faculty & Research
Immunity and aging
My main interest is to understand the interrelationship between immunity and aging. Aging is characterized by malfunctioning of immunity. Deregulation of the immune response during aging can result in cancer and other age-related diseases. The study in our group is aimed at elucidating the mechanisms that underlie such deregulation in order to develop proper interventions.
The most dramatic changes associated with aging involve immunity:
Decreased ability to mount an immune response
Increased susceptibility to infectious diseases and cancer
Reduced responsiveness to vaccination
Impaired function and clonal expansion of T and B cells
Aged mice have significantly lower levels of all TLRs
Enhanced innate immunity in older organisms give rise to an excessive immune response and inflammation
Extended longevity correlates with optimal functioning of innate immunity, attenuation of pro-inflammatory responses and decrease in pathogen burden
Enhanced pathogen resistance is a feature of strains with a long-lived background
The response and resistance of macro-organisms to microbial challenges comes at a cost:
While bolstered immunity offers protection against invaders, it may also elicit damage to host cells and tissues, which ultimately could lead to functional deficits
Excessive production of immunity effectors can also place substantial energy demands on the cellular machinery, which may result in trade-offs that negatively impact the maintenance of cellular homeostasis
Immune pathways are similar to those in humans
Life span is 60-70 days
Variety of genetically modified strains available at stock centers
Reverse correlation between typical Drosophila life span and changes in the levels of immune effectors (antimicrobial peptides, AMPs) and accumulation of oxidative stress and shifts in redox to more pro-oxidized state
The focus of my current research is to understand the role of redox regulation of the innate immunity and aging. One of the major regulators of cellular redox are enzymes named thiol-dependent peroxidases, or peroxiredoxins. They are widespread in all three kingdoms, highly conservative in all organisms starting from bacteria and extending into humans, Involved in a number of redox-related cellular functions: differentiation, proliferation, apoptosis, signaling processes, immune response.
Reactive oxygen and nitrogen species (ROS and RNS), produced during metabolic reactions, inflammation, and phagocytosis, not only cause tissue damage, but also act as messengers in signaling pathways, including modulation of the immune responses. The aim is to determine by how to maintain the “correct” levels of ROS/RNS in order to minimize the tissue damage and at the same time not to compromise the immune response. I am testing a hypothesis that peroxiredoxins may control the ‘switch’ in the redox state, excessive immune response and thus accelerated death. To address these questions, we are using a wide range of molecular biology and genetics techniques.
Practical terms: examine the differences in redox signaling that modulate immunity and aging in both young and old organisms; develop interventions, which take into account the differential effects on young versus old individuals.
Radyuk SN, Rebrin I, Klichko VI, Sohal BH, Michalak K, Benes J, Sohal RS, Orr WC. Mitochondrial peroxiredoxins are critical for the maintenance of redox state and the survival of adult Drosophila. Free Radic Biol Med. 2010 Dec 15;49(12):1892-902.
Radyuk SN, Michalak K, Klichko VI, Benes J, Orr WC. Peroxiredoxin 5 modulates immune response in Drosophila. Biochim Biophys Acta. 2010 Nov;1800(11):1153-63.
Radyuk SN, Michalak K, Klichko VI, Benes J, Rebrin I, Sohal RS, Orr WC. Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila. Biochem J. 2009 Apr 15;419(2):437-45.
Radyuk SN, Rebrin I, Luchak JM, Michalak K, Klichko VI, Sohal RS, Orr WC. The catalytic subunit of Drosophila glutamate-cysteine ligase is a nucleocytoplasmic shuttling protein. J Biol Chem. 2009 Jan 23;284(4):2266-74. Epub 2008 Nov 26.
Legan SK, Rebrin I, Mockett RJ, Radyuk SN, Klichko VI, Sohal RS, Orr WC. Overexpression of glucose-6-phosphate dehydrogenase extends the life span of Drosophila melanogaster. J Biol Chem. 2008 Nov 21;283(47):32492-9. Epub 2008 Sep 22.
Michalak K, Orr WC, Radyuk SN. Drosophila peroxiredoxin 5 is the second gene in a dicistronic operon. Biochem Biophys Res Commun. 2008 Apr 4;368(2):273-8.
Luchak JM, Prabhudesai L, Sohal RS, Radyuk SN, Orr WC. Modulating longevity in Drosophila by over- and underexpression of glutamate-cysteine ligase. Ann N Y Acad Sci. 2007 Nov;1119:260-73.
Radyuk SN, Michalak K, Rebrin I, Sohal RS, Orr WC.Effects of ectopic expression of Drosophila DNA glycosylases dOgg1 and RpS3 in mitochondria. Free Radic Biol Med. 2006 Sep 1;41(5):757-64.
Orr WC, Radyuk SN, Prabhudesai L, Toroser D, Benes JJ, Luchak JM, Mockett RJ, Rebrin I, Hubbard JG, Sohal RS. Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster. J Biol Chem. 2005 Nov 11;280(45):37331-8.
Radyuk, S.N., Klichko, V.I. and Orr, W.C. (2004) Profiling Cu,Zn-superoxide dismutase in Drosophila melanogaster - a critical regulatory role for intron/exon sequence within the coding domain. Gene. 328, 37-48.
Klichko, V.I., Radyuk, S.N. and Orr, W.C. (2004) Profiling catalase gene expression in Drosophila melanogaster during development and aging. Archives of Insect Biochemistry and Physiology. 56, 34-50.
Radyuk S.N., Sohal R.S., Orr W.C. (2003). Thioredoxin peroxidases can foster cytoprotection or cell death in response to different stressors - a study of thioredoxin peroxidase under- and over-expression in Drosophila cells. Biochem J. 2003 May 1;371(Pt 3):743-52.
Mockett R.J., Radyuk S.N., Benes J.J., Orr W.C., Sohal R.S. (2003). Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila. Proc Natl Acad Sci U S A 2003 Jan 7;100(1):301-6
Radyuk, S.N., Klichko, V.I., Spinola, B., Sohal, R.S., Orr, W.C. (2001). The peroxiredoxin gene family in Drosophila melanogaster. Free Radic. Biol. Med., Nov 1;31(9):1090-100
R21 07/01/2011-06/31/2013 (Principal Investigator in a subcontract with Oregon State University) Funded by National Institutes of Health, Direct cost $102970 for two years, ‘Role of circadian clocks in maintaining a healthy nervous system’.
R01 04/01/2011-03/31/2016 (Principal Investigator) Funded by National Institutes of Health, Direct cost $205000 per year, ‘Peroxiredoxins, immune signaling and aging’
R21 01/01/05-12/31/06 (Principal Investigator) Funded by National Institutes of Health, Direct cost $125000 per year, ‘The Role of Peroxiredoxins in Immunity and Aging’
SBIR 08/16/04-12/16/05 (Sub-Contract) Funded by US Airforce; Direct cost $75000 for 16 months, ‘Automated Individual Real-Time Toxic Exposure Monitoring (AIRTEM) System