The Ghazi Lab - Molecular Genetics of Aging

Aging is a universal phenomenon that is associated with many functional disabilities as well as susceptibility to diseases such as cancer, neurodegenerative ailments and diabetes. With a rapidly aging global population, it is a public health issue of great significance. Research on aging not only helps us understand a fundamental and fascinating biological process, but it may also be the least expensive and fastest path to simultaneously targeting multiple age-associated pathologies. Recent discoveries have suggested that aging is not just the result of stochastic cellular damage. Instead, it is strongly influenced by genes that appear to be conserved in their longevity functions, from worms to humans. Such longevity genes are the focus of our lab’s research.

ith a lifespan of only three weeks, C. elegans, helps the Ghazi Lab understand the genetics of aging. We study longevity genes in Caenorhabditis elegans, a model organism with a short lifespan of about three weeks. C. elegans displays many anatomical and functional changes that accompany human aging, as seen here in the scanning electron microscopy images of young and old C. elegans from our lab. Worm genes show strong homology with their human counterparts. Indeed, the most well known longevity pathway, the insulin/IGF1 signaling (IIS) cascade, was first identified for its role in aging in worms. Since then, many fundamental discoveries in the biology of aging have been made in C. elegans, and it continues to be a remarkably valuable system for aging research.

Our lab is especially interested in the relationship between reproduction and aging, and the genes that govern this complex interaction. Our recent studies have led us to focus on the role of three conserved, pro-longevity transcription factors and their roles in lipid-metabolism in governing the reproductive control of aging. These proteins (DAF-16, TCER-1, and NHR-49) appear to modulate lipid homeostasis by coordinately enhancing both lipid production and breakdown. Currently, we are investigating how lipid production and breakdown are coordinated and why this is important for health. Additional lab interests include the role of proteasomal protein degradation and miRNA pathways in aging.

The Ghazi Lab is currently focused on the following three key areas of research.

Transcription Factors that Mediate Signals From Reproductive Cells to Modulate Aging

While it is well recognized that increasing age impairs reproductive fitness, how the germline of an animal influences aging of its somatic cells is not known. Recent discoveries in worms, flies and mice have shown that signals from reproductive tissues indeed influence the length and quality of life of the whole organism.

In C. elegans, removal of a population of germline-stem cells (GSCs) extends lifespan and enhances stress resistance. These changes appear to be brought about by activation of a network of transcription factors in the intestinal cells. We have identified a group of such factors, and our current research focuses on three such conserved proteins:

NHR-49, a nuclear receptor that is the worm functional homolog of vertebrate PPARα protein, a major target for drugs against metabolic disorders
TCER-1, the worm homolog of a human transcription elongation and splicing factor, TCERG1
DAF-16, a longevity determinant whose human homolog, FOXO3A, has been implicated in human aging

We use these factors as tools to decipher the genetic network that extends lifespan in response to reproductive stimuli, using a combination of molecular genetic and genomic techniques.

The Role of Fat Metabolism in Reproduction and Aging

GSC-less mutants accumulate excessive lipids but are still long lived. The mechanisms underlying this ‘healthy obesity’ are unknown and intriguing. Germline loss is a major metabolic challenge that compels the animal to stop fat deposition into eggs and remodel its lipid reserves. Hence, these ‘healthy obese’ mutants are a valuable model to understand how lipid homeostasis is achieved following changes in procreation and age. Our recent studies have shown that the transcription factors, NHR-49/PPARα, DAF-16/FOXO3A and TCER-1/TCERG1, together activate both lipid anabolic and catabolic pathways in GSC-less mutants, and this concomitant augmentation is essential for longevity. Our current efforts are focused on understanding how these ostensibly antagonistic processes are simultaneously activated and how animals coordinate the production and breakdown of lipids.

Proteasomal Regulation of Aging

The programmed destruction of regulatory proteins by the proteasome pathway is widely used for controlling many important biological processes including aging. Previously, we discovered that the proteasomal pathway regulates aging in C. elegans. In mutants of the insulin/IGF-1 receptor daf-2, which live twice as long as normal worms, proteasomal E3 ligases are recruited for the ubiquitination and likely degradation of cellular proteins that inhibit longevity. Current efforts are focused on the identification of such E3 ligase substrates whose degradation is essential for lifespan extension.

Arjumand Ghazi, PhD

Principal Investigator
arjumand.ghazi@chp.edu
Read more »

Francis Amrit Gandhi, PhD
Post-doctoral Fellow
francis.gandhi@chp.edu

Hye Jin Hwang, PhD
Post-doctoral Scholar
hyejin.hwang@chp.edu

Rachana Kelkar, BS
Graduate Student
rsk43@pitt.edu

Julia A. Loose, BS
Graduate Student
jal260@pitt.edu

Nikki Naim, BS
Graduate Student
nin27@pitt.edu

Thayjas Patil
Undergraduate Researcher
tap97@pitt.edu

Contact Us

The Ghazi Laboratory is located at:

John G. Rangos Sr. Research Center
Room 7139
One Children's Hospital Drive
4401 Penn Avenue
Pittsburgh, PA 15224

To reach the lab by phone please call 412-692-9258.

For administrative matters, please contact Teresa Trimble at trimble2@chp.edu or 412-692-5412.

Alumni

Ramya Mallela, Technician, 2015-2016, Graduate student, University of Pittsburgh
Ramesh Ratnappan, Post-doctoral Fellow, 2012-2015, Post-doctoral fellow, George Washington University
Scott A. Keith, Technician, 2013-2015, Graduate student, Carnegie Mellon University
Kyle Holden, Technician, 2011-2014, Medical student, Lake Erie College of Osteopathic Medicine

Undergraduate Alumni

2018 Summer Team

Francis Gandhi, Arjumand Ghazi, Dom Piganelli, Julia Loose, Nikki Naim and Hye Jin Hwang celebrating the comprehensive exam success of Julia and Nikki.

2017 Summer Team

Francis Gandhi, Nikki Naim, Arjumand Ghazi, Carter Mason, Julia Loose, Alexandra Borelli¹, Joseph Garve¹, and Hye Jin Hwang

2016 Summer Team

Mark D’Alesio¹, University of Pittsburgh, Spring – Summer 2016
Sneha Rajendran², University of Pittsburgh, Spring – Summer 2016
Hannah Smith¹, Allegheny College, Summer 2016
Anika Fedak¹, Pittsburgh Science and Technology Academy, Summer 2016

2015 Summer Team

Nicholas DelBuono^{3, 5}, University of Pittsburgh, Fall 2012 – Summer 2015
Alekya Kothamasu, University of Pittsburgh, Spring 2014 – Fall 2015
Anika Manikurve¹, University of Pittsburgh, Summer – Fall 2015
Eva Roy¹, University of Pittsburgh, Summer 2015
Levi Kalka, University of Pittsburgh, Spring 2015

2014 Summer Team

Lia Petrose, University of Pittsburgh, Spring 2014
Laura Steenberge⁴, Illinois Wesleyan University, Summer 2014
Denise Monti¹, Washington University in St. Louis, Summer 2013, Summer 2014
Kayla Thomason¹, University of Pittsburgh, Fall 2012 – Summer 2014
Hetal Patel, University of Pittsburgh, Fall 2013

2013 Summer Team

Martin Echavarria, University of Pittsburgh, Fall 2012
Hasreet Gill⁴, Grove City College, Summer 2011
Sarah Winston¹, University of Pittsburgh, Spring – Summer 2012
Leisha Steenkiste⁴, Denison University, Summer 2012
Sarah Bass¹, Pennsylvania State University, Summer 2011

Support:
¹ Children’s Hospital of Pittsburgh of UPMC, Summer Fellowship
² University of Pittsburgh, Honors College, Health Sciences Summer Fellowship
³ University of Pittsburgh, Brackenridge Fellowship
⁴ University of Pittsburgh, Summer Undergraduate Research Program Fellowship
⁵ Neuroscience honors research thesis undertaken while in the lab.

The Longevity-promoting Factor, TCER-1, Widely Represses Stress Resistance and Innate Immunity
Amrit FRG, Naim N, Ratnappan R, Loose J, Mason C, Steenberge L, McClendon BT, Wang G, Driscoll M, Yanowitz JL, Ghazi A
Nature Communications
17 Jul 2019
See Also: PittHealthSciences/UPMC Children’s Hospital of Pittsburgh news release

Proteomic Identification of Virulence-Related Factors in Young and Aging C. elegans Exposed to Pseudomonas aeruginosa
King CD, Singh D, Holden K, Govan AB, Keith SA, Ghazi A* and Robinson RASR*
Journal of Proteomics
2018 Jun 15

Analysis of C. elegans Transcriptomic Data by the Tuxedo Suite of the Galaxy Pipeline
Amrit FRG and Ghazi A*
Journal of Visual Experimentation
2017 Apr 8

Influences of Germline Cells on Organismal Lifespan and Healthspan
Amrit FRG and Ghazi A*
Invited, peer-reviewed chapter
C. elegans and its Contribution to our Understanding of Aging and Longevity
Editors: Gill MS, Olsen A
2017

X Chromosome Crossover Formation and Genome Stability in Caenorhabditis elegans are Independently Regulated by xnd-1
McClendon TB, Rana M, Amrit FR, Fukushige T, Krause M, Ghazi A, Yanowitz JL*
G3: Genes, Genomes, Genetics
2016 Sep 27

DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans
Amrit FRG, Steenkiste E, Ratnappan R, Chen SW, Kostka, D, McClendon B, Yanowitz J, Olsen CP, Ghazi A*
PLoS Genet
2016 Feb 10

Nuclear hormone receptors as mediators of metabolic adaptability in response to reproductive perturbations
Ratnappan R, Ward, JD, Yamamoto, KR, Ghazi A*
Worm
2016 Jan-Mar

Graded Proteasome Dysfunction in C. elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-lysosome Pathway
Keith SA, Maddux S, Zhong Y, Ferguson AA, Ghazi A, Fisher AL
PLoS Genet
2016 Feb 1

Stress Signaling: Serotonin Spreads Systemic Stress
Ghazi A*, Lamitina T*
Current Biology
2015 Jan 19

Recent Discoveries in the Reproductive Control of Aging (Abstract)
Keith SA, Ghazi A*
Current Genetic Medicine Reports
2015 Mar

Germline Signals Deploy NHR-49 to Enhance Fatty-Acid β -Oxidation and Desaturation in Somatic Tissues of C. elegans
Ratnappan R, Amrit FG, Chen S-W, Gill H, Holden K, Ward J, Yamamoto K, Olsen CP, Ghazi A*
PLoS Genet
2014 Dec 4

The C. elegans Healthspan and Stress-response Assay Toolkit (PubMed Abstract)
Keith SA, Amrit FG, Ratnappan R and Ghazi A
Methods
2014 Aug

The C. elegans Lifespan Assay Toolkit
Amrit FG, Ratnappan R, Keith SA and Ghazi A
Methods
2014 Apr

Transciptional Networks that Mediate Signals from Reproductive Tissues to Influence Lifespan
Ghazi A
Genesis
2013 Jan

A Transcription Elongation Factor that Links Signals from the Reproductive System to Lifespan Extension in Caenorhabditis elegans
Ghazi A, Henis-Korenblit S, Kenyon C
PLoS Genet
2009 Sep 11
Recommended by Faculty of 1000

Regulation of Caenorhabditis elegans Lifespan by a Proteasomal E3 Ligase Complex
Ghazi A*, Henis-Korenblit S*, Kenyon C (*equal contribution)
Proc Natl Acad Sci USA
2007 Apr 3

Above research was the focus of the ‘Dispatch’ article
C. elegans Aging: Proteolysis Cuts Both Ways
Bowerman B
Current Biology
2007 Jul 3

Muscle Development in Drosophila (PDF)
Ghazi A, VijayRaghavan K
Proc Ind Natl Sci Acad
2003 No. 5

Prepattern Genes and Signaling Molecules Regulate Stripe Expression to Specify Drosophila Flight Muscle Attachment Sites
Ghazi A, Paul L, VijayRaghavan K
Mech Dev
2003 May

Puzzling Over Research on Aging
Ghazi, A
SAGE KE
2002 Jun 5

Developmental Biology: Control by Combinatorial Codes (abstract)
Ghazi A, VijayRaghavan K
Nature
2000 Nov 23

Apterous Mediates Development of Direct Flight Muscles Autonomously and Indirect Flight Muscles through Epidermal Cues
Ghazi A, Anant S, VijayRaghavan K
Development
2000 Dec

We welcome inquiries regarding research opportunities in aging. If you have interesting ideas about science and want to investigate available positions, please contact Arjumand Ghazi, PhD, Principal investigator at arjumand.ghazi@chp.edu.

Research in the Ghazi Lab is supported by:

National Institute on Aging, National Institutes of Health, 1R01AG051659-01A1
The Lawrence Ellison Foundation, New Scholar in Aging Award
American Federation for Aging Research, Research Grant
Stimulating Pittsburgh Research in Geroscience, Pilot Program Award
University of Pittsburgh, Dean’s Faculty Advancement Award
Biology of Aging Working Group, University of Pittsburgh, Pilot Program Award (Co-Principal Investigator)
UPMC Children’s Hospital of Pittsburgh, Research Advisory Committee Award
Pennsylvania Department of Health, Health Research Formula Funds
Clinical and Translational Science Institute, University of Pittsburgh, Translational Technologies Cores Pilot Program