Understanding the Mechanisms of Biological Aging: New NIH R56 Grant Awarded to Gurkar Laboratory for Exploring Influence of DNA Damage on Acetyl Co-A Metabolism
April 22, 2024
Aditi Gurkar, PhD, principal investigator of the Gurkar Laboratory at the Aging Institute of the University of Pittsburgh and UPMC has received a National Institute on Aging R56 grant to study how DNA damage and acetyl co-A metabolism work to influence mechanisms of biological aging.
Dr. Gurkar is an assistant professor of Medicine in the UPMC Division of Geriatric Medicine. She joined the division and Aging Institute in 2017. She is a prior recipient of an NIH K99/R00 Pathway to Independence grant from the National Institute on Aging. Before joining the University of Pittsburgh and the Aging Institute, Dr. Gurkar was a postdoctoral researcher at Massachusetts General Hospital/Harvard Medical School and Broad Institute of MIT and Harvard, and at the Scripps Research Institute in Florida. Dr. Gurkar earned her doctorate from Boston University School of Medicine.
Dr. Gurkar's lab studies biological aging and aims to understand mechanistically how and why individuals age differently at the molecular and cellular level. The goal of the lab’s research is to be able to predict how an individual will age biologically, and armed with this knowledge, allow for the design of personalized interventions and programs for more healthful aging and an extended healthspan.
DNA Damage, and Downstream Effects on Cellular Processes and Biological Aging
Genotoxic stress refers to damage inflicted on a cell's DNA by harmful agents, potentially causing cancer or cell death. It affects cellular functions by disrupting DNA replication and repair processes. As we age DNA repair systems are less efficient, and hence more prone to genotoxic stress.
Genotoxic stress can arise from various sources, including environmental toxins such as pollutants and UV light exposure, chemical exposures from things like chemotherapy or radiation, and lifestyle factors like smoking or consuming excessive amounts of alcohol. Additionally, internal processes like oxidative stress, which result from the body's metabolic activities, can also cause DNA damage. Each of these factors can disrupt the integrity of the individual’s genetic material, leading to mutations that can detrimentally affect cellular health and function.
DNA damage promotes cellular aging by initiating mechanisms that lead to a decline in cell function, replication capacity, or increase cellular senescence and apoptosis. This accumulation of damaged DNA over time impairs cellular repair processes and contributes to the aging process and the development of age-related diseases.
The primary modes of DNA oxidative stress involve the direct damage to DNA by reactive oxygen species (ROS), leading to mutations, strand breaks, and alterations in DNA structure. This oxidative stress can result from various environmental factors, cellular processes, and metabolic dysfunctions, significantly impacting cellular health and contributing to aging and diseases.
R56 Grant – Objectives and Novel Research Components
One specific area of research in Dr. Gurkar's lab is the study of acetyl-CoA metabolism. In prior work, Dr. Gurkar’s lab has found that DNA damage changes the metabolism of acetyl-CoA, which is a central metabolite that plays multiple critical roles in cellular metabolic processes throughout the body.
The research aims to understand how DNA damage can alter acetyl-CoA's behavior and distribution within cells, and how these alterations affect biological aging.
“Acetylation of proteins regulates their function, and acetyl-CoA is crucial for generating vital fats and maintaining cell membranes, among other metabolic processes in the body,” says Dr. Gurkar. “What we’ve seen in prior studies is that with DNA damage, acetyl-CoA tends to get reallocated all into the nucleus of the cell, opening up the chromatin, and driving gene expression in ways that are detrimental, for example, with immune cells, a persistent, never ceasing inflammatory state.”
Dr. Gurkar’s research uses innovative methods to induce and study DNA damage in a highly targeted and controlled manner, aiming to map its effects on acetyl-CoA metabolism distribution within cells spatially and temporally.
To study the effects of DNA damage and acetyl-CoA metabolism on aging, Dr. Gurkar's lab uses the model organism Caenorhabditis elegans (C. elegans).
“C. elegans is a very good model in which to study the basic mechanistic processes of biological aging,” explains Dr. Gurkar. “The short lifecycle of the animal allows for faster studies of the aging processes. C. elegans shares similar molecular processes as humans, so in the future should our findings point in the direction of specific molecular underpinnings we can easily translate the work in humans.”
Creating a Novel Method of Inducing and Targeting DNA Damage
As Dr. Gurkar explains, in the past it has been quite difficult to very narrowly target or induce specific DNA lesions or damage in specific cells or tissues. It’s been more about using systemic methods to disrupt or mutate DNA and then study the downstream effects in cells or tissues.
“When you use things like radiation or chemotherapy to induce DNA damage in a model, it can affect other parts of the cell or tissues that you want to study. It can kind of muddy the waters in terms of how specific cellular function is altered and how you can study it,” explains Dr. Gurkar.
To overcome these limitations, Dr. Gurkar along with colleagues from the University of Pittsburgh and Carnegie Mellon University, including the late Marcel Bruchez, PhD, adapted a new chemoptogenetic tool that allows them to induce DNA damage in a highly targeted way.
The tool uses a fluorogen-activating peptide (FAP) to control where, when, and how DNA damage is induced in cells or tissues.
“Using this fluorogen-activating peptide, we can tag and target any kind of tissue or cell, or cellular component, in our case DNA,” says Dr. Gurkar. “After the cell component is tagged, it is activated by delivering a drug called malachite green and subjecting the worms to a specific wavelength of red light.”
When the peptide is activated with the malachite green and red light, it produces reactive oxygen species (ROS), or single oxygen, which then attacks the DNA and induces the lesion. The ROS cannot travel far from where it is created so it targets whatever is closest to it, in this case the cell’s DNA.
“What’s also exciting about this approach is that the wavelength of light that we use can penetrates through the entire body of the worm,” says Dr. Gurkar. “For the first time, we are now able to cause specific kinds of DNA lesions in a specific cell or tissue and see what happens. If we want to only target neurons in the brain, or cardiomyocytes in the heart, this new tool allows for that level of precision. It’s a game-changing technology and process when it comes to studying the effects of DNA damage with precision.”
Dr. Gurkar’s research will also employ a combination of genetic, metabolic, and biochemical techniques, alongside the novel chemoptogenetic tool for inducing DNA damage. This approach allows for detailed study of acetyl-CoA's role in aging, assessing changes in its distribution and impact on cellular processes in response to DNA damage.
Overall, Dr. Gurkar's research aims to uncover the mechanisms behind aging and develop interventions to promote healthy aging. By understanding the role of DNA damage and Acetyl-CoA metabolism in the aging process, they hope to improve our understanding of aging and develop personalized strategies for healthy aging.
More About the Gurkar Laboratory and its Investigations
Dr. Gurkar’s research is centered on the mechanistic processes of biological aging, specifically in how damage to a person’s DNA alters metabolic processes that drive biological aging.
Dr. Gurkar became interested in studying the biological processes of aging due to observing the differences in aging among her own grandparents. She noticed that despite similar environmental factors, their aging processes were distinct. This led her to question why people age differently and sparked her curiosity in understanding the underlying mechanisms of aging.
“My career as a scientist and my interest in how biological aging works grew from my early observations of my grandparents,” explains Dr. Gurkar. “For the most part they were the same age, lived essentially the same kinds of lifestyles – diet, geography – but it was clear that one looked and functioned like they were older. I wanted to understand why that could be the case.”
Her lab focuses on understanding the basics of biological aging and aims to predict how a person will age biologically in order to design personalized interventions for healthy aging.
“The goal is to extend a person’s healthspan, allowing individuals to live healthy and active lives until the day they die,” says Dr. Gurkar. “It is great that we have extended a person’s lifespan by 20-30 years with all the technological advances, but most often their healthspan is not concurrently expanded- so it’s simply the person living longer with the same age-related chronic conditions and limitations.”
Dr. Gurkar's lab specifically studies DNA damage and its role in aging. They are interested in understanding how genotoxic stresses, such as environmental exposures and UV light, lead to changes in DNA and ultimately contribute to the aging process.
References
Spatial Acetyl-CoA metabolism as a regulator of Hallmarks of Aging. Project Number: 1R56AG082757. Principal Investigator: Aditi U. Gurkar, PhD.
Han S, Sims A, Aceto A, Schmidt BF, Bruchez MP, Gurkar AU. A Chemoptogenetic Tool for Spatiotemporal Induction of Oxidative DNA Lesions In Vivo. Genes (Basel). 2023 Feb 14;14(2):485. doi: 10.3390/genes14020485.
Further Reading
- Visit the Gurkar Laboratory website and Aging Institute website to learn more about Dr. Gurkar’s research.
The paper below from the Gurkar Laboratory was published in March 2024 and provides evidence for the molecular fingerprint of biological aging, uncovering blood-based biomarkers linked with healthy and rapid aging.
Hamsanathan S, Anthonymuthu T, Prosser D, Lokshin A, Greenspan SL, Resnick NM, Perera S, Okawa S, Narasimhan G, Gurkar AU. A Molecular Index for Biological Age Identified From the Metabolome and Senescence-Associated Secretome in Humans. Aging Cell. 2024; 00:e14104.
