06 Jun 2020
When we consider frontline health care, we often forget the role that research plays in guiding the practice and tools available to clinicians and carers. CHeBA’s researchers are on the cusp of the latest findings regarding healthy brain ageing, with long-term impact as a primary motivator. Dr Nady Braidy shares his drive to create longstanding impact by translating research into practice.
How did you get into researching the ageing brain?
I started with a Bachelor of Medical Science. My aim was to get into medicine. I was majoring in Pharmacology and Physiology, and my first project looked at mechanisms of action of polyphenols - specifically - resveratrol. This is a naturally occurring polyphenol which is found red wine, grapes and some other fruits and vegetables. Polyphenol molecules are key to the ‘French Paradox’. The French Paradox explains that in France there is a low death rate associated with neurodegenerative diseases compared to other countries. They live longer, but they suffer from hepatic disorders and kidney failure because they are heavy consumers of red wine. The naturally occurring ingredients in red wine are protective to the brain however, the alcohol component is not. During my Honours, my supervisors Professor Gilles Guillemin, Dr Ross Grant and I produced a patent where we developed a formulation which can be used to slow down ageing and neurodegenerative conditions involving the resveratrol molecule, antioxidants and another molecule known as nicotinamide adenine dinucleotide (NAD+). We went further to be the first group in the world to show that NAD+ declines with age. Currently groups in the US including those at Harvard University are working on developing precursors that can increase NAD+ as a strategy for anti-ageing and slowing down age-related degenerative diseases. All the papers these groups publish cite my seminal 2011 paper published in PLOS One.
The foundation for what I wanted to do with my life was to contribute to the community either as a GP, in medical services such as pharmacy or through research.
Medical researchers often have more information than doctors because they are on the frontline of new research. They are the ones developing the tools which doctors will eventually use for patients. Being a medical researcher, I can use my laboratory skills to help people in the longer term.
How I got to this point was through my Bachelor of Medical Science; a three-year course followed by the completion of an additional Honours. After this I studied a Master of Pharmacy at the University of Sydney and simultaneously completed a PhD at the University of New South Wales. Although I have a pharmacy degree, I am not a registered pharmacist as I have not done the requisite 2000 hours of clinical practice training.
Did you experience a ‘defining moment’ which led you to this field?
Whilst I was working on resveratrol, we found that they were not a direct activator of sirtuins, which are a family of NAD-dependent signalling proteins involved in metabolic regulation. Resveratrol still produced some beneficial effects, but through multiple pathways including NAD+, a principle molecule associated with ageing. We decided to find ways of applying this to human research. The first thing we wanted to know is how to measure NAD+ in the clinic and we were the first group to do this. We developed an assay that allows the measurement of at least 17 members of the NAD+ metabolome (or NADome). This can be applied in clinics which was undeniably a defining moment for me; plus the coincidental similarity between ‘NAD’ and my name – Nady!
Do you have any personal interests or activities which are protective behaviours against cognitive decline?
I exercise regularly; it is very important. I like to take long walks and often walk to UNSW’s Kensington campus from Central Station. It is more proactive than getting on a tram and can sometimes take the same amount of time regardless. I also follow a Mediterranean diet which is full of olive oil, fruits and vegetables. It is a diet rich in polyphenols which are packed with antioxidants, anti-inflammatory agents and naturally occurring NAD+ precursors. I am a strong advocate of the health benefits of broccoli; it is full of nicotinamide mononucleotide. Another precursor for NAD+ which I consume regularly and is a nutrient found in milk, is nicotinamide riboside. This compound is also considered one of the main entity precursors on the market when it comes to brain stimulation.
It is not only important to physically exercise, it is just as important to exert psychological effort. When it comes to brain stimulation it is important to do brain activities like reading challenging books. I remember back to when I was a child, I read Lord of the Rings in grades two and three. I finished the entire series as well as the Harry Potter books and other fantasy stories at quite a young age. Currently, I am reading predominantly biomedical journals or clinical textbooks. Other ways to exert psychological effort are by doing crosswords or other quizzes. You should do applications such as quizzes depending on what topics you enjoy; for example, for some people this might be movies – so do quizzes based on them. Another recommendation is sudoku. A few years back I was stuck on a fourteen-hour flight when I started playing with the numbers and realised that not only is it fun to do, it also provides a good brain reboot.
What are you currently researching?
My current laboratory aims are to fully characterise metabolic biomarkers; we want to develop simple tools to diagnose and test the progression and severity of neurodegenerative disease. My particular focus is on Alzheimer’s disease; this is the prognostic approach. My team and I are also looking at exploring therapeutic strategies which we hope can slow down cognitive decline and especially Alzheimer’s disease pathology. We hope to implement these in clinics within the next five to ten years. This involves looking at lipids, proteins and nucleotides which are abnormal in the blood of patients with mild cognitive impairment, Alzheimer’s disease and vascular dementia. We use blood samples from various human cohorts and utilise animal models to gain further insight into interactions between neurodegeneration and vascular pathologies. For example, what constitutes a difference between Alzheimer’s disease and vascular dementia? Some of these pathologies overlap, so there must be better ways to more appropriately diagnose each distinct disorder.
I am also looking at ways of slowing down the ageing process and reducing cognitive decline using methods which revolve around the NAD+ molecule. My group are finding less invasive ways to quantify NAD+ and developing formulations which we can use to increase NAD+ as well as simply understand it better. We are also managing to acquire a better realisation of how NAD+ works in the clinic. To this point, most of the work already done on NAD+ has been conducted on mice and we would like to translate this information directly to humans.
Another project we are working on utilises nanoparticles for theragnostic purpose; as in for therapy and diagnostics. This involves tagging nanoparticles which can cross the blood brain barrier safely with ligands. From a diagnostic point of view, the nanoparticle is coated with a ligand to pathological hallmark eg amyloid beta plaques. Practically, this translates to a clinician injecting a patient with the coated nanoparticle. The nanoparticle will then reach the brain and bind the ligand to amyloid plaque in the brain. Following this the patient would have an MRI scan showing that this nanoparticle has caused a contrast, revealing how the plaque is mapped and distributed in the brain.
We are hoping this method will replace PET imaging, which is expensive, highly toxic and cannot be performed widely. Contrasting this, MRIs are readily accessible and are a cost-effective means of providing more rapid diagnosis.
From a therapeutic perspective, tagging a nanoparticle with drugs which can directly reach the site of damage is more efficacious than current oral drugs which only provide symptomatic relief.
Why is your research important?
My research works in two ways; firstly to diagnose Alzheimer’s disease, vascular dementia and other dementias and, secondly, to provide new therapeutic strategies that can be used to treat these conditions. Significant failures are observable in the success rate of drugs used in clinical trials for Alzheimer’s disease which have cost several billions of dollars globally. By following a holistic approach, looking at naturally occurring products and enhancing cellular biogenetics, a cheaper and more effective alternative can be provided. When we look closely at the pathology of these diseases, we see that mitochondria dysfunction seems to be one of the main pathological hallmarks across almost every neurocognitive disorder.
At CHeBA I follow a multi-disciplinary approach to research. We work with protein and analytical chemists, bioinformatics experts, psychologists, psychiatrists, nurses and have a large student team.
Within CHeBA it has been a multicultural and cross-cultural experience. In my team we have people from some of the most interesting countries in the world. There are a lot of differing cultures at play, so we have learnt a lot about one another and developed some strong friendships.
Working at CHeBA provides you with a unique opportunity to expand your career compared to other institutes because we collaborate with many people within the University and externally. It is one of the leading institutes when it comes to dementia research and has had a profound impact on the dementia community in Australia and abroad.
What is the ultimate hope you have for your research?
I hope to find something that can be translated effectively into clinical practice, whether this is through better diagnosis or therapeutic care, or both. Importantly, something that is of great benefit to consumers and patients affected by Alzheimer’s disease. To be able to provide mums, dads, patients, friends, family and carers with renewed hope is a significant personal aspiration.
This interview was undertakenDr Nady Braidy
Dr Nady Braidy is a Senior Research Fellow and Head of the Brain and Ageing Laboratory at CHeBA. He studied a Bachelor of Medical Science and Honours at UNSW Sydney, completed a Master of Pharmacy at The University of Sydney and his PhD simultaneously at UNSW. Dr Braidy’s interests include answering critical questions surrounding how oxidative stress functions cause brain cell degeneration. Additionally, his work is contributing to the development of strategies that assist the maintenance and improvement of brain and cellular function in older age. He is an active member of the American Alzheimer's Association, International College for Geriatric Psychoneuropharmacology, the Australian Society for Medical Research, the Australian Neuroscience Society, International Society for Tryptophan Research and Neurotoxicity Society. Dr Braidy’s first research project explored naturally occurring polyphenols including resveratrol, a protective agent against cognitive decline found in red wine and grapes.