Associate Professor Doug Smith is a neuroscientist with a long-held interest in how aging impacts the nervous system. Everyone ages but it is clear some individuals age better than others, which suggests that aging is not necessarily non-modifiable. By understanding the mechanisms that cause normal aging it will be possible to increase the proportion of people that age well, thereby increasing a person's health span and quality of life. This will have enormous personal, social and economic impacts on individuals, their families and societies overall. Aging is the major risk factor for neurodegenerative disease, such as Alzheimer's and Parkinson's diseases, and improving our understanding of aging processes will lead to progress for these diseases.
Associate Professor Smith completed his doctoral studies at the University of Queensland and then spent nine years at the University of California San Diego, studying the neural consequences of the metabolic disorder Lesch-Nyhan disease. Since his return to Australia, he has been focusing on aging and uses both discovery-driven as well as more traditional hypothesis-driven approaches to advance our understanding of aging processes. He currently leads a group investigating how aging makes the brain susceptible to Alzheimer’s disease, and in a collaborative project is studying the effects of aging on pain signal processing.
What are your research interests?
We are trying to understand how aging makes the brain susceptible to Alzheimer’s disease (AD). The long-term goal is to understand the mechanisms of aging and AD so that interventions can be developed, allowing individuals to avoid dementia, and have improved quality of life as they age. Many elderly people will develop dementia, with Alzheimer’s disease being the most common dementia. Age is by far the biggest risk factor for this debilitating disease. By understanding how aging impacts the nervous system we hope to mitigate early disease processes, thereby preventing, delaying, or slowing progress to reduce the burden of AD on individuals, families and society.
We primarily use genomics (RNA-Seq, microarray, qPCR), lipidomics (LC and GC/MS), protein, electrophysiological and behavioural approaches to determine how aging changes central (brain and spinal cord) and peripheral (e.g. inner ear vestibular apparatus) nervous system structures and functions. For example, using RNA deep sequencing we have characterised how aging disrupts the transcriptome in various regions of the central nervous system (CNS). Intriguingly, we found not all CNS regions are similarly affected. This has implications for intervention, meaning a single intervention may not be beneficial for the whole CNS.
A major challenge to obtaining a comprehensive understanding of the impacts of aging on the brain and other nervous system structures, is that it is not known whether age-related changes are common across all cell types of the CNS, or whether they occur in a cell-type-specific manner. This is particularly important for the nervous system given it is extremely diverse in terms of cell types. To address this issue, we are characterising genomic changes in specific populations of cells using state-of-the-art, fluorescence-activated nuclei sorting (FANS), laser-based microdissection, and cell-type-specific genomics. FANS is particularly appealing as archived frozen tissue can be used as source material, making it applicable to human tissue. We are currently using these approaches to investigate how aging changes cholesterol metabolism in different brain cell types, as disrupted brain cholesterol metabolism is strongly implicated in AD.
An important aspect of our studies relates to the broader and important issue of whether aging processes can be modified. For example, intermittent fasting is thought to be beneficial to health span and we are finding out whether this type of intervention can alter age-related genomic, proteomic, and lipidomic changes in the brain. Early indications are that intermittent fasting has significant benefits to brain health span.
Why did you get into research?
I am curious and want to know how things work, and the brain is the most complex organ in the body and arguably the most challenging to understand – hence the appeal. Hopefully, in the long term I will make a meaningful contribution to understanding the aging brain and Alzheimer’s disease.
What would be the ultimate goal for your research?
The ultimate goal is an understanding of aging and AD processes so that it will be possible to modify the processes to improve the quality of life for the elderly. In other words, to increase brain health span.
Well over 1000 clinical trials for AD have been completed, yet an effective treatment has not resulted. This is likely due to our incomplete understanding of the disease processes. We are addressing this issue.
The longer-term goal is to move our basic neuroscience findings into practical human use.
- Aging laboratory model
- Alzheimer’s disease
- CNS cholesterol homeostasis
- CNS protein homeostasis
- HMRI Brain Neuromodulation Program
- Australasian Neuroscience Society
ABC Newcastle interview - 13 August 2019