Fundamental Research
We aim to add healthy years of life by delaying ageing, prolonging disease-free life and adding quality by allowing people to be more active and engaged
Our Goals
- To identify, understand and manipulate common pathways that modulate ageing and to seek methods for translation to humans
- To create a new “Health” care-based strategy for delaying or reversing ageing biomarkers in humans
Initiatives
Mouse Intervention platform:
- First-of-its-kind frailty measure in mice
- Relates to human frailty & responsive to short 6 months intervention in mice
- Suite of biomarkers that assess ageing in mice & humans
Theme-based programmatic grant:
- Repurposing drugs / natural products (B. Kennedy)
- Reproductive Longevity (B. Kennedy)
Biomarkers:
- SG90 & SG60 Longevity Cohorts - Generational cohort studies
- Ageing BIOlogy Study in Singaporeans (ABIOS) - Deep phenotyping
Sub-themes
HL TRP is a place where biologists, bioinformaticians, and clinicians work together to answer questions about ageing. Fundamental research in this sub-theme utilises cell lines, invertebrates, fish, and rodents as the main species to investigate biological mechanisms underlying ageing and to test the effects of interventions such as small molecules, drugs, or natural products on ageing biomarkers. These models enable us to find out whether the intervention increases healthspan or lifespan, or whether it delays systemic or organ-specific ageing (such as brain or reproductive system), and if so, through which pathways. Moving from cell and animal models, our bioinformaticians utilise quantitative models to predict biological ageing and identify targets of interest for ageing intervention. Last but not least, several ongoing clinical trials are being run to find out the effects of pharmaceutical and lifestyle intervention on ageing biomarkers in human.
Various dietary, pharmaceutical, and genetic interventions have been found to increase the lifespan of laboratory animals. Several of these interventions are now being explored for clinical application.
To understand the physiologic action and therapeutic potential of interventions in ageing, researchers must build quantitative models.
Do interventions delay the onset of ageing? Slow it down? Merely ameliorate some of its symptoms? If interventions slow some ageing mechanisms but accelerate others, can we detect or predict the systemic consequences? Statistical and analytic models provide a crucial framework in which to answer these questions and clarify the systems-level effect of molecular interventions in ageing.
The sub theme aims to survey approaches to modeling lifespan data and places them in the context of recent experimental work.
Exposure to stress could cause cells to become senescent and senescence is thought to be an initial step to ageing. An inflammatory response is one of the hallmarks of cellular senescence. It both propagates the senescence process and facilitates its clearance. Senescence–inflammatory response may support tumor proliferation and invasion. Blocking the response is potentially therapeutic in cancer and age-related diseases.
Our research investigates several stress response mechanisms, including but not limit to genomic stability, DNA damage response, ROS and redox mechanism, and autophagy.
The sub-theme aims to examine the intricate link between biological resilience in term of stress and infection to the process of cellular senescence.
Mitochondria play a key in the regulation of many immune functions through metabolic control, calcium homeostasis and ROS production, thus assisting host defenses against pathogens. Mitochondria integrate fuel metabolism to generate energy in the form of ATP. Mitochondria oxidize pyruvate (derived from glucose or lactate), fatty acids and amino acids to harness electrons onto the carriers NADH and FADH2. Ageing is associated with progressive mitochondrial dysfunction that occurs due to the accumulation of mitochondrial DNA (mtDNA) mutations and increased reactive oxygen species (ROS) production that causes oxidative damage to cellular macromolecules, thereby leading to reduced respiratory chain activity and adenosine triphosphate (ATP) generation.
Our research looks into mechanisms related to mitochondrial biogenesis, mitophagy, mitochondrial calcium & redox signaling upon ageing. We also try to understand mechanisms regulating ageing-related metabolic syndromes.
Our Goals
Mouse Model
To understand the mechanisms and age-related changes in ageing skeletal muscle:
- Altered mTOR signaling
- Abnormal metabolism
- Dysfunctions in neuromuscular junction
Clinical Studies
To explore biomarkers of frailty and sarcopenia in humans
Interventions
Lifestyle interventions, repurposing drugs and natural products on delaying frailty and sarcopenia:
- Mice
- Humans
Initiatives
Mouse Intervention platform:
- First-of-its-kind frailty measure in mice
- Relates to human frailty & responsive to short 6 months intervention in mice
Interventions:
- REjuvenate SenescenT hallmarks of Older adults through Regular Exercise (RESTORE)
- AKG Clinical Trial (ACT)
Our Goals
- Continue to build on our strengths in neural plasticity, neurodegenerative and neurological disorders
- Expand to healthy brain ageing using various animal models and in humans
- To form a Mental Health Research Alliance for Singapore
Initiatives
NUSMed-FoS Joint Program on Health Transformation:
- Healthy Brain Ageing - Preservation of functional brain connectivity and plasticity
LKCMed / NUSMed / NHG alliance to study Mental Health:
- 500,000 from each institution to kick-start a seed grant call (Deadline: 30 June 2020)
- Mental health symposium (2021) co-organized by NUSMed / IMH / GIS / LKCMed / Broad Institute
Vision: To form a Mental Health Research Alliance for Singapore
Prospective grant:
- LCG on mental health
Sub-themes
Neuroscience is inherently interdisciplinary in its quest to explain the brain. Like all biological structures, the brain operates at multiple levels, from nano-scale molecules to meter-scale systems.
Synaptic degeneration and death of nerve cells are defining features of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the two most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable.
Neurodegenerative diseases affect millions of people worldwide. Alzheimer’s disease and Parkinson’s disease are the most common neurodegenerative diseases. Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. Although treatments may help relieve some of the physical or mental symptoms associated with neurodegenerative diseases, there is currently no way to slow disease progression and no known cures.
The risk of being affected by a neurodegenerative disease increases dramatically with age. More Americans living longer means more people may be affected by neurodegenerative diseases in coming decades. This situation creates a critical need to improve our understanding of what causes neurodegenerative diseases and develop new approaches for treatment and prevention.
Scientists recognize that the combination of a person’s genes and environment contributes to their risk of developing a neurodegenerative disease. That is, a person might have a gene that makes them more susceptible to a certain neurodegenerative disease. But whether, when, and how severely the person is affected depends on environmental exposures throughout life.
Key research challenges are identifying and measuring exposures that may have occurred before an individual is diagnosed and disentangling the effects of these exposures.
Our Goals
- To understand the disease mechanisms underlying stroke and vascular cognitive impairment (VCI)
- Explore blood-based, genetic and neuroimaging biomarkers for assessing clinical progression of VCI and commercial applications
- Conduct intervention trial to prevent cognitive decline
Initiatives
Theme-based programmatic grant:
- LCG: Vascular cognitive impairment
Sub-themes
Ageing is the most robust non-modifiable risk factor for incident stroke, which doubles every 10 years after age 55 years. Approximately three-quarters of all strokes occur in persons aged ≥65 years.
With ageing, both cerebral micro- and macro-circulations undergo structural and functional alterations. Age-related microcirculatory changes are presumably mediated by endothelial dysfunction and impaired cerebral autoregulation and neurovascular coupling. Whereas endothelial dysfunction promotes neuro-inflammation, impaired cerebral autoregulation may lead to microvascular injury, and impaired neurovascular coupling fosters a decline in cortical function, all potential targets for future therapeutic interventions. Ageing, in otherwise healthy individuals, is associated with numerous noticeable changes in human intracranial and extracranial cerebral arteries that predict the risk of future stroke.
As human life expectancy rises, the aged population will increase. Ageing is accompanied by changes in tissue structure, often resulting in functional decline. For example, ageing within blood vessels contributes to a decrease in blood flow to important organs, potentially leading to organ atrophy and loss of function. In the central nervous system, cerebral vascular ageing can lead to loss of the integrity of the blood-brain barrier, eventually resulting in cognitive and sensorimotor decline. One of the major of types of cognitive dysfunction due to chronic cerebral hypoperfusion is vascular cognitive impairment and dementia (VCID). In spite of recent progress in clinical and experimental VCID research, our understanding of vascular contributions to the pathogenesis of VCID is still very limited. The prevalence of vascular cognitive impairment (VCI), which includes milder forms of cognitive impairment, is strongly age related. In subjects aged 65 to 84 years, the prevalence of mild forms of VCI not qualifying for dementia is higher than that of Vascular dementia (VaD).