Research

Fig. 1: We are working on the molecular mechanisms of ageing, with a focus on the multi-faceted roles of NAD+ in healthy longevity.

Fig. 2: The NAD+ synthetic pathways and the NAD+-consuming enzymes. Image: Fang EF et al., Trends Molecular Medicine, 2017.

Fig. 3. A schematic representation of the molecular mechanisms of mitophagy. Image: Kerr J et al., Fang EF, Trends Neuroscience, 2017.

Fig. 4. A schematic of defective mitophagy in AD and its relations to the AD disease defining pathologies, Abeta and Tau.
Image: Kerr J et al., Fang EF, Trends Neuroscience, 2017.

Fig. 5. Screening of novel compounds which can increase healthy longevity. This is the central roundel of a 4th-century AD mosaic floor from a villa at Hinton St. Mary, Dorset. It is one of the most important early Christian remains from the Roman Empire. The roundel is probably the earliest known mosaic picture of Christ. At either side are pomegranates, signalling immortality. We recently reported that a small compound Urolithin A (UA), affluent in pomegranate, inhibits memory loss in different animal models of Alzheimer´s disease (Fang EF et al., Nature Neuroscience 2019).
Image: Evandro Fang taken from The British Museum. 


Research topics of the Fang group

We are fascinated with the molecular mechanisms of human ageing. We work on several ageing theories, including DNA damage, mitochondrial dysfunction, and stem cell exhaustion. The final goal is to apply our findings to the development of effective interventional strategies for human aging and age-related diseases. There are three major research topics in the laboratory:

1. NAD+ in ageing (Figures 1-2)
The coenzyme NAD+ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of ageing that may lead to a wide range of chronic diseases. Maintenance of NAD+ levels is important for cells with high energy demand and for proficient neuronal function. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, cardiovascular disease, muscle atrophy, and accelerated aging diseases. Emerging evidence suggests that NAD+ decreases in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD+ levels might retard aspects of ageing and forestall some age-related diseases. We are interested in the networks between NAD+ and the 10 hallmarks of ageing. We work on the molecular mechanisms of NAD+ metabolism and consumption, and are exploring its clinical applications. 


2. Defective mitophagy as a new contributor of Alzheimer´s disease (Figures 3-4)
2.1. Mechanisms of mitophagy.
Mitochondria are the powerhouse of the cell. There is an age-dependent deterioration in the quality of mitochondria. Mitochondrial dysfunction contributes to normal aging and to a wide spectrum of age-related diseases. Thus, it is important to maintain a healthy mitochondrial population, which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. We work on the discovery of new mitophagy proteins and how age affects mitophagy machinery.
Image: Kerr JS et al. Fang EF, Trends in Neuroscience 2017

2.2 Mechanisms of defective mitophagy in AD
Alzheimer’s disease (AD) affects 44 million people worldwide and causes formidable economic challenges. Continued failures in clinical anti-AD drug development suggest successful treatments may be found by investigating other molecular mechanisms in AD.  AD neurons experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and leads to the disease- defining Ab and Tau pathologies. Emerging findings suggest that the autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is also compromised in AD, resulting in the accumulation of dysfunctional mitochondria. Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to AD; however, molecular mechanisms remain largely unexplored 4. We are extremely interested in the molecular mechanisms of defective mitophagy in AD and how mitophagy deficiency contributes to AD progression… Strategies directed at maintaining a healthy mitophagy level in AD might have beneficial effects. We are now using AD human iPSCs and AD animal models (mice and C. elegans) in combination with cutting-edge proteomics, microarray, imaging and biochemistry techniques to approach these questions. Our final goal is to unveil AD etiology and discover novel AD drug candidates, which may be more likely to succeed in the clinic.
Image: Kerr JS et al. Fang EF, Trends in Neuroscience 2017

3. The application of artificial intelligence in screening small compounds for Alzheimer´s disease and healthy longevity (Figure 5)
In view of the importance of mitophagy in neuroprotection and healthy longevity, we aim to screen robust but non-toxic mitophagy inducers. We collaborate with the leading artificial intelligence (AI) company Aladdin to propel the speed of drug development.