VY Lab

The continued and steady rise of the ageing population worldwide will post major challenges to societies for managing the socioeconomic impacts caused by the dramatic increase in disease burdens as ageing is widely recognized as the single most significant risk factors for majority of the major diseases affecting humans. Ageing is mediated, in part, by accelerating accumulation and/or decelerating removal of damaged cells and intracellular components resulting from oxidative stress and oncogenic events triggered by carcinogens or mutations.

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Cellular senescence, a hallmark of ageing, is an irreversible form of cell cycle arrest that is acquired when cells fail to recover from damages. While short-term inflammation can facilitate removal of senescent cells by the immunosurveillance system, a decline in removal of senescent cells during ageing promotes chronic inflammation and development of diseases. Hence, understanding how distinct cell types and tissues respond to cellular damages may yield novel insights therapeutic solutions to mitigate the functional decline associated with the ageing process. While some compounds such as rapamycin and senolytics have already shown promising results in slowing down ageing-associated declines in pre-clinical models, in-depth understanding of the ageing process at the molecular, cellular and organ levels is required to permit development of targeted approaches in addressing ageing-associated diseases in specific organs such as liver.

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MOAP-1 (Modulator-of-apoptosis-1) was originally cloned as a Bax-binding protein enriched in the outer mitochondrial membrane to facilitate Bax-mediated apoptosis signalling. Recently, we also uncovered additional functions of MOAP-1 in regulating oxidative stress response and autophagy signalling. 

Interestingly, recent observation by comparing the wild-type and MOAP-1 knockout (KO) C57BL/6 mice (18-24 months old) mimicking the ageing population in human showed that about half of the aged MOAP-1 KO mice exhibited abnormalities in the liver, while none of the wild-type mouse at the same age displayed any notable abnormality. Analysis using an in vitro model of the human hepatocytes also showed that MOAP-1 deficiency leads to a marked elevation in the percentage of cells displaying higher level of senescence and inflammation markers.

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Emerging evidence suggests that age is a major risk factor for non-alcoholic fatty liver disease (NAFLD). NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and even liver cancer. Based on phenotypes observed in MOAP-1 deficient aged mice and hepatocytes, we hypothesize that MOAP-1 is a key negative regulator of development of NAFLD-associated disorders in the liver during ageing.