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Research Interests

Our research focuses on the role of epigenetic changes in the aging process. Ample evidence including our recent work in epigenetic reprogramming suggests that the progressive loss of epigenetic information over time is a key driver of aging. Moving forward, we will investigate how the epigenetic landscape is set up and maintained, how it is disrupted during aging, and how epigenetic deterioration contributes to age-related diseases such as neurodegeneration and cancer. Long-lived species are a great resource for understanding how aging is regulated. We are interested in their cellular and molecular strategies that promote longevity and resistance to age-related diseases. To translate our findings, we will test potential therapeutic effects using human cells and xenograft models.

1. Epigenetic basis of aging

Single nuclei multiomics in aged tissue.

The epigenome establishes cellular identity and function during differentiation. However, alterations to the epigenome accumulate over time, disturbing gene expression patterns and consequently compromising cellular and tissue function. There are many ways epigenetic information can be disrupted such as through DNA repair, stress response, unfaithful transmission post cell division, and stochastic events. Our studies demonstrate that epigenetic information loss induced by DNA double-strand break repair is a cause of mammalian aging. We are currently investigating the epigenetic maintenance mechanisms and their response to different stimuli, aiming to understand the molecular basis of epigenetic deterioration during aging. Future challenges include designing interventions to modify the epigenetic landscape to extend healthspan and lifespan.

2. Cellular rejuvenation to counteract age-related diseases

Aging is the primary risk factor for chronic ailments such as Alzheimer’s disease, cancer, and diabetes. Is it possible to target aging for therapeutic benefits? Our research indicates that age-related epigenetic changes can be reversed by reprogramming factors, and complex tissue functions can be improved. Moving forward, we are interested in testing different cell rejuvenation strategies in disease settings. Our goal from this study is to understand how aging leads to diseases.

Neurogenesis in dentate gyrus.

3. Aging rate determination

This is a naked mole rat, the longest-lived rodent.

Mammalian species age at drastically different rates. For instance, the forest shrew (Myosorex varius) has a lifespan of just two years, while the bowhead whale (Balaena mysticetus) can live beyond 200 years. This lifespan disparity is even seen among closely related species: both being rodents, a naked mole rat (Heterocephalus glaber) lives more than 10 times longer than a lab mouse (Mus musculus). Intriguingly, the longevity evolved in nature isn’t just about lifespan, it’s about a prolonged healthspan with a diminished susceptibility to age-related diseases. For example, naked mole rats rarely get cancer or other age-related diseases. Our previous research has revealed both universal longevity mechanisms such as enhanced DNA double-strand break repair, and species-specific strategies such as high molecular mass hyaluronan (HMM HA) in naked mole rats. We also found that the longevity mechanisms found in long-lived species can be integrated into other species, underlining the profound potential implications of identifying new mechanisms from long-lived species.

Recent studies including ours have revealed that most, if not all, aging hallmarks are attenuated in long-lived species, such as genomic and epigenomic instability, loss of proteostasis, and stem cell exhaustion. Our goal is to understand how their cells counteract these aging mechanisms, thereby slowing down the pace of aging, and decipher how long-lived organisms deter age-related diseases.

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