20 Dec 2012

In 2005, researchers from the Department of Biochemistry of The University of Hong Kong Li Ka Shing Faculty of Medicine discovered that the malfunction of Lamin A protein causes problems in DNA repair and unstable genome, leading to Hutchingson-Gilford Progeria Syndrome (HGPS), a severe early onset of premature aging disorder in human. After six years of continuous hard work, the team further identified Lamin A protein as an activator of the longevity gene SIRT1. They found that Resveratrol, a substance in grape, enhances the binding between Lamin A and SIRT1 to activate SIRT1. Through targeting SIRT1, HKU team has restored stem cells and thus delays the onset of aging and extends healthy lifespan in mouse model of HGPS. It is believed that these findings can be further developed into a novel therapeutic strategy in the management of premature aging and aging-associated degenerative diseases. The study also has a profound impact on the solution of the problems brought about by aging population to our society. The research findings have just been published in the latest issue of a leading scientific journal - Cell Metabolism.

This 6-year study was led by Dr Zhou Zhongjun, Associate Professor and mostly done by Dr Liu Baohua, Research Assistant Professor of the Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine. “We used a mouse model of Hutchinson-Gilford Progeria Syndrome (HGPS) in our study. This work for the first time demonstrates that restoration of stem cells can extend healthy lifespan in accelerated aging. As HGPS shares paralleled mechanism with normal aging, this study may have an important implication in normal aging and aging–related human degenerative disorders. It is particularly important to Hong Kong where the population has become the most long-lived in the world recently for both male and female”, said Dr Zhou.

HGPS: An Important Disease Model for Aging Research

In early 2005, the same research group at HKU uncovered that genomic instability results in HGPS using the same mouse model and patient samples. It revealed that the problems in DNA repair leads to unstable genome, which highly associated with the premature aging occurrence. HGPS patients exhibit aging symptoms as early as six months after birth. They are clinically characterised with early growth retardation, short stature, reduced subcutaneous fat tissue, hair loss, stiff joints and osteoporosis. Patients only survive with an average lifespan of 13 years. Over 90% of the patients die of cardiovascular problem such as atherosclerosis. HGPS is predominantly caused by a specific mutation in LMNA gene. A specific mutation in LMNA gene giving rise to a mutant Lamin A protein, termed as Progerin, causes accelerated aging.

Progerin is also found in normal individual and accumulates in many tissues along aging, suggesting normal aging processes share common mechanisms with HGPS. The difference between normal aging and HGPS patient is that the accumulation of Progerin in HGPS patient is significantly higher than normal people. Aging is a life-long progressive process with gradual deterioration of physiological functions, making the underlying mechanisms extremely difficult to be investigated. Therefore, HGPS provides an important disease model for aging research.

Current study: The Impact of Stem Cells on Aging

In the current study, HKU researchers have investigated the defects in stem cells and the impact of the longevity gene, namely SIRT1, to HGPS. Although dozens of studies showed the reduction in stem cell during aging, it is not clear if the reduction both in number and functions of stem cells are the cause or consequence of aging. In the current study, scientists from HKU found that stem cells decline rapidly in HGPS mouse model and the decline occurs before the appearance of aging. In addition, the activity of SIRT1, a well-known longevity gene involved in various degenerative diseases, was found significantly reduced in the presence of Progerins due to the deposition from the nuclear matrix. While increasing SIRT1 activity could restore stem cells, the study for the first time revealed Lamin A as an endogenous SIRT1 activator and the binding of SIRT1 to Lamin A protein is required for its activity.

Resveratrol activates longevity protein SIRT1 through Lamin A

The researchers tested the effects of resveratrol, a substance which has been claimed to be effective for anti-aging, on stem cells in HGPS mice and got exciting results that resveratrol protects stem cells but not somatic cells. The study further revealed that resveratrol itself cannot activate longevity protein SIRT1. It increases the binding between Lamin A and SIRT1, therefore enhancing Lamin A-mediated SIRT1 activation. Enhancing SIRT1 activity by resveratrol could restore stem cells, delay the onset of aging, improve the general health conditions and extend lifespan by 30% in progerial mice. This suggests that targeting on SIRT1 activity would likely provide a novel therapeutic strategy for HGPS and aging-associated degenerative diseases.

The current study demonstrates that targeting and preventing stem cells from decline would likely delay the onset of HGPS as well as other degenerative diseases. The study provides a therapeutic strategy in restoring stem cells and extending healthy lifespan by targeting on the longevity protein SIRT1. This may have a profound impact on the elderly societies such as Hong Kong.

This therapeutic strategy not only allows the elderly to enjoy a longer healthy life but also significantly reduces the healthcare cost for the society. In addition, by targeting the interaction between Lamin A and SIRT1, novel drugs can be developed to protect our stem cells, prevent and treat degenerative diseases, maintain the good health status and extend our healthy lifespan.

About Research Team and Future Research Prospects

The research team, led by Dr Zhou Zhongjun, come from the Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine. It comprises research staff and postgraduate students, namely Dr Liu Baohua, Shrestha Ghosh, Yang Xi and Wang Zimei. Dr Zhou’s group is now looking for new molecules mimicking Lamin A that can significantly enhance SIRT1 activity, aiming to develop new drugs targeting on stem cells to treat aging related degenerative diseases, such as osteoporosis, cardiovascular and neurological disorders.

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