CUHK develops the world's first senescent cell atlas in skeletal muscle revealing cell ageing ‘‘switches’’ and a new anti-ageing drug that can reverse sarcopenia
The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine) has developed the world’s first atlas mapping cell ageing in human skeletal muscle. Leveraging advanced single nucleus multiomics and a proprietary, unified senescence scoring (USS) algorithm, the research team has successfully characterised thesenescence, or cell ageing, and regulatory mechanisms of human skeletal muscle. The study also discovered new druggable targets for precise muscle ageing intervention and treatment, and unravels the potential of Maraviroc, a small-molecule drug, to slow and mitigate this process. It paves the way for the development of new drug senotherapeutics for sarcopenia, which will revolutionise anti-muscle ageing strategies. The groundbreaking findings have been published in the prestigious journal Nature Communications.
Featured are research team members including (from left) Dr Michael Tim-yun Ong, Clinical Assistant Professor from theDepartment of Orthopaedics and Traumatology; Professor Huating Wang and Dr Yang Li, the co-first author of the study and post-doctoral fellow, both from theDepartment of Orthopaedics and Traumatology.
Effective pharmacological intervention is needed for sarcopenia
Skeletal muscle is a vital organ to maintain the steady state and mobility of the human body. Sarcopenia is not merely a result of a loss of the muscle mass due to ageing, but also a progressive decline in muscle strength and function that raises the risk of falls and fractures. In severe cases, excessive muscle loss can lead to disability or even death.
Dr Michael Ong highlights that age, gender, genetic factors, chronic disease, lifestyle risks and sarcopenic obesity are key risk factors of sarcopenia but early diagnosis is extremely challenging and there has been no effective medication for the disease.
Ms Tang shares that she was not aware of having sarcopenia until she visited the clinic due to backpain two years ago. Apart from having physical therapy, more regular exercise and nutritional supplementation, the potential development of a novel drug treatment would be great news to those with sarcopenia.
Up to 10% of individuals aged 60 and above are estimated to be affected by sarcopenia globally. In Hong Kong, one in seven people aged 65 or above, and one in two aged over 80 are estimated to suffer from the disease. The serious health risks faced by patients should not be overlooked but the underlying causes of sarcopenia remain less understood.Senescent cells and the associated secretory phenotypes (SASPs) are recognised as key drivers of tissue ageing but their roles in muscle tissue have been underexplored.
The first cell ageing atlas set new benchmarks for action against muscle ageing
The research team collected live muscle tissue samples from 10 healthy male participants[1] and isolated over 50,000 nuclei for single nucleus multiomics sequencing. By integrating data from five senescence gene databases, the team developed the USS algorithm and created the first atlas to map cell ageing in aged human muscle.
According to the atlas, a robust induction of SASP factors were found in aged cells of the skeletal muscle of the elderly adults. Muscle stem cells (herein MuSCs) exhibited abnormally high expression of SASP factors such as CCL3, CCL4, CCL5 and their receptor CCR5, spreading ageing signals to surrounding cells and promoting chronic inflammation, fibrosis and progenitor cell (also considered a regenerative cell) dysfunction which accelerate sarcopenia progression.
Drug repurposing offers new directions for clinical intervention in muscle ageing
Professor Huating Wang shares that the remarkable anti-ageing effect of Maraviroc, a CCR5 antagonist and a small-molecule anti-HIV drug, in mice offers a new strategy to reverse sarcopenia caused by cell ageing.
Maraviroc, a CCR5 antagonist and a small-molecule anti-HIV drug, was found to be a potential new drug for sarcopenia. Having been administered with a high dose of Maraviroc for three months, the elderly mice improved remarkably in muscle morphology, including increased cross-sectional areas of muscle fibres and improved muscle function. Grip strength and running endurance improved significantly. Based on histological analysis, inflammatory infiltration dropped by 50% and cell ageing declined notably. The findings prove that Maraviroc can reverse muscle ageing by blocking SASP-mediated intercellular signalling.
Cell ageing switches identified as new druggable targets for therapeutic purposes
ATF3 and JUNB, two key transcription factors that serve as “switches” of SASP activation were also identified. With a 133% increase in expression level, JUNB was proven to be highly active in aged MuSCs, a critical regulator of cell ageing. This major discovery, further validated in mice, presents a new target for drug development aimed at muscle ageing intervention.
‘‘The atlas enables researchers to explore further intothe molecular mechanisms and pathways driving age-related muscle ageing. The ageing scoring system so developed also helps identify ageing cells within tissues,” said Dr Li Yang, the co-first author of the study and a postdoctoral fellow. Another co-first author is Dr Li Chuhan, a recent PhD graduate of CUHK.
Dr Michael Ong Tim-yun, Clinical Assistant Professor from theDepartment of Orthopaedics and Traumatology, added: ‘‘Most people begin to experience muscle loss from the age of 30, and individuals aged 65 and above are at high risk of developing sarcopenia. However, the disease has no obvious symptoms, leaving many cases underdiagnosed. There are no effective medications available and current treatments are largely limited to non-pharmacological approaches such as physical therapy and nutritional supplementation. The findings open a new horizon for anti-ageing drug therapy that will help lower the risk of hospitalisation and mortality of this hidden disease.”
Professor Wang Huating from theDepartment of Orthopaedics and Traumatology, said: ‘‘The ageing population is among the most pressing global challenges nowadays. The shrinking of the workforce that it caused has a profound impact on social systems, fiscal pressure and industrial structures. Slowing or reversing ageing-related organ ageing has become a major focus in biomedical research. Going forward, we are planning to conduct human clinical trials and advance clinical translation of the related drug to explore more novel treatment for sarcopenia, particularly osteoarthritis-associated sarcopenia.”
The research was funded by InnoHK initiative of the Hong Kong government’s Innovation and Technology Commission, the Hong Kong Research Grants Council, and several national programmes of the Chinese government.
[1] The samples were collected from five young adults aged 19 to 27 and five elderly adults aged 60 to 77. Compared with young muscle tissues, ageing cells among the four major cell types within the microenvironment of aged skeletal muscle, namely muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), endothelial cells (ECs) and smooth muscle cells (SMCs) surged by 54%, 715%, 34% and 757% respectively.
