Mapping the cellular landscape of aging muscles

A new atlas of aging human muscle reveals processes behind muscle deterioration and could spotlight paths to combat sarcopenia and frailty.

Muscle aging leads to sarcopenia and frailty, and can have a profound impact on quality of life, independence and healthcare costs. Now the publication earlier this week of the first comprehensive cell atlas of aging human muscle should shed light on how the effects of aging on muscles can be tackled.

Longevity.Technology: Understanding the intricacies of muscle aging – both the why and the how – has long been a pursuit in scientific research, and this human muscle cell atlas represents a significant milestone in geroscience. The new human muscle map should reveal the genetic and cellular processes governing muscle deterioration and the mechanisms deployed by our bodies to counteract these effects.

Researchers from the Wellcome Sanger Institute and Sun Yat-sen University, China collaborated to understand the complex interplay of cellular dynamics within aging muscles. By leveraging single-cell technologies and advanced imaging techniques, they analyzed skeletal muscle samples from 17 individuals spanning the adult lifespan. Through comparative analyses, they uncovered novel cell populations and identified the compensatory mechanisms employed by muscles to combat the ravages of time [1].

The resultant atlas, published in Nature Ageing, not only maps the cellular blueprint of aging muscles, but also by identifying compensatory mechanisms used by muscles to combat aging and identifying distinct cell populations that dictate the pace of muscle aging, opens a door to potential therapeutic targets for ameliorating age-related muscle decline.

The researchers identified dysregulation in genes governing ribosomal function – a hallmark of impaired protein synthesis – in aged muscle stem cells. This impairment compromises the cells’ regenerative capacity, exacerbating age-related muscle degeneration. Additionally, heightened production of the pro-inflammatory molecule CCL2 by non-muscle cell populations further exacerbates muscle deterioration, underscoring the role of inflammation in age-related pathophysiology [1].

The study also identified several compensatory mechanisms orchestrated by muscles to mitigate the loss of fast-twitch muscle fibers – a critical component of explosive muscle performance. Notably, a phenotypic shift in slow-twitch fibers towards characteristics characteristic of the lost fast-twitch subtype was observed, alongside enhanced regeneration of extant fast-twitch fiber subtypes [1]. These adaptive responses underscore the remarkable plasticity of muscle tissue in the face of aging-related stressors.

In addition, the researchers identified specialized nuclei populations within the muscle fibers; these help rebuild the connections between nerves and muscles that decline with age, and knockout experiments using lab-grown human muscle cells were used by the research team to confirm the importance of these nuclei in maintaining muscle function [1].

Veronika Kedlian, first author of the study from the Wellcome Sanger Institute, said: “Our unbiased, multifaceted approach to studying muscle ageing, combining different types of sequencing, imaging and investigation reveals previously unknown cellular mechanisms of ageing and highlights areas for further study [2].”

Professor Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, China, said: “In China, the UK and other countries, we have ageing populations, but our understanding of the ageing process itself is limited. We now have a detailed view into how muscles strive to maintain function for as long as possible, despite the effects of ageing [2].”

This study is part of the Human Cell Atlas initiative, an international collaborative consortium that is aiming to map every cell type in the human body in an effort to transform understanding of health and disease.

Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: “Through the Human Cell Atlas, we are learning about the body in unprecedented detail, from the earliest stages of human development through to old age. With these new insights into healthy skeletal muscle ageing, researchers all over the world can now explore ways to combat inflammation, boost muscle regeneration, preserve nerve connectivity, and more. Discoveries from research like this have huge potential for developing therapeutic strategies that promote healthier ageing for future generations [2].”

Against the backdrop of an aging global population, the prevalence of sarcopenia has escalated, with recent estimates suggest that approximately 25% of older adults are afflicted by sarcopenia [3]. Sarcopenia has various adverse outcomes including frailty, falls, immobility and diminished autonomy, and despite its burgeoning impact, sarcopenia has no approved pharmacotherapies, with current advice being increased physical activity and a healthy diet.

By deepening our understanding of muscle biology and muscle cell aging, the new muscle cell atlas should pave the way for targeted interventions aimed at preserving muscle health and extending healthspan. Hopefully insights gained from this comprehensive cellular roadmap will lead to innovative therapeutics that attenuate age-related muscle decline, and promote independence and vitality in aging populations.