| Title: | Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia |
| Journal: | Nature Aging |
| Published: | 16 Dec 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37118545/ |
| DOI: | https://doi.org/10.1038/s43587-022-00309-6 |
Publication 10829
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Abstract
Age-related muscle dysfunction and sarcopenia are major causes of physical incapacitation in older adults and currently lack viable treatment strategies. Here we find that sphingolipids accumulate in mouse skeletal muscle upon aging and that both genetic and pharmacological inhibition of sphingolipid synthesis prevent age-related decline in muscle mass while enhancing strength and exercise capacity. Inhibition of sphingolipid synthesis confers increased myogenic potential and promotes protein synthesis. Within the sphingolipid pathway, we show that accumulation of dihydroceramides is the culprit disturbing myofibrillar homeostasis. The relevance of sphingolipid pathways in human aging is demonstrated in two cohorts, the UK Biobank and Helsinki Birth Cohort Study in which gene expression-reducing variants of SPTLC1 and DEGS1 are associated with improved and reduced fitness of older individuals, respectively. These findings identify sphingolipid synthesis inhibition as an attractive therapeutic strategy for age-related sarcopenia and co-occurring pathologies.</p>
23 Authors
- Pirkka-Pekka Laurila
- Martin Wohlwend
- Tanes Imamura de Lima
- Peiling Luan
- Sébastien Herzig
- Nadège Zanou
- Barbara Crisol
- Maroun Bou-Sleiman
- Eleonora Porcu
- Hector Gallart-Ayala
- Michal K. Handzlik
- Qi Wang
- Suresh Jain
- Davide D'Amico
- Minna Salonen
- Christian M. Metallo
- Zoltan Kutalik
- Thomas O. Eichmann
- Nicolas Place
- Julijana Ivanisevic
- Jari Lahti
- Johan G. Eriksson
- Johan Auwerx
1 Application
| Application ID | Title |
|---|---|
| 48020 | Exploring Diet/Lifestyle/Health factors as causes and modifiers of genetic determinants of healthspan, ageing and longevity |
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