Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans
Nikolaos Tataridas-Pallas,
Yahyah Aman,
Rhianna Williams,
Hannah Chapman,
Kevin J.H. Cheng,
Casandra Gomez-Paredes,
Gillian P. Bates,
John Labbadia
Affiliations
Nikolaos Tataridas-Pallas
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London WC1E 6BT, UK
Yahyah Aman
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London WC1E 6BT, UK
Rhianna Williams
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London WC1E 6BT, UK
Hannah Chapman
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London WC1E 6BT, UK
Kevin J.H. Cheng
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London WC1E 6BT, UK
Casandra Gomez-Paredes
Huntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
Gillian P. Bates
Huntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
John Labbadia
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London WC1E 6BT, UK; Corresponding author
Summary: Fasting has emerged as a potent means of preserving tissue function with age in multiple model organisms. However, our understanding of the relationship between food removal and long-term health is incomplete. Here, we demonstrate that in the nematode worm Caenorhabditis elegans, a single period of early-life fasting is sufficient to selectively enhance HSF-1 activity, maintain proteostasis capacity and promote longevity without compromising fecundity. These effects persist even when food is returned, and are dependent on the mitochondrial sirtuin, SIR-2.2 and the H3K27me3 demethylase, JMJD-3.1. We find that increased HSF-1 activity upon fasting is associated with elevated SIR-2.2 levels, decreased mitochondrial copy number and reduced H3K27me3 levels at the promoters of HSF-1 target genes. Furthermore, consistent with our findings in worms, HSF-1 activity is also enhanced in muscle tissue from fasted mice, suggesting that the potentiation of HSF-1 is a conserved response to food withdrawal.
