Longer lipids mark aging and constrain lifespan.

Weisha Li, Bauke V Schomakers, Maria M Trętowicz, Laura Hartshorne, Jonathan Sulc, Helgi I Ingólfsson, Tugba N Ozturk, Rob Ofman, Luc Legon, Kasandra Ippel, Michel van Weeghel, Martin A T Vervaart, Eric J M Wever, Simone W Denis, Signe Mosegaard, Adriana S Passadouro, Arwen W Gao, Hans R Waterham, Joris Hoeks, Patrick Schrauwen, Gajja S Salomons, Evan G Wiliams, Paul M L Janssen, Vincent A J Warnaar, Linda Partridge, Johan Auwerx, Sebastian Grönke, Mirre J P Simons, Jolanda van der Velden, Frédéric M Vaz, Riekelt H Houtkooper, Georges E Janssens

Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands. · pubmed

Paper

Abstract

Aging drives molecular changes that impair cellular and tissue function. Lipids are central to membrane structure, signaling and energy storage, yet their remodeling during aging remains unclear. Here, using cross-species, multi-tissue lipidomics, we identify elongation of lipid acyl chains as a conserved hallmark of aging across mice, Caenorhabditis elegans, Drosophila and humans. Similar lengthening occurs during the progression of human heart disease, whereas dietary restriction shortens cardiac lipids in mice. Integrated analyses reveal that aging is characterized by a shift toward longer lipids accompanied by depletion of shorter species, indicating ratiometric remodeling. Following this, we identify the lipid remodeler Plb1 as a regulator of this process, with expression correlating with lifespan in mice and genetic analyses supporting a causal role in human frailty. In C. elegans, Plb1 knockdown reverses lipid elongation and extends lifespan in a lipid-length-dependent manner. Together, these findings establish lipid chain length remodeling as a conserved, actionable hallmark of aging.

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Research summary

Lipid acyl chain elongation is a conserved hallmark of aging that can be reversed by targeting the lipid remodeler Plb1 to extend lifespan. This paper is highly relevant because it identifies a specific, conserved molecular mechanism (lipid remodeling) that causally links to lifespan extension in model organisms and correlates with human frailty, offering a potential therapeutic target for aging itself rather than just age-related symptoms.

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