Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging
- 1Yale University School of Medicine
Abstract
Elevated sulfur-containing amino acids (SAA; methionine and cystine) are linked to human mortality. While methionine restriction (MR) extends lifespan in animals, it is often ignored that traditional longevity-promoting MR diets also lack cystine. When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via cystathionine {gamma}-lyase (CTH) in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged Cth-/- mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.
Related
- Complete Response Demonstrated by [11C]methionine-PET Imaging of a Patient With Squamous-cell Carcinoma of the Tongue Treated With Chemotherapy, Immunotherapy and Methionine Restriction Without Radiation or Surgery: A Potential New Low-toxicity Treatment Paradigm for a Recalcitrant Disease
- Cysteine promotes islet α-cell glucagon secretion by limiting oxidative inhibition of voltage-gated sodium channels
- Intratumoral Fusobacterium nucleatum promotes ferroptosis resistance and a disulfide-stress-associated vulnerability under glucose restriction.
- Motor Module-Guided Human-Machine Interaction Promotes Improvement of Neuromuscular Coordination and Reduction in Motor Impairment in Chronic Stroke: A Pilot Study
- A pH-Dependent Curcumin–Iminosugar Hybrid Promotes GCase Enhancement and Reactive Oxygen Species Reduction
BibTeX
@misc{orliaguet2026cysteine,
title = {{Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging}},
author = {L. Orliaguet and H.-H. Kim and P. Gupta and A. Lee and Y. Lei and R. Li and C. Zeng and Y.-H. Youm and T. Dlugos and C. Guan and A. Wang and M. Artyomov and Y. Kluger and B. Schumacher and V. D. Dixit},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749519},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749519v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging
AU - L. Orliaguet
AU - H.-H. Kim
AU - P. Gupta
AU - A. Lee
AU - Y. Lei
AU - R. Li
AU - C. Zeng
AU - Y.-H. Youm
AU - T. Dlugos
AU - C. Guan
AU - A. Wang
AU - M. Artyomov
AU - Y. Kluger
AU - B. Schumacher
AU - V. D. Dixit
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749519
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749519v1
AB - Elevated sulfur-containing amino acids (SAA; methionine and cystine) are linked to human mortality. While methionine restriction (MR) extends lifespan in animals, it is often ignored that traditional longevity-promoting MR diets also lack cystine. When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via cystathionine {gamma}-lyase (CTH) in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged Cth-/- mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.
ER -