Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Mariah F. Calubag; Ismail Ademi; Cara L. Green; Dulmalika N.H. Manchanayake; Hashan S.M. Jayarathne; Ryan N. Marshall; Sandra M. Le; Penelope Lialios; Lucia E. Breuer; Shoshana Yakar; Reji Babygirija; Michelle M. Sonsalla; Isaac Grunow; Chung Yang Yeh; Yang Liu; Bailey A. Knopf; Sarah Yandell; Charles I. Opara; William A. Ricke; Teresa T. Liu; Mark P. Keller; Alan D. Attie; Marianna Sadagurski; Dudley W. Lamming

doi:10.1038/s43587-026-01169-0

Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Mariah F. Calubag
, Ismail Ademi
, Cara L. Green
, Dulmalika N.H. Manchanayake
, Hashan S.M. Jayarathne
, Ryan N. Marshall
, Sandra M. Le
, Penelope Lialios
, Lucia E. Breuer
, Shoshana Yakar
, Reji Babygirija
, Michelle M. Sonsalla
, Isaac Grunow
, Chung Yang Yeh
, Yang Liu
, Bailey A. Knopf
, Sarah Yandell
, Charles I. Opara
, William A. Ricke
, Teresa T. Liu

Mark P. Keller, Alan D. Attie, Marianna Sadagurski, Dudley W. Lamming

Department for Health

University of Wisconsin-Madison
William S. Middleton Memorial Veterans Hospital
Department of Medicine
Wayne State University
New York University College of Dentistry
Endocrinology and Reproductive Physiology Program
Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging
St. John Fisher University
University of Wisconsin Carbone Cancer Center

Research output: Contribution to journal › Article › peer-review

Abstract

Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

Original language	English
Number of pages	33
Journal	Nature Aging
Early online date	24 Jul 2026
DOIs	https://doi.org/10.1038/s43587-026-01169-0
Publication status	E-pub ahead of print - 24 Jul 2026

Data Availability Statement

RNA sequencing data have been deposited with the Gene Expression Omnibus and are accessible through accession no. GSE298741. Source data are provided with this paper.

Funding

The Lamming Laboratory is supported in part by the National Institutes on Aging (NIA; grant nos. AG056771, AG081482, AG084156, AG085898 and AG094153), the Wisconsin Partnership Program, and startup and other funds from UW–Madison. D.W.L. and W.A.R. are members of the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, and this work was supported by facilities and resources within the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging (grant no. P30 AG092586). The Lamming Laboratory was supported in part by the US Department of Veterans Affairs (grant no. IS1-BX005524), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. M.F.C. was supported by F31AG082504. C.L.G. was supported in part by Dalio Philanthropies, a Glenn Foundation Postdoctoral Fellowship, and by Hevolution Foundation award HF-AGE AGE-009. R.N.M. was supported by a Glenn Foundation Postdoctoral Fellowship and a Glenn Foundation Postdoctoral Fellowship Continuation Award. R.B. was supported by F31AG081115. C.-Y.Y. was supported in part by a NIA F32 postdoctoral fellowship (grant no. F32AG077916) and a NIA K99 award (grant no. K99AG084921). The Sadagurski Laboratory is supported in part by the National Institute of Environmental Health Sciences (grant no. R01ES033171) and NIA (grant no. RF1AG078170). T.T.L. was supported by K01 AG059899. The authors used the UW–Madison Biotechnology Center Gene Expression Center (RRID: SCR_017757), which is supported in part by the UWCCC (grant no. P30CA014520). The UWCCC Experimental Animal Pathology Laboratory is supported by P30 CA014520 from the NIH/National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the US government.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Ageing
Geriatrics and Gerontology

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10.1038/s43587-026-01169-0Licence: CC BY-NC-ND

Cite this

Calubag, M. F., Ademi, I., Green, C. L., Manchanayake, D. N. H., Jayarathne, H. S. M., Marshall, R. N., Le, S. M., Lialios, P., Breuer, L. E., Yakar, S., Babygirija, R., Sonsalla, M. M., Grunow, I., Yeh, C. Y., Liu, Y., Knopf, B. A., Yandell, S., Opara, C. I., Ricke, W. A., ... Lamming, D. W. (2026). Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice. Nature Aging. Advance online publication. https://doi.org/10.1038/s43587-026-01169-0

Calubag, MF, Ademi, I, Green, CL, Manchanayake, DNH, Jayarathne, HSM, Marshall, RN, Le, SM, Lialios, P, Breuer, LE, Yakar, S, Babygirija, R, Sonsalla, MM, Grunow, I, Yeh, CY, Liu, Y, Knopf, BA, Yandell, S, Opara, CI, Ricke, WA, Liu, TT, Keller, MP, Attie, AD, Sadagurski, M & Lamming, DW 2026, 'Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice', Nature Aging. https://doi.org/10.1038/s43587-026-01169-0

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abstract = "Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23\%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.",

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AU - Jayarathne, Hashan S.M.

AU - Marshall, Ryan N.

AU - Le, Sandra M.

AU - Lialios, Penelope

AU - Breuer, Lucia E.

AU - Yakar, Shoshana

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AU - Sonsalla, Michelle M.

AU - Grunow, Isaac

AU - Yeh, Chung Yang

AU - Liu, Yang

AU - Knopf, Bailey A.

AU - Yandell, Sarah

AU - Opara, Charles I.

AU - Ricke, William A.

AU - Liu, Teresa T.

AU - Keller, Mark P.

AU - Attie, Alan D.

AU - Sadagurski, Marianna

AU - Lamming, Dudley W.

PY - 2026/7/24

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Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Abstract

Data Availability Statement

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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