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Peer-reviewedCC BY-NC-NDNature Aging

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

  • Mariah F. Calubag1,2,3,4
  • Ismail Ademi1,3,4
  • Cara L. Green5,1,3,4
  • Dulmalika N. H. Manchanayake6,7,8
  • Hashan S. M. Jayarathne6,7,8
  • Ryan N. Marshall1,3,4
  • Sandra M. Le1,3,4
  • Penelope Lialios1,3,4
  • Lucia E. Breuer1,3,9
  • Shoshana Yakar10,4
  • Reji Babygirija1,2,3,4
  • Michelle M. Sonsalla11,1,3,4
12 more authors
  • Isaac Grunow1,3,4
  • Chung-Yang Yeh1,3,4
  • Yang Liu1,12,3,4
  • Bailey A. Knopf1,2,3,4
  • Sarah Yandell13,14
  • Charles I. Opara13,8
  • William A. Ricke15,16,4
  • Teresa T. Liu17,15
  • Mark P. Keller13
  • Alan D. Attie13,18,16
  • Marianna Sadagurski6,7
  • Dudley W. Lamming19,20,21,22,23,24,25,26
26 affiliations
  1. 1Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
  2. 2Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA
  3. 3William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
  4. 4University of Wisconsin-Madison
  5. 5Department for Health, University of Bath, Bath, UK
  6. 6Department of Biological Sciences, Wayne State University, Detroit, MI, USA
  7. 7Institute of Environmental Health Sciences, Integrative Biosciences Center, Wayne State University, Detroit, MI, USA
  8. 8Wayne State University
  9. 9New York University
  10. 10New York University College of Dentistry, New York, NY, USA
  11. 11Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, USA
  12. 12Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA
  13. 13Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
  14. 14St. John Fisher University
  15. 15George M. O'Brien Center of Research Excellence, Department of Urology, University of Wisconsin, Madison, WI, USA
  16. 16Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, Madison, WI, USA
  17. 17Department of Pharmaceutical Sciences, St. John Fisher University, Rochester, NY, USA
  18. 18University of Wisconsin-Madison Comprehensive Diabetes Center, Madison, WI, USA
  19. 19Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, USA. [email protected]
  20. 20Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA. [email protected]
  21. 21Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA. [email protected]
  22. 22Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA. [email protected]
  23. 23University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA. [email protected]
  24. 24University of Wisconsin-Madison Comprehensive Diabetes Center, Madison, WI, USA. [email protected]
  25. 25William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. [email protected]
  26. 26Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, Madison, WI, USA. [email protected]
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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 consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

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Cite

BibTeXRIS
BibTeX
@article{calubag2026lifelong,
  title = {{Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice}},
  author = {Mariah F. Calubag and Ismail Ademi and Cara L. Green and Dulmalika N. H. Manchanayake and Hashan S. M. Jayarathne and Ryan N. Marshall and Sandra M. Le and Penelope Lialios and Lucia E. Breuer and Shoshana Yakar and Reji Babygirija and Michelle M. Sonsalla and Isaac Grunow and Chung-Yang Yeh and Yang Liu and Bailey A. Knopf and Sarah Yandell and Charles I. Opara and William A. Ricke and Teresa T. Liu and Mark P. Keller and Alan D. Attie and Marianna Sadagurski and Dudley W. Lamming},
  journal = {Nature Aging},
  year = {2026},
  month = jul,
  doi = {10.1038/s43587-026-01169-0},
  url = {https://doi.org/10.1038/s43587-026-01169-0},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice
AU  - Mariah F. Calubag
AU  - Ismail Ademi
AU  - Cara L. Green
AU  - Dulmalika N. H. Manchanayake
AU  - Hashan S. M. Jayarathne
AU  - Ryan N. Marshall
AU  - Sandra M. Le
AU  - Penelope Lialios
AU  - Lucia E. Breuer
AU  - Shoshana Yakar
AU  - Reji Babygirija
AU  - Michelle M. Sonsalla
AU  - Isaac Grunow
AU  - Chung-Yang Yeh
AU  - Yang Liu
AU  - Bailey A. Knopf
AU  - Sarah Yandell
AU  - Charles I. Opara
AU  - William A. Ricke
AU  - Teresa T. Liu
AU  - Mark P. Keller
AU  - Alan D. Attie
AU  - Marianna Sadagurski
AU  - Dudley W. Lamming
PY  - 2026
DA  - 2026/07/24
JO  - Nature Aging
DO  - 10.1038/s43587-026-01169-0
UR  - https://doi.org/10.1038/s43587-026-01169-0
AB  - Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
SN  - 2662-8465
ER  -