Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Cara L Green; Michaela E Trautman; Krittisak Chaiyakul; Raghav Jain; Yasmine H Alam; Reji Babygirija; Heidi H Pak; Michelle M Sonsalla; Mariah F Calubag; Chung-Yang Yeh; Anneliese Bleicher; Grace Novak; Teresa T Liu; Sarah Newman; Will A Ricke; Kristina A Matkowskyj; Irene M Ong; Cholsoon Jang; Judith Simcox; Dudley W Lamming

doi:10.1016/j.cmet.2023.10.005

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Cell Metab. 2023 Nov 7;35(11):1976-1995.e6. doi: 10.1016/j.cmet.2023.10.005.

Authors

Cara L Green¹, Michaela E Trautman², Krittisak Chaiyakul³, Raghav Jain⁴, Yasmine H Alam⁵, Reji Babygirija⁶, Heidi H Pak², Michelle M Sonsalla⁷, Mariah F Calubag⁶, Chung-Yang Yeh¹, Anneliese Bleicher¹, Grace Novak¹, Teresa T Liu⁸, Sarah Newman¹, Will A Ricke⁸, Kristina A Matkowskyj⁹, Irene M Ong¹⁰, Cholsoon Jang⁵, Judith Simcox¹¹, Dudley W Lamming¹²

Affiliations

¹ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
² Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
³ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Integrated Program in Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁵ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁶ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁷ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁸ George M. O'Brien Center of Research Excellence, Department of Urology, University of Wisconsin, Madison, WI 93705, USA.
⁹ William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA; University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53705, USA.
¹⁰ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA; University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53705, USA; Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA.
¹¹ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Integrated Program in Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹² Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA; Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, USA; University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53705, USA. Electronic address: dlamming@medicine.wisc.edu.

Abstract

Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.

Keywords: aging; branched-chain amino acids; frailty; isoleucine; lifespan; metabolic health; mice; nutritional interventions; protein restriction.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acids, Branched-Chain / metabolism
Animals
Female
Health Promotion
Isoleucine* / pharmacology
Longevity*
Male
Mice
Mice, Inbred C57BL

Substances

Isoleucine
Amino Acids, Branched-Chain

Abstract

Publication types

MeSH terms

Substances

Grants and funding