A Cross-sectional Study of Functional and Metabolic Changes During Aging Through the Lifespan in Male Mice

Overview

Journal Elife

Specialty Biology

Date 2021 Apr 20

PMID 33876723

Citations 34

Authors

Michael A Petr

Irene Alfaras

Melissa Krawcyzk

Woei-Nan Bair

Sarah J Mitchell

Christopher H Morrell

Stephanie A Studenski

Nathan L Price

Kenneth W Fishbein

Richard G Spencer

Morten Scheibye-Knudsen

Edward G Lakatta

Luigi Ferrucci

Miguel A Aon

Michel Bernier

Rafael de Cabo

Affiliations

Soon will be listed here.

Abstract

Aging is associated with distinct phenotypical, physiological, and functional changes, leading to disease and death. The progression of aging-related traits varies widely among individuals, influenced by their environment, lifestyle, and genetics. In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and toward redox-related pathways, mainly in liver and heart. Collectively, the data provide a framework to further understand and characterize processes of aging at the individual organism and organ levels.

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References

Hardy O, Czech M, Corvera S . What causes the insulin resistance underlying obesity?. Curr Opin Endocrinol Diabetes Obes. 2012; 19(2):81-7. PMC: 4038351. DOI: 10.1097/MED.0b013e3283514e13. View

Fischer K, Hoffman J, Sloane L, Gelfond J, Soto V, Richardson A . A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY). 2016; 8(10):2370-2391. PMC: 5115894. DOI: 10.18632/aging.101059. View

Xia J, Wishart D . Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis. Curr Protoc Bioinformatics. 2016; 55:14.10.1-14.10.91. DOI: 10.1002/cpbi.11. View

Schrack J, Zipunnikov V, Simonsick E, Studenski S, Ferrucci L . Rising Energetic Cost of Walking Predicts Gait Speed Decline With Aging. J Gerontol A Biol Sci Med Sci. 2016; 71(7):947-53. PMC: 4906328. DOI: 10.1093/gerona/glw002. View

Wilson A, Lichtwark G . The anatomical arrangement of muscle and tendon enhances limb versatility and locomotor performance. Philos Trans R Soc Lond B Biol Sci. 2011; 366(1570):1540-53. PMC: 3130454. DOI: 10.1098/rstb.2010.0361. View

Mitchell S, Bernier M, Aon M, Cortassa S, Kim E, Fang E . Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. Cell Metab. 2018; 27(3):667-676.e4. PMC: 5854409. DOI: 10.1016/j.cmet.2018.02.001. View

de Cabo R, Mattson M . Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019; 381(26):2541-2551. DOI: 10.1056/NEJMra1905136. View

Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M . Gait speed and survival in older adults. JAMA. 2011; 305(1):50-8. PMC: 3080184. DOI: 10.1001/jama.2010.1923. View

Longo V, Panda S . Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab. 2016; 23(6):1048-1059. PMC: 5388543. DOI: 10.1016/j.cmet.2016.06.001. View

10.

Rosario B, Rosso A, Aizenstein H, Harris T, Newman A, Satterfield S . Cerebral White Matter and Slow Gait: Contribution of Hyperintensities and Normal-appearing Parenchyma. J Gerontol A Biol Sci Med Sci. 2016; 71(7):968-73. PMC: 4906323. DOI: 10.1093/gerona/glv224. View

11.

Rosso A, Verghese J, Metti A, Boudreau R, Aizenstein H, Kritchevsky S . Slowing gait and risk for cognitive impairment: The hippocampus as a shared neural substrate. Neurology. 2017; 89(4):336-342. PMC: 5574674. DOI: 10.1212/WNL.0000000000004153. View

12.

Palliyaguru D, Moats J, Di Germanio C, Bernier M, de Cabo R . Frailty index as a biomarker of lifespan and healthspan: Focus on pharmacological interventions. Mech Ageing Dev. 2019; 180:42-48. PMC: 7307802. DOI: 10.1016/j.mad.2019.03.005. View

13.

Chong J, Wishart D, Xia J . Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis. Curr Protoc Bioinformatics. 2019; 68(1):e86. DOI: 10.1002/cpbi.86. View

14.

Adelnia F, Ubaida-Mohien C, Moaddel R, Shardell M, Lyashkov A, Fishbein K . Proteomic signatures of in vivo muscle oxidative capacity in healthy adults. Aging Cell. 2020; 19(4):e13124. PMC: 7189997. DOI: 10.1111/acel.13124. View

15.

Kane A, Hilmer S, Boyer D, Gavin K, Nines D, Howlett S . Impact of Longevity Interventions on a Validated Mouse Clinical Frailty Index. J Gerontol A Biol Sci Med Sci. 2015; 71(3):333-9. PMC: 4757961. DOI: 10.1093/gerona/glu315. View

16.

Higham T, Biewener A, Delp S . Mechanics, modulation and modelling: how muscles actuate and control movement. Philos Trans R Soc Lond B Biol Sci. 2011; 366(1570):1463-5. PMC: 3130451. DOI: 10.1098/rstb.2010.0354. View

17.

Bellantuono I, de Cabo R, Ehninger D, Di Germanio C, Lawrie A, Miller J . A toolbox for the longitudinal assessment of healthspan in aging mice. Nat Protoc. 2020; 15(2):540-574. PMC: 7002283. DOI: 10.1038/s41596-019-0256-1. View

18.

Mitchell S, Madrigal-Matute J, Scheibye-Knudsen M, Fang E, Aon M, Gonzalez-Reyes J . Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab. 2016; 23(6):1093-1112. PMC: 4911707. DOI: 10.1016/j.cmet.2016.05.027. View

19.

Scheen A . Possible survivorship bias rather than reverse causality in EMPA-REG OUTCOME. Diabetes Res Clin Pract. 2017; 127:290. DOI: 10.1016/j.diabres.2016.12.008. View

20.

White D, Neogi T, Nevitt M, Peloquin C, Zhu Y, Boudreau R . Trajectories of gait speed predict mortality in well-functioning older adults: the Health, Aging and Body Composition study. J Gerontol A Biol Sci Med Sci. 2012; 68(4):456-64. PMC: 3593620. DOI: 10.1093/gerona/gls197. View