Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers

Watanabe, K.; Wilmanski, Tomasz; Baloni, Priyanka; Robinson, Max; Garcia, Gonzalo G.; Hoopmann, Michael R.; Midha, Mukul K.; Baxter, David; Morrone, Seamus R.; Crebs, Kelly M.; Kapil, Charu; Kusebauch, Ulrike; Wiedrick, Jack; Lapidus, Jodi; Pflieger, Lance; Lausted, Christopher; Roach, Jared C.; Glusman, Gustavo; Cummings, Steven R.; Schork, Nicholas J.; Price, Nathan D.; Hood, Leroy; Miller, Richard A.; Moritz, Robert L.; Rappaport, Noa

doi:10.1038/s42003-023-05128-y

Cited by 8 publications

(2 citation statements)

References 84 publications

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“…Remarkably, all three of these proteins were significantly increased in the Aged Low Ile-fed animals, but not in the Aged Low AA-fed animals. Recent transcriptomic analysis has revealed that systemic shifts in fatty acid oxidation, particularly in the liver, are associated with lifespan-extending interventions (Watanabe et al, 2023). We identified age-dependent increases in the fatty acid regulators FASN, ACACA1, ACLY, PLIN1, and PLIN3 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

Yeh

Chini

Gallagher

et al. 2023

Preprint

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A growing number of geroprotectors have demonstrated healthspan extension in young animals, but the effectiveness of these therapies when commenced in midlife or later has been under-studied. We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either all amino acids (Low AA) or of isoleucine alone (Low Ile) in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphotidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.

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Section: Resultsmentioning

confidence: 99%

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

Yeh

Chini

Gallagher

et al. 2023

Preprint

Self Cite

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“…In agreement with our previous studies, modules of immune response demonstrated a strong positive association with aging and a negative correlation with maximum lifespan 28,33 . In contrast, modules of mitochondrial function, oxidative phosphorylation, and lipid metabolism were positively correlated with longevity and negatively associated with age, highlighting their role in the regulation of healthspan 33,35,66,84,85 . Overall, most modules demonstrated opposite associations with aging and lifespan.…”

Section: Co-regulated Gene Expression Modules Of Aging and Longevitymentioning

confidence: 93%

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

Tyshkovskiy,

Kholdina,

Ying

et al. 2024

Preprint

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SUMMARYHealth is strongly affected by aging and lifespan-modulating interventions, but the molecular mechanisms of mortality regulation remain unclear. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models. These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They includedCdkn1aandLgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension. Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.

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Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

Miller,

Harrison,

Cortopassi

et al. 2024

GeroScience

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Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers

Cited by 8 publications

References 84 publications

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

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