Abstract
Significant advances in understanding aging have been achieved through studying model organisms with extended healthy lifespans. Employing 1H NMR spectroscopy, we characterized the plasma metabolic phenotype (metabotype) of three long-lived murine models: 30% dietary restricted (DR), insulin receptor substrate 1 null (Irs1–/–), and Ames dwarf (Prop1df/df). A panel of metabolic differences were generated for each model relative to their controls, and subsequently, the three long-lived models were compared to one another. Concentrations of mobile very low density lipoproteins, trimethylamine, and choline were significantly decreased in the plasma of all three models. Metabolites including glucose, choline, glycerophosphocholine, and various lipids were significantly reduced, while acetoacetate, d-3-hydroxybutyrate and trimethylamine-N-oxide levels were increased in DR compared to ad libitum fed controls. Plasma lipids and glycerophosphocholine were also decreased in Irs1–/– mice compared to controls, as were methionine and citrate. In contrast, high density lipoproteins and glycerophosphocholine were increased in Ames dwarf mice, as were methionine and citrate. Pairwise comparisons indicated that differences existed between the metabotypes of the different long-lived mice models. Irs1–/– mice, for example, had elevated glucose, acetate, acetone, and creatine but lower methionine relative to DR mice and Ames dwarfs. Our study identified several potential candidate biomarkers directionally altered across all three models that may be predictive of longevity but also identified differences in the metabolic signatures. This comparative approach suggests that the metabolic networks underlying lifespan extension may not be exactly the same for each model of longevity and is consistent with multifactorial control of the aging process.
Highlights
Life expectancy in humans is increasing rapidly,[1,2] with an estimated 30 years being added to average life expectancy in developed countries since 1900.3 One unmistakable consequence of living longer is that the probability of developing diseases such as type 2 diabetes, osteoporosis, sarcopenia, and various cancers and dementias increases significantly with advancing age.[2,4−6] a significant proportion of research into aging is engaged in identifying the mechanisms underlying the aging process
Typical median 1H CPMG nuclear magnetic resonance (NMR) plasma spectra obtained from each mouse strain or treatment pair are shown in Supplementary Figure S1, Supporting Information
We show that commonality exists across long-lived dietary restriction (DR), Irs1−/− and Ames mice, in metabolites associated with phosphatidylcholine metabolism
Summary
Life expectancy in humans is increasing rapidly,[1,2] with an estimated 30 years being added to average life expectancy in developed countries since 1900.3 One unmistakable consequence of living longer is that the probability of developing diseases such as type 2 diabetes, osteoporosis, sarcopenia, and various cancers and dementias increases significantly with advancing age.[2,4−6] a significant proportion of research into aging is engaged in identifying the mechanisms underlying the aging process. Short-lived model organisms such as yeast, the nematode worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster and the mouse have proved invaluable to increasing our knowledge of the aging process.[5,7−9] it is well established that significant commonality exists in the agerelated pathologies suffered by both model organisms and humans.[5,10] the challenge for researchers is to identify the mechanisms underlying healthy lifespan in model organisms to translate this knowledge into practical therapies for humans It has been established for several decades that dietary restriction (DR), a reduction in food intake without malnutrition, extends mean and maximum lifespan in a range of animals (for review, see ref 11). Pharmacological interventions acting on these pathways, including rapamycin[24,25] and metformin,[26,27] have been shown to extend lifespan in mice
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