Plasma as Proxy for Tissue Metabolism When Extending Lifespan in Mice.

Objective

Despite most often used in research and medicine, it is unclear how well blood metabolite levels can reflect metabolic changes in tissues.

Methods

We used untargeted metabolomic data from plasma, liver, gastrocnemius muscle, kidney, inguinal fat, and gonadal fat tissues from mice treated with lifespan-extending interventions: caloric restriction, rapamycin, canagliflozin, 17-α estradiol, and acarbose.

Results

For each tissue, about 37% of the identified metabolites were also found in plasma and used for comparative analyses. We found that plasma metabolites do not primarily reflect the metabolome of a single tissue type. Caloric restriction caused the highest proportion of significantly altered metabolites detected in both organs and blood. Unsaturated triacylglycerols, diacylglycerols, amino acid-derivatives, and sphingomyelins had the most concordant overlaps between four tissues and plasma, followed by carbohydrates with three tissue/plasma intersections. Concordant plasma/tissue changes were found more pronounced in male mice than in female mice. Surprisingly, many compounds that responded similarly to lifespan-extending treatments in tissues and in plasma originated from dietary compounds, specifically, ergothioneine, DHA-containing fats, and diacylglycerides. Ergothioneine, previously associated with healthy aging in humans, showed concordant treatment responses in blood and all tissues except gonadal fat. DHA-containing fats showed consistent regulation between blood and inguinal and gonadal adipose tissue. The kidneys showed coherent trends with blood metabolite levels for LPC 15:0, LPC 17:0, and pinitol. Under treatments with strong life-extending effects, 1,5-anhydro-glucitol blood levels were co-regulated with both liver and kidney levels.

Conclusions

Overall, plasma can only serve as limited proxy for tissue metabolism. Yet, several potential blood biomarkers were discovered as concordant in plasma and tissues in lifespan-extending interventions.