The practice of calorie restriction improves health and extends life, though the effect on life span is much larger in short-lived species such as mice than in long-lived species such as humans. Researchers here focus on changes in lipids in mice that result from calorie restriction and a number of different calorie restriction mimetic drugs. One of course expects fat tissue to change greatly as a result of a low calorie diet sustained over time, but changes in lipid levels and distributions of different lipids change throughout the body. Calorie restriction mimetic drugs only capture a fraction of the overall effects of calorie restriction, but still tend to push things in a similar direction. The interesting observation here is that, overall, these changes look like rejuvenation, tending to move measures lipid metabolism towards a more youthful outcome.
Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose.
These interventions generally have a stronger effect in males than in females. Using Jonckheere's trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney.
We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.
Link: https://doi.org/10.1111/acel.14465
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