In the latest installment of “Shocker! Exercise is Good!” and “Being Aerobically Fit Seems Like a Smart Idea,” THIS STUDY identified proteomic and metabolomic signatures associated with high cardiorespiratory fitness.  Basically, they took people with the highest fitness levels and tried to determine if there were identifiable consistencies in key biomarkers related to various proteins and metabolic processes.

Maybe the researchers thought, “This will come in handy for the people who need more MOLECULAR MECHANISMS to get them off the couch!”  Although we have robust observational data showing that folks with the highest cardiorespiratory fitness have the lowest risk of all-cause mortality, cardiovascular disease, diabetes, et cetera…there HAS to be confounding, right?

First things first, people in the highest quintile of cardiorespiratory fitness in this data set from the UK Biobank had 22% lower all-cause mortality and were 51% less likely to develop diabetes.  That’s about par for the course.  But interestingly, the metabolomic signature associated with the highest fitness levels seemed to have an even stronger inverse association with bad stuff, such as:

• 39-64% lower all-cause mortality
• 90% lower risk of type 2 diabetes
• 42-47% lower risk of cardiovascular disease

The proteomic analysis of fit people was less impressive, but still was associated with 17% lower all-cause mortality, 39% less diabetes incidence, and 22% less cardiovascular disease.

But what were these metabolic signatures?  Well, in general, they were very much in line with the mantra “Control Your Insulin, Control Your Life.” Those with the highest fitness levels, somewhat unsurprisingly, showed upregulation of pathways related to fatty acid oxidation and mitochondrial function. Conversely, there was downregulation of pathways related to:

• Glycolysis (they are less dependent on SUGAR and more efficient at using their FATTY ACID savings accounts).
• Triglycerides (their cellular mailboxes are not always full and are thus able to accommodate the delivery of the Lipoprotein Mailmen…once again, this is consistent with efficient substrate utilization).
  • The TRIGLYCERIDE-RICHNESS of ApoB particles (such as VLDL, IDL, and LDL) and HDL particles was also significantly reduced. This is consistent with this interesting study showing a 62% increased risk of heart disease in those with the highest LDL-triglycerides.
• PI3K-Akt and MAPK (these are pathways stimulated by INSULIN, and given folks with high fitness levels tend to be insulin sensitive, it would make sense that these pathways are not constantly “turned on”).
• Inflammation (such as IL-1B) and platelet activation (such as VWF).  People with high fitness levels tend to have less systemic inflammation.  Conversely, people with excess adiposity tend to have inflammatory citizens who resent their state of chronic overnutrition.

There are a million other interesting things that we could discuss here, but I think I would rather just go to the gym now.  As much as I love metabolomic signatures, I don’t really need one to convince me that if Exercise Was a Drug, It Would Be A Miracle Pill😊