A recent study published in Cell Metabolism has shown that metformin, a drug that has been previously shown to be effective against some aspects of aging, ameliorates inflammaging by promoting autophagy, the cellular recycling of damaged components.
Mitochondrial dysfunction, autophagy, and TH17
Mitochondrial dysfunction is one of the hallmarks of aging, the root causes that cause us all to age. The mitochondria are the powerhouses of the cell, but as we age, our mitochondria have their DNA damaged by sources such as reactive oxygen species, harming their ability to perform their fundamental job. This gradual increase in dysfunctional mitochondria causes our cells to lose their ability to utilize energy, leading to a panoply of age-related diseases.
Autophagy is the consumption of damaged or dysfunctional organelles by intracellular processes. Through autophagy, cells are able to recycle and renew their internal components, and, as the researchers of this paper explain, CD4+ (helper) T cells that do not properly perform autophagy behave like older cells.
Cytokines are known for causing inflammation, and, as the researchers demonstrate, the TH17 subset of cytokines is strongly associated with the chronic, age-related inflammation known as inflammaging, a key driver of multiple age-related diseases.
In order to demonstrate the relationship between autophagy, mitochondrial dysfunction, and TH17, the researchers used RNA silencing to disrupt the ability of cultured cells to engage in autophagy. Such cells that were taken from a young subject had their mitochondrial function decreased to the level of an older person. This RNA silencing also set the TH17 cytokine profile of these cells to become one associated with age and diabetes.
Obviously, what we want is the reverse of this process, and the researchers found that metformin, a commonly researched drug in the rejuvenation biotechnology field, was able to accomplish this in human cell cultures, spurring autophagy and reversing the TH17 cytokine profile.
Summary
Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.
Conclusion
This is a cell culture study, not a human trial, so the usual caveat applies: it may fail in this respect for reasons as of yet unknown. However, as metformin has a well-known safety profile and is already approved by the FDA for other conditions, including diabetes itself, conducting a human trial to assess its effectiveness in stimulating autophagy is easier than testing a novel drug would be. We look forward to such a trial and hope for its success.
