Key Points
- One of the earliest triggers of inflammation in senescent cells is the release of broken fragments of chromosome from the nucleus into the cytoplasm, where there are proteins which sense DNA and release inflammatory signals in an effort to purge these DNA
- Harvard researchers analyzed how such large pieces of nuclear chromosome material can be released and found that the cell co-opts the same machinery used by viruses when they are escaping the nucleus of an infected cell
- The diabetes drug metformin was found to be very effective in blocking this release and thus preventing the start of inflammation
- When aging mice were given metformin, it lowered inflammation in the gut
Inflammaging: The rise of sterile inflammation as we age
The rise of chronic inflammation, even without any infection, is one of the hallmarks of aging. With age, the recycling machinery of our body (aka autophagy), gets impaired and our tissues begin to collect more senescent cells. These are old and damaged, sometimes called ‘zombie cells’, that release a large variety of inflammatory proteins collectively called Senescence-Associated Secretory Phenotype (SASP).
The production of SASPs is triggered when senescent cells generate damaged parts of itself. Some important examples are broken pieces of its own chromosome, pieces of damaged mitochondrial DNA, rise of uric acid which is the end-product of DNA and RNA breakdown, increase in S100 proteins which sense calcium levels and sharp drop in the energy molecule ATP inside the cell. Together, these are called damage-associated molecular patterns (DAMP). These trigger the vicious cycle of inflammation which causes more damage, and over time leads to organ dysfunction and chronic age-associated diseases.
Regular aerobic exercise and calorie restriction have been shown to reduce the level of DAMPs by increasing autophagy, the body’s recycling machinery. In particular, aerobic exercise lowers the level of cell-free mitochondrial DNA indicating lower inflammation. In the current paper published in Nature Aging, researchers have identified a readily available way to block another important inflammation trigger: release of broken chromosomes.
Metformin blocks the release of broken chromosome fragments from the nucleus and lowers inflammation
Scientists have known that senescent cells release fragments of their broken chromosome from the nucleus into the cytoplasm which then triggers inflammation. But how this happens was not well understood.
In this article the researchers showed that:
- The cell uses the same machinery used by viruses to push broken fragments of their own chromosomes out of the nucleus
- Those chromatin fragments then activate the cGAS-STING immune pathway, which helps drive inflammaging
- In cells in vitro, either metformin or low glucose blocked this process by lowering a key trafficking protein called ALIX
- In aged mice, roughly comparable to a 70-year-old person, metformin reduced this inflammatory signaling in the small intestine
- The findings suggest metformin may calm age-related inflammation partly by stopping inflammatory DNA fragments from escaping the nucleus
Potential for lowering inflammation by metformin or lowering glucose
Many studies have demonstrated that lowering blood sugar is associated with a reduction in overall inflammation. There are many ways to achieve this. A non-ketogenic low-carb diet is associated with mild but clear reduction in inflammation, with a diet composed of less than 10% of total carbs producing a more pronounced result. Ketogenic diets also lead to a modest but clear reduction in inflammatory markers.
Metformin also reduces overall inflammation, and this is now known to be through the many effects metformin has on the cell. First, it blocks the pro-inflammatory release of mitochondrial DNA. Second, it reactivates cells recycling machinery (autophagy) by activating AMPK leading to mTOR inhibition. Third, metformin prevents the formation of an important inflammatory protein complex called the ‘inflammosome’ from forming, by reducing the level of its most important protein component called NLRP3. Finally, in the current article, metformin blocks the release of chromatin fragments into the cytoplasm where it sets off inflammation. The ability of metformin to inhibit inflammation in multiple ways, including blocking perhaps the most important trigger, release of DNA fragments into the cytoplasm, suggests that it can be part of an important defense against inflammaging.
Can the anti-inflammatory effect of metformin be replicated by diet or other glucose lowering drugs?
Since in vitro studies in this paper were done by lowering glucose levels, a natural question is, can all the inflammation blocking effects of metformin be achieved by lowering blood glucose levels by other means? Based on the findings of this paper, it seems plausible that the effect in this paper may be achievable by lowering blood glucose. However, there are other known functions of metformin that lower inflammation, independent of its role in glycemic control. Metformin acts on the protein complex ETC1 in mitochondria and lowers ATP, leading to the blockade of the pro-inflammatory mitochondrial DNA release. Metformin also keeps an important inflammatory protein NF-kB under check and prevents it from producing many other inflammatory signals. This is thought to be why metformin has many beneficial effects against heart disease. In a clinical trial, metformin lowered the production of an aging-associated inflammatory protein CCL11 in non-diabetic patients.
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