How To Keep Your Mitochondria Healthy (And Maybe Slow Ageing)

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The mitochondria are the vital organelles within our cells that are responsible for producing adenosine triphosphate (ATP), the cell’s universal fuel. Billions of years ago, mitochondria were separate organisms that subsequently became a permanent feature of complex cells. As a result, they still have their own unique genetic material, separate from the DNA within the cell nucleus. Unfortunately, this makes mitochondrial DNA particularly exposed to damage from natural chemical byproducts of cellular metabolism. As we age, our mitochondria accumulate mutations in their DNA, degrading their ability to produce ATP efficiently and causing them to churn out harmful reactive molecules that damage the rest of the cell.

This mitochondrial stress activates a response within the cell which includes changes in gene expression and metabolic activity. These changes are known as the mitochondrial integrated stress response (ISRmt). This response is cell’s way of trying to limit mitochondrial damage, which might offer us a way to prevent mitochondrial dysfunction by amplifying the ISRmt. In this review, researchers discuss what is known about how this response works and the implications for human health and longevity.

How is the ISRmt Triggered?

Recent research has revealed multiple ways in which the stress response can be triggered. As already mentioned, defects in mtDNA can activate the ISRmt. So can issues with proteins destined for mitochondria that are encoded by DNA in the nucleus. Blockages in the mitochondria’s main ATP production pathway (oxidative phosphorylation, OXPHOS) and dysfunctions in mitochondrial dynamics (how they fuse and divide) are other activators of the ISRmt.

Ways in which the ISRmt can be activated.
*The mitochondrial integrated stress response: A novel approach to anti-aging and pro-longevity*
*https://doi.org/10.1016/j.arr.2024.102603*

Importantly33[,] when it comes to human implications, we also already have drugs that can activate the ISRmt. Since blockages in the electron transport chain activate the ISRmt, drugs like the common anti-diabetic drug metformin (which blocks the electron transport chain among other effects) can also activate the ISRmt.

What Does the ISRmt Do?

The stress response unfolds in phases:

First, the activity of key genes ramps up significantly, leading to a reduction in overall protein production in the cell, but an increase in the production of specific stress-related proteins. This helps conserve energy and temporarily alleviate metabolic stress.
Next, the cell starts absorbing more glucose (sugar) for ATP production, boosts production of key amino acid building blocks needed for mitochondrial metabolism, and also stimulates production of glutathione (an antioxidant). Antioxidants are ‘sacrificial’ molecules that can take chemical damage in the place of other more important molecules like DNA.
Finally, the cell activates a cellular stress response gene called ATF3, which can do different things depending on the severity of the stress – either helping the cell survive if the stress is mild, or triggering cell death if there is severe damage.

Using the ISRmt to Treat Diseases:

So, we know how the ISRmt works, but how might we harness it to treat human diseases? Things get a little more complicated here, as it seems like the ISRmt can be helpful in some situations and detrimental in others. In the case of cognitive function and neurodegenerative disease, for example, there’s animal evidence that the ISRmt can be beneficial. Delivering FGF21 (fibroblast growth factor 21, which is involved in the initial stages of ISRmt) to the brains of mice helped their brains to maintain glucose metabolism, reduced neuron damage and ultimately preserved cognitive function. Yet in mouse models of prion disease, suppressing the ISRmt was found to be beneficial.

ISRmt may also help protect against resistance to the blood sugar-lowering hormone insulin, and therefore against type II diabetes. As mentioned in the previous section, the ISRmt involves increased glucose absorption by cells, something that the cells of diabetic patients struggle to do. The researchers note that some short-term clinical trials have tried giving FGF21 to diabetics, but unfortunately the effects on blood sugar were not statistically significant.

Ways in which ISRmt could be targeted to improve human health.
*The mitochondrial integrated stress response: A novel approach to anti-aging and pro-longevity*
*https://doi.org/10.1016/j.arr.2024.102603*

What About Ageing?

The ISRmt has been found to extend lifespan in yeast, worms, and flies. This doesn’t necessarily mean that it slows ageing down, but it is one of the expected outcomes of delayed ageing. It also extends lifespan in mice, but the case in mammals is nuanced. It may be that this response to mitochondrial stress is beneficial under usual circumstances, but becomes harmful in the context of some chronic diseases when the stress response never turns off.

What Can You Do?

While the strategy of activating the ISRmt with drugs is not yet proven to be either beneficial or safe, there may be natural ways to take advantage of this mechanism. Calorie restriction (a sharp reduction in calorie intake without causing malnutrition), protein restriction, physical exercise and exposure to cold temperatures all result in mitochondrial stress and activate the ISRmt. These methods all have many other proven health benefits and are safe to do (though more extreme forms of cold exposure like cryotherapy may need expert supervision).

Another thing you may be able to do to improve mitochondrial health is to look after your liver, since the liver is a particularly important source of FGF21. This means maintaining a healthy weight and limiting the consumption of alcohol and sugar, especially fructose since this type of sugar is particularly harmful to the liver if intake is too high.