Longevity Briefs: Could Breathing Low Oxygen Counter Mitochondrial Ageing?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The mitochondria are the ‘power plants’ within our cells, responsible for consuming nutrients (such as glucose) and oxygen in order to produce ATP, the cell’s universal fuel. Deep in our evolutionary past, mitochondria were independent organisms and so they still posses some of their own DNA. This mitochondrial DNA is stored inside each mitochondria, separate from the 46 chromosomes stored within the cell nucleus (nuclear DNA). It encodes mitochondrial proteins that are essential for ATP production. Unfortunately, the mitochondrial DNA is far less protected than the nuclear DNA and accumulates damage with age. This leads to faulty mitochondrial proteins that make ATP production less efficient and cause the build-up of harmful byproducts called reactive oxygen species, which leak outside the mitochondria and damage the rest of the cell.

One such mitochondrial protein is known as complex I. When complex I malfunctions (such as in rare mitochondrial diseases in which mitochondrial DNA is mutated) the effects are devastating: they include neurodegeneration, muscle weakness, and early death. Dysfunction of complex I as a result of normal, age-related damage is also likely to contribute to the development of age-related diseases. One thing that ties all of these problems together is elevated oxygen levels. Excess oxygen reacts with other molecules to generate reactive oxygen species, resulting in cellular damage and inflammation. In this study, researchers lead a deeper investigation into the link between elevated oxygen and a variety of diseases, and ask whether something as simple as breathing less oxygen might actually help reverse said diseases.

The discovery:

The researchers had shown in previous work that low oxygen conditions (hypoxia) might be beneficial in certain diseases, including rare mitochondrial diseases. To determine what might be responsible for this, they began by using a screening approach to identify genes that were linked with cellular responses to oxygen. They used CRISPR gene-editing technology to disable different genes in a human cancer cell line. They then observed which genes, when disabled, caused problems for cells under normal oxygen conditions but recovered under low-oxygen conditions. By cross-referencing the results with a list of known genetic disorders, they were able to identify a particular gene that stood out: Htra2.

What does Htra2 do? This gene is particularly interesting because it encodes a protein (HTRA2) that acts as a “quality control inspector” for proteins inside the mitochondria . When it detects misfolded proteins, it teams up with another protein called CLPB to untangle them. When HTRA2 was is defective or absent, cells suffer in normal oxygen conditions but appear to be rescued by low oxygen. To test whether this would have an effect in living mice, researchers used a mouse model carrying a naturally occurring defective form of the Htra2 gene. These mice suffer from neurodegenerative disease, muscle wasting, and usually die within weeks of birth. However, when 13 of these mice were kept in low-oxygen conditions, starting at 11 days post-birth (11% oxygen, compared to 21% in normal air at sea-level), their maximum lifespan nearly tripled compared to 15 mice exposed to normal oxygen levels. They also had significantly better performance in several tests of motor function and had reduced brain inflammation.

How was low oxygen having this effect? The researchers found that without HTRA2, a specific misfolded subunit of complex I accumulated and destabilised the entirety of complex I. This led to excess oxygen within the mitochondria, further damaging mitochondrial proteins. Breathing low-oxygen air reduced oxygen levels in the mitochondria and partially restored complex I activity.

The implications:

This research provides a mechanism to explain how breathing low oxygen could potentially benefit a range of mitochondrial diseases. Though this research focussed on HTRA2, any mitochondrial disease linked to complex I dysfunction and elevated oxygen levels could potentially benefit from this approach.

This could also have some implications for human longevity and ageing. Both mitochondrial dysfunction and disrupted proteostasis (protein quality control) are considered to be hallmarks of ageing. People living at high altitudes live longer on average than comparable populations at sea level (though as we recently covered, they might age faster in other ways, so things are not so straightforward). HTRA2 generally seems to increase during normal ageing, probably as a response to mitochondrial damage. However, it is still plausible that low-oxygen conditions might improve mitochondrial health and extend lifespan by limiting the production reactive oxygen species. That said, the tripling of mouse lifespan shown here has little to do with normal ageing, as the control mice were only living a few weeks on average. There’s some evidence that low oxygen levels extend lifespan in mouse models of accelerated ageing, but not in normal healthy mice.