Longevity Briefs: Does High Altitude Accelerate 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:

Living at high altitude has its pros and cons when it comes to health. Higher altitude means lower atmospheric oxygen concentration which, over time, triggers some beneficial adaptations in the body. Red blood cell production increases and the heart and lungs become more efficient, which is why athletes will often train at high altitude (or in an environment with artificially low oxygen) in order to boost fitness. There is also evidence that high altitude boosts metabolic health, lowering blood sugar and decreasing the risk of type II diabetes. On the other hand, having ‘thicker’ blood increases the risk of blood clots and strokes. Some studies have also linked it to accelerated cognitive decline. Now, scientists have found evidence that low oxygen concentration might even accelerate ageing, at least temporarily.

Epigenetic alterations are modifications to the DNA molecule that alter how it is read without changing the genetic code itself. Epigenetic alterations occur throughout life, and some of these changes are thought to contribute to ageing by suppressing genes in cells where they are needed and vice-versa. This is known as epigenetic ageing. One of the main types of epigenetic alteration is DNA methylation, in which molecular ‘tags’ called methyl groups are added to specific sites within the DNA, usually resulting in gene activity being suppressed. Interestingly, scientists have known for a while that many methylation changes associated with advancing age occur near genes that respond to hypoxia (low oxygen levels). This led researchers to wonder whether hypoxia might actually have something to do with promoting epigenetic ageing, and in this study, they set out to investigate.

The discovery:

In the study, which is still awaiting final publication, researchers first designed an experiment to test whether intermittent hypoxia (repeated cycles of low and normal oxygen) could accelerates epigenetic ageing. They took 18 ‘young’ 11 month-old mice and 18 ‘old’ 23 month-old mice (roughly comparable to 30 year-old and 70 year-old humans). Each age group was then divided into 3 groups of 6 mice and exposed to one of three conditions: one month of intermittent hypoxia, one month of intermittent hypoxia followed by one month of recovery in normal oxygen, or normal oxygen as a control. Intermittent hypoxia involved daily 8-hour sessions where oxygen levels cycled between 21% (normal) and 5% (very low) every 2.5 minutes. For reference, low atmospheric pressure at the summit of Everest would effectively equate to around 7% oxygen at sea level.

At the end of this experiment, researchers measured the mice’s epigenetic age – that is to say, how old the mice were estimated to be based on patterns of DNA methylation. They found that epigenetic age was unaffected in young mice, but in old mice, exposure to hypoxia without recovery significantly increased epigenetic age by around 3 – 5 months, depending on which organ they looked at. This is a large effect relative to the lifespan of a mouse, equivalent to around 15-20 years in humans. However, in mice that were returned to normal oxygen for one month, most of this acceleration reversed.

To see if a similar effect existed in humans, researchers analysed blood DNA methylation data from 19 young adults (ages 19-23) who rapidly ascended to high altitude (5,260 meters). Partially consistent with the mouse findings, these people showed significant epigenetic age acceleration within days of arrival with increases of 3.5 to 4.8 years by day 16, and this effect was reversed upon return to sea level. The difference was that these people were young, whereas young mice did not experience accelerated epigenetic ageing after a month of intermittent hypoxia. This could be because of differences between mouse and human physiology, or because the intermittent hypoxia used in the mouse experiment does not have the same effect as sustained hypoxia experienced living at high altitude.

The implications:

This study suggests that low oxygen availability can cause reversible epigenetic changes that are linked to ageing. While interesting, we do have to be a little careful how much we read into this. While it is likely that some epigenetic changes do contribute to ageing, estimating epigenetic age based on these changes remains a case of correlation and not necessarily causation. As an analogy, it may be possible to accurately estimate the age of a car based on the number of scratches on the paint, but this doesn’t necessarily mean that the scratches are the reason the car eventually breaks down, or that scraping the paint on narrow bushy lanes will ‘age’ the car any faster.

Likewise, when we see that epigenetic changes that occur with age are also caused by low oxygen levels, this doesn’t tell us that ageing has been accelerated, and few would argue that humans are genuinely ageing 5 years when they climb a mountain. These epigenetic changes could simply be responses to forms of cellular stress that are common to both ageing and intermittent hypoxia – it’s just that the latter is reversible while the former is not. It should also probably be mentioned that people living at high altitudes generally live longer than comparable populations at sea level!