Get less oxygen, live longer? It’s true in ageing mice

The problem is scientists don’t know why exactly it’s true.

Updated - November 22, 2023 03:07 pm IST

Published - June 19, 2023 03:45 pm IST - Bengaluru

Representative image of a pressurised oxygen cylinder with a gauge on top.

Representative image of a pressurised oxygen cylinder with a gauge on top. | Photo Credit: Samuel Ramos/Unsplash

In addition to its tranquil quality and a sense of peace, the fresh, crisp, pollutant-free mountain air could help some animals live longer.

Specifically, the lower oxygen content at high altitudes increases lifespan significantly in ageing mice, according to a study published in PLOS Biology on May 23, 2023.

Why study hypoxia?

The researchers have noted that theirs is the first study to demonstrate that oxygen restriction, or continuous hypoxia, can extend lifespan in an ageing mammal. Previous reports on oxygen restriction lengthening lifespan have come from mammalian cells grown in Petri dishes, yeast, and in less complex lab animals such as roundworms and fruit flies.

This line of research has been interesting, at least in part, by the naked mole rat: a rodent that spends most of its life in an oxygen-deficient burrow with a lifespan much longer than scientists have been able to predict based on its size or evolutionary history.

“Because of several observations about the effects of hypoxia in other organisms, we were motivated to assess the effect of chronic continuous hypoxia in a mammalian ageing model,” Vamsi Mootha, a researcher at the Howard Hughes Medical Institute, Maryland, and professor at Harvard Medical School, whose team made the discovery, told The Hindu.

What was the study design?

For its experiments, the team worked with a strain of mutant mice that age prematurely and have a shorter lifespan, of fewer than six months. “Wild type mice (without the mutations causing a shortened lifespan) can live over three years, which would have been a very long first experiment to assess survival, so we chose a mouse model of accelerated ageing,” said Dr. Mootha.

The strains they used “also responds powerfully to the best-known intervention to extend lifespan across organisms – caloric restriction.” Caloric restriction, or dietary restriction without malnutrition, first described in 1935, is the gold-standard for increasing lifespan in diverse species like yeast, roundworms, fruit flies, mice, and rats.

To test the effect of low oxygen level on these mice, the researchers housed them in hypoxic chambers with an oxygen concentration of 11%, similar to that at the base camp of Mt. Everest. They achieved hypoxic conditions by diluting the air with nitrogen.

The median lifespan of mice living with normal oxygen – at 21% of the atmosphere, a.k.a. normoxia – was about 16 weeks. But mice living in hypoxic conditions had a median lifespan of 24 weeks, or 50% longer.

“We were pleasantly surprised by the results,” Dr. Mootha said. “We have long been excited by the possibility that hypoxia could be beneficial in an ageing model and wanted to rigorously test this hypothesis, but we had no assumptions that it would actually have a significant effect.”

The animals housed in hypoxic conditions also displayed better neurologic function than their counterparts living in normoxic conditions. Sixteen-week-old mice living in normoxia had neurologic debility, measured by a motor performance test, while mice maintained in hypoxic conditions performed the test significantly better.

How does hypoxia work?

Next, the researchers tried to understand how hypoxia affected the body, leading to longer lifespan, but with little success. They examined whether hypoxia prompted the mice to restrict their diets. But they found that the hypoxic mice ate slightly more food than those living in normoxia, ruling out dietary restriction as the fundamental underlying mechanism.

Looking for differently expressed genes, DNA damage repair, and changes in signalling pathways didn’t provide any definitive clues either.

“There are many open questions at this point,” Dr. Mootha said. “At present we don’t know the mechanism by which hypoxia extends lifespan in these mice and it remains to be seen whether these findings would generalise to wildtype mice with a three-year lifespan. Much more research is required here.”

Is the study significant?

“This paper is one in a fabulous series of interesting papers from the Mootha lab,” Arvind Ramanathan, associate professor at Bengaluru’s Institute for Stem Cell Science and Regenerative Medicine, whose work includes metabolic regulation of tissues during mammalian ageing, told The Hindu. “The mechanism by which hypoxia leads to increased lifespan is unclear.”

Parminder Singh, a researcher of ageing at the Buck Institute for Research on Aging, California, said, “The study provides valuable insights into the potential of hypoxia to enhance healthy lifespan. The findings open up new avenues for exploring the mechanisms underlying hypoxia’s impact on lifespan and hold promise for potential interventions in the future.”

But he, like Dr. Ramanathan as well, said more research is required.

“Ageing is a highly complex phenomenon, involving numerous molecular mediators,” Dr. Ramanathan said. Hypoxia may not target many aspects of ageing since it doesn’t affect the expression of a gene (p21) that’s an important marker of ageing, he added. “Moving to areas with lesser oxygen is quite premature and may even be unwise under certain underlying disease contexts.”

Do the findings apply to humans?

Dr. Singh agreed: “Caution should be exercised in directly translating these findings to human populations, as more work is required to establish their applicability and to address limitations, including variations in species, environmental conditions, and broader health outcomes.”

“It’s very premature to extrapolate our findings to humans or to make any recommendations for human health based on our current findings,” Dr. Mootha also said. “To my knowledge, there is no evidence that people living at high altitude have a longer maximal lifespan, but there are some clues that median lifespan might be increased at higher altitude, and the most interesting epidemiological clue about the human health effects of living at altitude is actually provided by modern Indian history.”

He was referring to a study published in 1977, in which physicians of the Indian Army compared the health outcomes of 1.3 lakh soldiers stationed on plains and their 20,000 comrades stationed at 3,700-5,600 metres above sea level, over three years. They found that the incidence of common age-related disorders like diabetes, hypertension, and heart disease was lower among soldiers at the high altitudes than those at sea level.

Dr. Mootha said a lot more work is required to understand the effect of hypoxia on ageing in people and the molecular mechanisms through which it might be beneficial. “We view this initial report as laying the foundation for this important line of future research.”

Sneha Khedkar is a biologist-turned freelance science journalist based out of Bengaluru.

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