Fast-Aging Mice Live Longer When Oxygen Is Restricted

Massachusetts General Hospital scientists have, for the first time, shown that oxygen restriction increases lifespan in a mouse model of aging. The research is published in PLOS Biology.

Restricted oxygen delays aging processes in cell cultures and other lab models

Aging is a significant risk factor for common diseases including neurodegeneration, diabetes and cancer. The field of aging and longevity research has accelerated over the last decade, with several biological hallmarks of aging identified. Equipped with this knowledge of the molecular underpinnings of aging, science continues its pursuit of interventions that can prolong a healthy lifespan by targeting such processes, with some drugs entering clinical trials. 

As with any clinical research, interventions targeting the aging process are first tested for their safety and efficacy in laboratory models before progressing to human studies. Restricted oxygen intake – also known as continuous hypoxia – has been reported to delay cellular senescence in common aging models such as nematodes, yeast and fruit flies. Based on this data, Dr. Robert Rogers and colleagues at Massachusetts General Hospital chose to explore the potential of continuous hypoxia for slowing mammalian aging.

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Discussing their rationale, the researchers write, “The naked role mat, whose lifespan far exceeds that which would be predicted by phylogeny or body mass, experiences significant durations of relative ambient hypoxia because of extreme crowding in their burrows (though the precise oxygen tension has not been measured in their natural environment).”

“Second, in genetically heterogenous HET3 mice, a hypoxia transcriptomic signature appears to be shared among myriad interventions shown to extend lifespan,” they add.

Continuous hypoxia extends lifespan

Rogers and colleagues used a specific mouse model of aging in their study, known as Ercc1 Δ/-. This model ages quickly while maintaining the anatomical, physiological and molecular features of advanced aging across its tissues.

The researchers compared the lifespan of mice living in normal atmospheric oxygen levels (21% oxygen) to mice that had been moved to an environment with lower levels (11% oxygen) at 4 weeks of age. Rogers explains that 11% atmospheric oxygen is equivalent to what would be experienced at Everest Base Camp.

Mice living in the lower oxygen environment lived 50% longer than mice in normal oxygen environments on average. They also showed a delayed onset of neurological deficits associated with aging.

As calorie restriction has been shown to extend the lifespan of this animal model, the team questioned whether hypoxia might extend lifespan by causing mice to consume less food. “Importantly, hypoxia did not induce dietary restriction in Ercc1 Δ/- mice. Daily food intake was measured for 14 consecutive days between weeks 8 and 12 of life, and Ercc1 Δ/- mice in hypoxia actually consumed more food than those in normoxia,” the researchers describe.

A proof-of-concept study on oxygen restriction in mammalian aging

Rogers and team acknowledge that further studies are required to confirm whether the findings from the Ercc1 Δ/- model can be generalized to wild-type aging. In addition, the sample size used in the study – 14 males and 12 females in the 21% oxygen group vs. 11 males and 9 females in the continuous hypoxia group – is arguably small and warrants further investigation with a larger cohort of mice.

Limitations aside, the research is a proof-of-concept study in a mammalian model, Rogers explains: “While caloric restriction is the most widely effective and well-studied intervention to increase lifespan and health span, this is the first time that ‘oxygen restriction’ has been demonstrated as beneficial in a mammalian aging model.”

What could this data tell us about human aging and age-related diseases?

Some of the anti-aging interventions emerging from preclinical research are arguably more practical than others to implement in humans, should the evidence support this. Unless you live at a high altitude, oxygen restriction might not fall into that category.

Nonetheless, deciphering how continuous hypoxia might affect biological processes involved in aging could perhaps help scientists to interpret “intriguing” human data. Rogers and team provide one example in their paper: “In a longitudinal study of over 20,000 soldiers of the Indian Army assigned to serve at 2-to-3-mile elevations above sea level for 3 years between 1965 and 1972, their risk of developing the major sources of age-related morbidity in modern societies – diabetes mellitus, hypertension and ischemic heart disease – was a fraction of the risk of their comrades serving at sea level.”

“An important future goal is to define the mechanism by which chronic continuous hypoxia is extending lifespan in this model, and the extent to which this mechanism overlaps with that of pathways known to be involved in aging,” the researchers conclude.

Reference: Rogers R, Wang H, Durham T, et al. Hypoxia extends lifespan and neurological function in a mouse model of aging. PLOS Biology. 2023. doi:10.1371/journal.pbio.3002117

This article is a rework of a press release issued by Massachusetts General Hospital. Material has been edited for length and content.