Researchers headed by a team at Massachusetts General Hospital have, for the first time, shown that reduced oxygen intake, or “oxygen restriction,” is associated with longer lifespan, and reduced neurological deterioration in a mammalian model, highlighting its anti-aging potential.
The study, carried out in a mouse model of accelerated aging, is reported by senior author Robert Rogers, PhD, at MGH, and colleagues, in a paper in PLOS Biology. Commenting on the results, Rogers said, “We find that chronic continuous hypoxia (11% oxygen, equivalent to what would be experienced at Everest Base Camp) extends lifespan by 50% and delays the onset of neurologic debility in a mouse aging model. While caloric restriction is the most widely effective and well-studied intervention to increase lifespan and healthspan, this is the first time that “oxygen restriction” has been demonstrated as beneficial in a mammalian aging model.”
The team’s published study is titled “Hypoxia extends lifespan and neurological function in a mouse model of aging.”
Research efforts to extend healthy lifespan have identified a number of chemical compounds that show promising effects in mammalian lab animals. The widely used diabetes drug metformin, for example, is now being tested in human clinical trials in older adults to evaluate its potential effects on the onset of common age-related chronic diseases, and mortality. Among the list of interventions that slow aging, dietary restriction “stands out”, the authors wrote, both for the size of its effect, and the number of species- including yeast, roundworms, fruit flies, mice and rats—for which it has been proven effective.
Oxygen restriction, or continuous hypoxia, has also been linked to longer lifespan in yeast, nematodes, and fruit flies. However, its effects in mammals have to date remained unknown. “A natural question is therefore whether oxygen restriction, like dietary restriction, may be beneficial in mammalian aging,” the team continued.
To explore the anti-aging potential of oxygen restriction in mammals, Rogers and colleagues conducted lab experiments with mice (Ercc1 Δ/- animals) that have been bred to age more quickly than other mice, while showing classic signs of mammalian aging throughout their bodies. “The Ercc1 Δ/- mouse is a particularly useful model of accelerated aging because it exhibits a shortened lifespan of less than six months and early onset of anatomic, physiological, and molecular features of advanced age across multiple tissues,” the investigators stated. Importantly, prior studies have shown that dietary restriction and come chemical interventions that extend lifespan in wild-type organisms do also confer similar benefits on the Ercc1 Δ/- mice.
For their newly reported study the researchers compared the lifespan of Ercc1 Δ/- mice living at normal atmospheric oxygen levels (about 21%) to the lifespans of animals that, at four weeks of age, had been moved to a living environment with just 11% oxygen, which is a level similar to that experienced at an altitude of 5000 meters. They found that the mice in the oxygen-restricted environment lived about 50% longer than the mice in normal oxygen levels, with a median lifespan of 23.6 weeks compared to 15.7 weeks.
Given that prior research has shown that dietary restriction extends the lifespan of the same kind of fast-aging mice, the researchers wondered if oxygen restriction extended their lifespan simply by causing a change in the animals’ eating habits. However, they found that oxygen restriction did not affect food intake, suggesting that other mechanisms were at play. “Chronic continuous hypoxia did not impact food intake and did not significantly affect markers of DNA damage or senescence, suggesting that hypoxia did not simply alleviate the proximal effects of the Ercc1 mutation, but rather acted downstream via unknown mechanisms,” they wrote.
The oxygen-restricted mice also had delayed onset of aging-associated neurological deficits Interestingly, the authors noted, chronic continuous hypoxia has been reported as beneficial in at least three other mouse models of neurological disease. “Our findings add to a nascent but burgeoning literature on the beneficial effect of hypoxia in a wide variety of neurologic disease models,” they wrote. “The ability of hypoxia to alleviate brain degeneration in such diverse models points either to the pleiotropic effects of oxygen restriction, or alternatively, the existence of a downstream and convergent neuroprotective mechanism.”
The newly reported findings support the anti-aging potential of oxygen restriction in mammals, perhaps including humans. “Our initial findings establish oxygen restriction as a potential aging intervention, motivating the search for underlying mechanisms and generalizability to other mammalian models,” they stated. However, the investigators acknowledged, extensive additional research will be needed to clarify the potential benefits of oxygen restriction, and illuminate the molecular mechanisms by which it operates.
One important future goal will be to define the mechanism by which chronic continuous hypoxia extends lifespan in the mouse model, and to what degree this mechanism overlaps with that of pathways that are already known to be involved in aging, the team continued. “In addition to defining the molecular mechanism of chronic continuous hypoxia, future work must determine if this mechanism operates powerfully across all organs, or rather, if its effects are most notable in the brain,” they stated. “.… it will also be important to determine whether more practical hypoxia regimens, such as intermittent hypoxia, or a more moderate degree of hypoxia (e.g., 17% oxygen, equivalent to the effective oxygen tension in Denver) are effective.”
In their discussion, the team further pointed out that there is some epidemiologic evidence indicating that lifelong oxygen restriction might slow the aging process in humans. “Though there are many potential confounders to this finding, recent cross-sectional studies in Bolivia have demonstrated significant enrichment for nonagenarians and centenarians at very high altitudes,” they wrote. There is also what the team termed “intriguing data” suggesting that moving to altitude in adulthood may have health benefits. A longitudinal study of over 20,000 soldiers of the Indian Army who were assigned to serve at two to three mile elevations above sea level for three years between 1965 and 1972, found that their risk of developing conditions such as diabetes mellitus, hypertension, and ischemic heart disease, was just “a fraction” of the risk of their comrades stationed at sea level.
