In the realm of scientific understanding, few discoveries have had as profound an impact on our comprehension of life’s sustenance as Antoine-Laurent Lavoisier’s groundbreaking work on oxygen in the late 18th century. Lavoisier, a distinguished French chemist, meticulously explored the properties and behavior of this life-sustaining gas, forever changing our perception of the fundamental element that allows organisms to thrive. With an unwavering commitment to empirical research, Lavoisier revealed that oxygen is an indispensable component of the air we breathe, playing a central role in respiration. Despite the well-established understanding of oxygen’s vital role in sustaining life, recent research has presented intriguing evidence suggesting that limiting this critical element could offer life-extending benefits. While it may seem contradictory to the prevailing knowledge, these new findings have sparked considerable interest and discussion among scientists.
Previous studies have demonstrated that hypoxia delays the senescence of cultured cells and extends the lifespan of simple organisms such as yeast, nematodes, and fruit flies. However, an intriguing study by Harvard University researchers has taken this exploration further by investigating the impact of oxygen restriction on mice [Rogers RS, Wang H, Durham TJ, et al. Hypoxia extends lifespan and neurological function in a mouse model of aging. PLOS Biology, 2023: 21(5):e3002117 https://doi.org/10.1371/journal.pbio.3002117].
Interestingly, the study utilized a fascinating connection between calorie restriction, a known lifespan-extending intervention observed in multiple species, and the activation of hypoxia-induced gene expression and pathways.
Hypoxia and Longevity
Hypoxia-induced pathways are known to offer several benefits in biological processes. These pathways activate in response to low oxygen levels, promoting angiogenesis, enhancing cellular survival, and regulating metabolism. These pathways have also been shown to trigger protective mechanisms in cells, boosting their survival and reducing cell death. Furthermore, numerous animal species utilize these pathways to enter a state of stasis during extended periods of hibernation or shorter periods of torpor.
Apart from laboratory experiments, the natural world has provided compelling examples that suggest hypoxia may confer longevity advantages. Certain animal species that experience hypoxic conditions in their natural habitats have enhanced lifespans. For instance, naked mole rats live in low-oxygen underground environments and exhibit remarkable resistance to age-related diseases. High-altitude birds like bar-headed geese and Andean condors have adapted to thrive in oxygen-deprived areas, displaying extended lifespans compared to their low-altitude counterparts. Diving marine mammals like seals, sea lions, and whales face hypoxia while holding their breath underwater but demonstrate impressive longevity. These examples highlight the connection between hypoxic conditions and enhanced lifespans in various animal species and make hypoxia a good candidate for examination as a lifespan-extending intervention.
To explore the effects of hypoxic therapy, a short-lived mutant strain of mouse, Ercc1 Δ/-, was used. Ercc1 Δ/- mice are genetically modified to have a deletion or knockout of the Ercc1 gene. The Ercc1 gene encodes for the protein ERCC1-XPF, which is involved in DNA repair mechanisms. ERCC1-XPF plays a crucial role in the nucleotide excision repair (NER) pathway, one of the cellular mechanisms responsible for repairing DNA damage.
The deletion of the Ercc1 gene in these mice results in reduced or impaired NER capacity. As a consequence, Ercc1 Δ/- mice exhibit accelerated aging and increased susceptibility to various age-related diseases, including neurodegeneration, liver degeneration, and early onset of age-related functional decline. These mice have become an important research model for studying the molecular mechanisms underlying aging and age-related diseases, as well as for exploring potential interventions and therapies.
In this study, mice were housed in specialized environmental chambers where they were exposed to 11% oxygen, representing a significant reduction from the normal atmospheric oxygen level of 21% that mice are typically exposed to. This controlled hypoxic environment led to a robust improvement, of approximately 50%, in the median mortality rate, which refers to the point at which half of the mice in the study population had died. Notably, these results were similar in both male and female mice. Furthermore, the overall survival of these mice was increased by 23%, indicating a substantial enhancement in their longevity compared to mice under normal oxygen conditions.
Aligned with the enhanced lifespan, these mice also exhibited notable improvements in their health. This mutant mouse strain typically experiences an early onset of neurological impairments, resulting in a decline in physical well-being and motor function. However, the hypoxic treatment effectively delayed the onset and progression of these symptoms, preserving their neurological health for an extended period.
While animal studies often fall short of directly translating to humans, it is especially important to approach with caution the results of using a mutant strain. The model strain used in this study exhibits a compromised ability to efficiently repair DNA damage, leading to an accelerated state of aging. Given this understanding, it is reasonable to speculate that hypoxia treatment might primarily act to support DNA maintenance and repair mechanisms, potentially having a limited impact on the natural aging process itself. Surprisingly, hypoxia treatment did not impact the accumulation of DNA damage compared to the untreated control, nor did it improve senescent cell burden, a key indicator of cellular aging.
While the authors of the study did not identify a direct molecular mechanism explaining the observed improvements in health and lifespan resulting from hypoxia treatment, they acknowledged the need for further investigations. Despite this, the research instills cautious optimism that hypoxic therapy could potentially benefit individuals with neurological pathologies resembling those observed in the mutant mouse strain studied. By delving deeper into the underlying mechanisms, researchers aim to unravel the intricate relationship between oxygen restriction, gene expression, and the extension of lifespan, and through continued exploration, a more comprehensive understanding of the therapeutic potential of hypoxia may be obtained.