Fight Aging!

Intermittent mild hypoxia has been shown to slow aging and improve health in animal studies, and is used in medicine in some contexts. It is a form of stress and encourages a hormetic response from cells that on balance improves health. Long term hypoxia or severe hypoxia tips over into outright harm, overwhelming any beneficial mechanisms that attempt to compensate. Human data suggests that high altitude living, at the point where mild hypoxia is induced by the lower oxygen content of the air, results in accelerated aging. For example, researchers have shown that these populations exhibit accelerated immune aging. These populations are not yet large enough or well studied enough to go much beyond this sort of investigation of a few aspects of their physiology. Epidemiology for more solid evidence of accelerated aging is lacking, for example, and much of the existing data on mortality and age-related disease could be explained by comparative poverty rather than any sort of comprehensive acceleration of aging.

Recall that epigenetic age is usually assessed from a blood sample, and the only cells in a blood sample with nuclei and nuclear DNA are immune cells. Thus epigenetic age assays are really a measure of immune aging rather than systemic aging. To the degree that those two correlate, this is fine. But they are not the same thing, and the immune system is subject to pressures and mechanisms not relevant to other cell types in other tissues. Thus epigenetic age in those other cell types and tissues is more interesting in a research context.

Today's open access paper provides more evidence for intermittent hypoxia to accelerate epigenetic age, though the question remains as to whether aging is a good description for is actually occurring inside cells, meaning a shift in nuclear DNA structure in response to low oxygen levels. In mice, the researchers looked at a few different tissues, and found that epigenetic age acceleration only occurred in old mice, and went away when hypoxia treatment was halted. The researchers also note human data from the AltitudeOmics study, which involved blood samples rather than tissue samples, and so measured immune aging rather than tissue aging.

Intermittent hypoxia induces reversible epigenetic age acceleration in old mice

Epigenetic mechanisms are considered adaptive regulators of gene expression, yet mechanisms driving aging-associated DNA methylation remain unclear. Prior work hinted that epigenetic aging might reflect a response to oxygen availability, with age-differential methylation in immune cells enriched near binding sites for hypoxia-responsive factors ARNT and REST. To test this hypothesis, we exposed adult (11 months) and old (23 months) mice to 1 month of intermittent hypoxia (IH) followed by normoxic recovery.

IH induced epigenetic age acceleration in lungs, spleen, and heart in old mice only. This acceleration reversed upon return to normoxia. Reversible shifts were enriched at bivalent domains and PRC2 targets, indicating oxygen-sensitive chromatin remodeling.

Human translational validation from the AltitudeOmics project in which 19 young adults underwent baseline testing near sea level then again after rapid ascent to 5260m confirmed rapid, conserved epigenetic aging. Our findings establish oxygen availability as a primary, conserved modulator of epigenetic aging across tissues and species, showing that oxygen fluctuations are a potent, reversible driver of epigenetic aging.