To test this idea, Mootha, Rogers, and their colleagues worked with a strain of mice that age prematurely. These animals succumb to age-related diseases at about 3 or 4 months of age, compared with normal, or “wild type” mice, who live about two years.
Once the mice were weaned at around four weeks after birth, the researchers moved them into a hypoxic chamber with an oxygen concentration of just 11 percent, the equivalent of the oxygen levels at the base of Mount Everest.
Rather than decreased barometric pressure — the reason for such low oxygen tension at high altitudes — the hypoxic chamber’s low oxygen content was caused by dilution with nitrogen gas.
The median life span of these mice living at normal 21 percent oxygen was just shy of 16 weeks. However, animals housed in the hypoxic chamber lived to about 24 weeks, on average, or about 50 percent longer than expected.
The maximum life span of these animals also increased under low-oxygen conditions — by about 30 percent, or about 31 weeks, compared with 26-week life spans of their peers living in normal oxygen concentrations.
Life span wasn’t the only outcome that changed for the animals residing under oxygen restriction, Rogers explained.
Mice living in the reduced oxygen environment also preserved neurologic function longer, as measured by their performance on a standard test of coordination and strength.
Seeking to understand the mechanism behind these effects, the researchers examined food intake to see if the animals ate less, since caloric restriction has proved to be a potent life span extender in multiple animal models.
To the researchers’ surprise, mice living in the hypoxic chamber ate slightly more food than those living under normal oxygen concentrations. A search for unusual gene activity, DNA damage, or changes in signaling pathways in the oxygen-restricted mice turned up some tantalizing clues but no definitive answers, Rogers said.
Future studies, he added, should examine whether oxygen restriction can similarly extend life span in wild-type mice, should seek to define what mechanisms might be responsible for the life-extending effects of restricted oxygen, and determine whether these mechanisms affect all organs.
Authorship, funding, disclosures
Additional authors included Hong Wang, Timothy Durham, Jonathan Stefely, Norah Owiti, Andrew Markhard, Lev Sandler, and Tsz-Leung To.
This work was funded by a gift from the J. Willard and Alice S. Marriott Foundation to Mootha. Mootha is an Investigator of the Howard Hughes Medical Institute. Rogers is supported by the Parker B. Francis Family Foundation Fellowship.
Mootha is on the scientific advisory board of 5am Ventures. He is listed as an inventor on patents filed by Massachusetts General Hospital on the therapeutic uses of hypoxia.
