Female rats with one of two mitochondrial DNA variants (inherited only from the mother) appear likely to outlive females with the other variant, aging researcher Arlan Richardson said; final results are expected in 6–10 months
Female rats with one of two mitochondrial DNA variants (inherited only from the mother) appear likely to outlive females with the other variant, aging researcher Arlan Richardson said; final results are expected in 6–10 months
On November 2, Richardson and biologist Steven Austad discussed an ongoing experiment in genetically diverse rats on the Longevity.Technology Unlocked podcast: each rat has a different combination of nuclear genes, while its mitochondrial DNA is one of two variants. At the time of recording, 30–40% of the rats had died.
The ITP program tests anti-aging compounds in mice bred from four strains, with each mouse carrying a different combination of nuclear genes. Mitochondria are inherited only from the mother, and the mothers are always daughters of BALB/c females, so all the experimental mice have the same mitochondrial DNA. While planning to breed a rat equivalent of the ITP mice, Richardson noticed this and wondered whether introducing a second mitochondrial DNA variant would make a difference.
Researchers have looked for effects of mitochondrial variants in humans: D4a, a group of related variants, was more common among Japanese people older than 105 than in control groups. However, the authors of an analysis of 112 people of this age concluded that population structure, meaning shared ancestry, explained the association: the variant could simply have been inherited alongside nuclear genes that affect lifespan.
Rats offer two substantially different variants, Austad explains. Laboratory mouse strains descend from a handful of ancestors that lived a century ago, and even distantly related strains may differ at just 3–5 nucleotides out of 16 000 in their mitochondrial DNA. Rats were domesticated repeatedly in different places, and the mitochondrial DNA of the Brown Norway and Wistar Kyoto strains differs at 94 positions, comparable to the difference between two people with distant ancestry.
Four rat strains were crossed in two pairs, and the resulting hybrids were then crossed in both directions, switching which hybrid supplied the mother and which supplied the father. The maternal hybrid determines the offspring’s mitochondrial DNA: one group inherits it from Brown Norway, the other from Wistar Kyoto. Almost all nuclear genes are randomly mixed in both groups, with each of the four strains contributing an equal share on average.
Richardson expected a small effect because mitochondrial DNA accounts for only a small fraction of all DNA. Yet the mitochondrial DNA variant affected age-related changes in these rats, almost always in males alone or females alone. In September, a paper was published, coauthored by Richardson, on the ovaries of these rats: the reserve of immature eggs was the same in both groups at 4 months; by 9 months, it was substantially smaller in females with Wistar Kyoto mitochondrial DNA than in females with Brown Norway mitochondrial DNA; and by 14 months, it was the same again. The authors conclude that the variant changes the rate at which the reserve is depleted.
In the lifespan experiment, Richardson said, the results so far suggest that females with one variant will outlive females with the other.
The same rats are also being used to test 17α-estradiol, a close relative of the female hormone estradiol with weak hormonal activity. In the ITP, it increased median lifespan in male mice by 19% when treatment began at 16 months, but did not benefit females. In a 2023 experiment, it prevented weight gain in rats fed a high-fat diet: females benefited with either variant, while males benefited only with Brown Norway mitochondrial DNA. In the current experiment, male rats have yet to show the lifespan extension seen in male mice, but Richardson said that “the situation could change over the next six months.”
If the experiment shows that the mitochondrial DNA variant does make a difference, and rat findings translate to humans better than mouse findings do, Austad said, “this could mean a major shift back to rats, the preferred animal in the early days of aging research.”