A dietary supplement being studied for its potential effects on aging and disease produced dramatically different results in male and female mice with lung cancer.
In a new UCLA study published in Cell Reports, calcium alpha-ketoglutarate, or Ca-αKG, was linked to smaller lung tumors in female mice. In male mice, however, the supplement was associated with larger tumors in one experiment. The findings come from animal research, not a clinical trial, and do not show that the supplement prevents cancer in women or promotes it in men.
Instead, the study offers a striking example of something that can get lost in conversations about supplements: The same compound may not affect everyone the same way.
“These findings offer a glimpse into the complicated relationship among metabolism, cancer and biological sex,” said Dr. Claudio Scafoglio, an associate professor of pulmonary and critical care medicine at UCLA and senior author of the study. “The fact that we observed opposite responses in male and female mice underscores the importance of understanding how sex and tumor genetics shape the response to these types of interventions.”
Alpha-ketoglutarate, often shortened to αKG, is a substance the body naturally produces as part of normal metabolism. The calcium alpha-ketoglutarate tested in this study is a supplemental form that people would generally have to intentionally seek out rather than something they would consume in meaningful amounts through an ordinary diet. Ca-αKG supplements are marketed for purposes including healthy aging and longevity, although research into their effects in people remains limited.
For the new study, researchers used mice genetically engineered to develop a common form of lung cancer called lung adenocarcinoma. The mice received either a standard diet or one containing Ca-αKG for 16 weeks.
Female mice receiving the supplement had smaller tumors and less tumor-cell growth than females eating the control diet. Male mice receiving Ca-αKG had larger tumors and more tumor-cell growth.
The supplement did not significantly change how many tumors developed in either group. That suggests it was affecting how existing tumors grew rather than whether cancer developed in the first place.
Researchers then looked for clues about why the results differed so much. Their experiments suggest Ca-αKG may have changed the way certain genes behaved inside the tumors, with different changes occurring in males and females.
One gene, called TBX5, emerged as a possible part of the explanation. Ca-αKG increased levels of the TBX5 protein in tumors from female mice and decreased them in tumors from males. In existing data from people with lung cancer, higher TBX5 levels were associated with better five-year survival among women.
But that human finding comes with an important distinction. Those patients were not given Ca-αKG as part of a study, and researchers did not know whether they had taken the supplement. The analysis therefore cannot tell us whether Ca-αKG would increase TBX5 or improve cancer outcomes in people.
Genetics added another complication.
When researchers conducted an experiment using mice whose tumors carried an additional genetic change, the supplement no longer significantly affected tumor growth in either females or males. That suggests the genetics of an individual tumor could help determine how it responds.
Even the concerning result in the original group of male mice wasn't consistent. When researchers tested male mice with a different genetic background, the supplement did not increase tumor growth.
“At this time, we cannot explain why male mice treated with Ca-αKG developed larger tumors than those on control diet,” the researchers wrote in the study. They added that they do not believe the finding can necessarily be generalized because it did not appear in the second group of male mice.
There are other reasons to be cautious. This was primarily an animal study, researchers still don't fully understand why the effects differed by sex and genetics, and the dose used in the mouse diet cannot simply be translated into a supplement dose for people.
Most importantly, the research does not provide evidence that people should take Ca-αKG to prevent or treat lung cancer. Nor does it establish that the supplement is dangerous for men.
What it does show is why supplement research can be considerably more complicated than asking whether something "works." Biological sex, genetics and the characteristics of a particular disease may all influence the answer.
“This study is an early step toward the full characterization of metabolic and epigenetic modifications induced by nutritional interventions,” Scafoglio said.
The research was supported by the National Cancer Institute, American Cancer Society, LUNGevity Foundation, Tobacco-Related Disease Research Program, UCLA training and fellowship programs and the Gates Millennium Scholars Program through the Bill & Melinda Gates Foundation.