Researchers have identified a novel mechanism by which a type of low-carb, low-calorie diet—called a “ketogenic diet”—could delay the effects of aging. Their discovery reveals how such a diet could slow the aging process and may one day allow scientists to better treat or prevent age-related diseases including heart disease, Alzheimer’s disease, and many forms of cancer.
Scientists at the Gladstone Institutes, led by senior investigator Eric Verdin, M.D., examined the role of the compound β-hydroxybutyrate (βOHB), a so-called “ketone body” that is produced during a prolonged low-calorie or ketogenic diet. While ketone bodies such as βOHB can be toxic when present at very high concentrations in people with diseases such as type 1 diabetes, Dr. Verdin and colleagues found that at lower concentrations, βOHB helps protect cells from oxidative stress.
“Over the years, studies have found that restricting calories slows aging and increases longevity—however the mechanism of this effect has remained elusive,” says Dr. Verdin, the paper’s senior author, who directs the Center for HIV & Aging at Gladstone and is also a professor at the University of California, San Francisco. “Here, we find that βOHB—the body’s major source of energy during exercise or fasting—blocks a class of enzymes that would otherwise promote oxidative stress, thus protecting cells from aging.”
Oxidative stress occurs as cells use oxygen to produce energy, but this activity also releases potentially toxic free radicals. As cells age, they become less effective in clearing these free radicals—leading to cell damage, oxidative stress, and the effects of aging.
Dr. Verdin and his team found that βOHB might actually help delay this process. In a series of laboratory experiments—first in human cells in a dish and then in tissues taken from mice—the team monitored the biochemical changes that occur when βOHB is administered during a chronic calorie-restricted diet. The researchers found that calorie restriction spurs βOHB production, which blocked the activity of a class of enzymes called histone deacetylases, or HDACs.
Normally HDACs keep a pair of genes, called Foxo3a and Mt2, switched off. But increased levels of βOHB block HDACs from doing so, which activates the two genes. Once activated, these genes kick-start a process that helps cells resist oxidative stress. This discovery not only identifies a novel signaling role for βOHB, but it could also represent a way to slow the detrimental effects of aging in all cells of the body.
“This breakthrough also greatly advances our understanding of the underlying mechanism behind HDACs, which had already been known to be involved in aging and neurological disease,” says Gladstone investigator Katerina Akassoglou, Ph.D., one of the paper’s co-authors. “The findings could be relevant for a wide range of neurological conditions such as Alzheimer’s, Parkinson’s, autism, and traumatic brain injury.”
“Identifying βOHB as a link between caloric restriction and protection from oxidative stress opens up a variety of new avenues to researchers for combating disease,” adds Tadahiro Shimazu, a Gladstone postdoctoral fellow and the paper’s lead author. “In the future, we will continue to explore the role of βOHB—especially how it affects the body’s other organs, such as the heart or brain—to confirm whether the compound’s protective effects can be applied throughout the body.”
The study, called “Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor”, appears in the latest issue of the journal Science.