How 'ketogenic diet' increases longevity
Gladstone Institutes' scientists 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.
This fundamental 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.
Gladstone Senior Investigator Eric Verdin and his team examined the role of the compound beta-hydroxybutyrate (beta'OHB), a so-called "ketone body" that is produced during a prolonged low-calorie or ketogenic diet.
While ketone bodies such as beta'OHB can be toxic when present at very high concentrations in people with diseases such as Type I diabetes, Dr. Verdin and colleagues found that at lower concentrations, beta'OHB helps protect cells from "oxidative stress"-which occurs as certain molecules build to toxic levels in the body and contributes to the aging process.
"Over the years, studies have found that restricting calories slows aging and increases longevity-however the mechanism of this effect has remained elusive," Dr. Verdin said.
"Here, we find that beta'OHB-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," he explained.
Oxidative stress occurs as cells use oxygen to produce energy, but this activity also releases other potentially toxic molecules, known as 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.
However, Dr. Verdin and his team found that beta'OHB 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 beta'OHB is administered during a chronic calorie-restricted diet. The researchers found that calorie restriction spurs beta'OHB 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 beta'OHB block the HDACs from doing so, which by default 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 beta'OHB, 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," said Gladstone Investigator Katerina Akassoglou, PhD, an expert in neurological diseases and 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-diseases that afflict millions and for which there are few treatment options," she noted.
The finding appeared in the latest issue of the journal Science.