Happy Stem Cells Run on Fat

Yilmaz recognized that he had discovered a very interesting phenomenon, where some period of fasting seemed to have beneficial effects on stem cells in both young and older individuals. But what mechanisms were at play? Through clever experimentation, the researchers discovered that fatty acid oxidation may be the cause of improved stem cell function in fasted mice. When Yilmaz and colleagues turned off fat metabolism through genetic engineering, they were able to block the benefits of fasting on the mice’s intestinal stem cells.

“If you look at the Western diet, under normal dietary conditions we and our cells derive about 60 to 70 percent of our energy from carbohydrates or sugar, about 20 percent from fat, and the remainder from amino acids,” Yilmaz said. “What’s really interesting is that when you fast, you start to derive much more energy, respectively, from the breakdown of fat. What we think is happening in our mice is that during fasting, the intestinal stem cells in both young and old animals switch from utilizing carbohydrates to using fat as a primary energy source, and that this metabolic switch is driving an improvement in stem cell function.”

The researchers don’t know yet exactly what is happening downstream of fat metabolism that is improving stem cell function in response to fasting, but they are on the hunt for the molecular players. Stem cells may function better when burning fats for fuel, but lose the ability to metabolize fats efficiently as they age.

“We know that the utilization of fat for energy in stem cells is associated with improved function; the next step is to work to understand why that is,” Yilmaz said.

“Fasting increases FAO [fatty acid oxidation] in ISCs [intestinal stem cells] by driving both a robust PPAR-mediated FAO program in ISCs and by increasing circulating levels of triglycerides and FFAs [circulating free fatty acids] that can be then used by cells to generate acetyl-CoA for energy.” — Cell Stem Cell, 2018

Keto diets have been used clinically to treat patients with seizures and related disorders for decades. Improvements in neurological symptoms that accompany keto diets and intermittent fasting have been associated with ketone bodies produced during the metabolism of fats and their use as an energy source in the brain. But it’s not clear exactly how fatty acid oxidation contributes to rejuvenation in other tissues in response to fasting.

Fasting has also been associated with cellular turnover through autophagy or the dying off of aged, senescent cells that are damaged and can no longer divide. By selectively targeting senescent cells, fasting may improve tissue function such as that seen in the fasted mice’s intestines. However, Yilmaz says, a 24-hour fast for a mouse is short in the grand scheme of things. It’s unlikely that the observed improvement inintestinal tissue and stem cell function within that time frame would be primarily due to a clearing out of damaged, pro-inflammatory senescent cells.

“We think we are improving the quality of the existing stem cells, rather than generating new stem cells under these conditions,” Yilmaz said. “But with these types of interventions, there’s never one simple answer. Autophagy or the clearing out of senescent stem cells could be contributing to this improvement. However, we didn’t see any significant increase in cell death of intestinal stem cells in our fasted mice.”

If, as Yilmaz suspects, fasting is able to improve the function of existing intestinal stem cells in mice through fat metabolism, then the mitochondria in these cells, the “energy powerhouses” responsible for producing cellular energy, are key players. Fat metabolism occurs in mitochondria, where fat that enters the cell is immediately shuttled for breakdown and “burning.” Impaired energy production as a result of aging and dysfunctional mitochondria might be a reason why human brains are susceptible to age-related diseases — and why fasting and fatty acid oxidation have been associated with cognitive improvements.

A Pill for Fasting?

Even though fasting is a relatively simple health intervention, not everyone can or should practice long fasts. For example, fasting is contraindicated for Type 1 diabetics, pregnant women, and other individuals suffering from malnutrition or muscle wasting. Yilmaz is investigating whether some of the metabolic benefits of fasting might be activated synthetically, or with drugs that drive fatty acid oxidation.

“At the end of the day, fasting may be a powerful health intervention, but it requires a lot of discipline. Fasting for 24 hours is a huge task,” Yilmaz said. “But if we drive fatty acid oxidation with a drug that turns on genes associated with fat metabolism, we are able to reproduce much of the benefit we observe from fasting mice for 24 hours.”

Ketone supplementation, on the other hand, may be tricky. Most ketones supplements are likely to be unstable in the bloodstream, Yilmaz says. If you take ketones artificially, you’ll probably end up peeing most of them out within a short period, he says. We likely need more research in this area to justify ketone supplementation as an alternative to or driving of fasting benefits. The drug Yilmaz used to reproduce the metabolic health and intestinal tissue function benefits of fasting in mice actually turns on or activates genes that ultimately help break down fat. However, there are still unknowns in terms whether such drugs could have unintended consequences in humans who were still consuming a diet high in carbohydrates and sugars.

All animal studies have limitations in terms of translating the findings to humans. One limitation that stands out for this study is that a 24-hour a fast for a mouse is equivalent to a much longer fast in a human — a mouse fasted for 24 hours loses 3 to 5 percent of its body mass. But Yilmaz says that there are some very strong hints from a range of research studies that fasting on the range of 24 hours in humans has health benefits.

“What is the optimal period of fasting for humans? There’s probably not one answer to this question to fit everyone,” Yilmaz said. “I think the important thing is knowing that skipping a meal every now and then will likely be good for one’s health. This is an area where we need more high-quality controlled studies in humans, but it’s difficult to recruit large numbers of patients for fasting intervention studies.”

Omer H. Yilmaz, MIT.

Yilmaz is also now studying whether a ketogenic diet and 24-hour fasting may have similar effects on the function of intestinal stem cells in mice, or if fasting has unique benefits.

Yilmaz himself practices intermittent fasting on a regular basis, including over Ramadan for 17–18 hours per day. He was even fasting while conducting the interview for this blog post!

“This definitely isn’t a controlled study, but I feel really good while fasting,” Yilmaz said. “I feel more alert, and healthy — you get used to it over time. I should take an intestinal biopsy to see what my intestinal stem cells look like and how they function while I’m fasting!”