How Fasting Can Slow Down Aging

Dietary trends such as ketogenesis and intermittent fasting are currently extremely popular due to their rapid weight loss effects. However, scientists are now beginning to find out how they can actually help the body in other ways. In fact, a molecule produced during fasting has recently been found to provide the vascular system with a longevity boost, which will, in turn, slow down the aging process of the entire body.

While fasting, the human body enters a metabolic state called ketosis, which means that the body begins to rely on fat instead of glucose as a source of energy. One of these energy sources, collectively known as ketones, is a molecule called β-Hydroxybutyrate.

According to senior study author Dr. Ming-Hui Zou, "previously, studies on ketone bodies focused on energy metabolism, but this study showed that there are other physiological effects which regulate cell cycle to retardate aging progression."

A previous study, carried out at Harvard University in 2017, found that the activity of mitochondrial networks inside our cells can become altered due to fasting, in turn leading to better health, slower aging, and an increased lifespan.

Zou's study, though, aims to explore how high levels of β-Hydroxybutyrate might display similar effects by interfering with senescent cells, which are cells that are unable to divide or multiply. 

The team discovered that β-Hydroxybutyrate actually slows down these senescent vascular cells at the perfect moment, which prompts them to divide, thereby preventing them from aging. When tested on mice, the team discovered that it was also able to keep blood vessels young by promoting stem cell factors that protect against DNA-related senescence.

"We think this is a very important discovery, and we are working on finding a new chemical that can mimic the effect of this ketone body's function," said Zou. 

"We're trying to take the global approach to reducing cardiovascular disease and Alzheimer's disease. It's difficult to convince people not to eat for the next 24 hours to increase the concentration of this compound, and not everybody can do that, but if we can find something that can mimic this effect and people can still eat, it would make life more enjoyable and help fight disease."

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Fasting triggers stem cell regeneration of damaged, old immune system

In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study shows that cycles of prolonged fasting not only protect against immune system damage — a major side effect of chemotherapy — but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal.

In both mice and a Phase 1 human clinical trial involving patients receiving chemotherapy, long periods of not eating significantly lowered white blood cell counts. In mice, fasting cycles then “flipped a regenerative switch,” changing the signaling pathways for hematopoietic stem cells, which are responsible for the generation of blood and immune systems, the research showed.

Learn more: Fasting-mimicking diet

• A low-calorie fasting-like diet, plus chemotherapy, enables the immune system to recognize and kill skin and breast cancer cells, according to a new USC-led study on mice.

• Evidence is mounting that a diet mimicking the effects of fasting has health benefits beyond weight loss, with a new USC-led study indicating that it may reduce symptoms of multiple sclerosis.

• A diet that mimics fasting appears to slow againt.

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as people age. By outlining how prolonged fasting cycles — periods of no food for two to four days at a time over the course of six months — kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.

“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” said corresponding author.

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” Longo said. “What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”

Fasting cycles

Prolonged fasting forces the body to use stores of glucose, fat and ketones, but it also breaks down a significant portion of white blood cells. Longo likens the effect to lightening a plane of excess cargo.

During each cycle of fasting, this depletion of white blood cells induces changes that trigger stem cell-based regeneration of new immune system cells. In particular, prolonged fasting reduced the enzyme PKA, an effect previously discovered by the Longo team to extend longevity in simple organisms and which has been linked in other research to the regulation of stem cell self-renewal and pluripotency — that is, the potential for one cell to develop into many different cell types. Prolonged fasting also lowered levels of IGF-1, a growth-factor hormone that Longo and others have linked to aging, tumor progression and cancer risk.

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the OK for stem cells to go ahead and begin proliferating and rebuild the entire system,” explained Longo, noting the potential of clinical applications that mimic the effects of prolonged fasting to rejuvenate the immune system. “And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”

Prolonged fasting also protected against toxicity in a pilot clinical trial in which a small group of patients fasted for a 72-hour period prior to chemotherapy, extending Longo’s influential past research.

“While chemotherapy saves lives, it causes significant collateral damage to the immune system. The results of this study suggest that fasting may mitigate some of the harmful effects of chemotherapy,” said co-author of the study. “More clinical studies are needed, and any such dietary intervention should be undertaken only under the guidance of a physician.”

“We are investigating the possibility that these effects are applicable to many different systems and organs, not just the immune system,” said Longo, whose lab is in the process of conducting further research on controlled dietary interventions and stem cell regeneration in both animal and clinical studies.

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The science of fasting and longevity

When it comes to what, when and how we eat, fasting — voluntarily abstaining from food for varying periods of time — is having a moment. It was the most popular diet of 2018, according to a survey from the International Food Information Council Foundation (IFICF), and forms of fasting rank among Google’s top-trending diet searches. Seemingly ageless celebrities praise the practice for helping them to look, feel and even sleep better.

Yet fasting is far from a fad. It was a part of life in ancient civilizations, and many religions today retain some form of the rite, often as a way to achieve focus and clarity. In scientific circles, no less than Hippocrates, known as the father of modern medicine, is said to have prescribed it to spur healing.

When Time magazine named Valter Longo to its first-ever list of the 50 Most Influential People in Health Care, they called him “the fasting evangelist.” Evangelism captures the passion that Longo, director of the USC Longevity Institute and the Edna M. Jones Professor of Gerontology at the USC Leonard Davis School, brings to his research exploring the life-extending benefits of fasting-like diets. It also connects to the many faith traditions that make fasting an age-old practice. And it’s a techie term used in Silicon Valley circles for spurring mainstream adoption of an innovation.

The word works. One in 10 people today are following a fasting diet, according to the IFICF survey.

Today, heath and renewal remain key reasons for fasting’s enduring popularity, and they are at the heart of a thriving field of scientific inquiry that aims to leverage fasting-like diets as a way to extend life and help treat and prevent disease.

“I want to optimize the chance for people to make it to 110 healthy,” said Longo.

Starving for Answers

Longo, who earned his PhD in biochemistry, has been at the forefront of the modern fasting movement for more than 20 years. His work grew out of earlier food-related findings showing that reducing calories without malnutrition extended healthy life spans and reduced cancer and other diseases in animal models. But these studies, as well as some later ones in humans, also revealed harmful consequences of severe caloric restriction and proved to be very difficult for people to maintain.

“Those experiments told us that there is no doubt there is this secret to many diseases in those calorie-restriction studies, but calorie restriction is not the answer,” Longo said. “So, the goal was always to come up with something that was as good as calorie restriction, if not better, but take away the burden and take away the side effects.”

Longo’s search led him to study the genetics of aging, where his early experiments showed that yeast cells starved of nutrients lived longer and were more resistant to stress. “If you starve them, they become very protected,” he said. “So I started thinking, what would this be useful for? And the first idea was chemotherapy.”

Findings from the Field

In a landmark 2008 study, Longo found that fasting for two days protected healthy cells against the toxicity of chemotherapy, while the cancer cells stayed sensitive. These results opened the door to a new way of thinking about cancer treatments — one that shields healthy cells to allow for a more powerful assault on cancerous ones. They also led to the creation of the first fasting-mimicking diet, which Longo developed as a way to put patients with cancer, or mice in the lab, in a fasting state while still allowing them to eat.

“The oncologists did not want to fast the patients, and the patients did not want to fast,” Longo said. “We went to the National Cancer Institute, and they came up with a call for a fasting-mimicking diet, essentially saying: ‘Let’s develop something that people can eat but [that], to the body — whether it’s a mouse or a person — is going to be like water-only fasting, meaning that it will cause very similar changes, as if they were not eating at all.’”

Longo answered the call, and in the past decade, he and other researchers have clinically demonstrated that brief cycles of periodic fasting-mimicking diets (FMD) have a range of beneficial effects on aging and on risk factors for cancer, diabetes, heart disease and other age-related diseases in mice and humans. More recent studies have also shown promise for treating multiple sclerosis and Crohn’s disease.

“If the results remain positive, I believe this FMD will represent the first safe and effective intervention to promote positive changes associated with longevity and health span, which can be recommended by a physician to almost any adult,” Longo said.

Based on his USC research, Longo founded L-Nutra, a nutri-technology company that offers packaged versions of the FMD. Longo says the company is gathering clinical data related to efficacy and side effects, and it aims to one day gain FDA approval for use of the diet as a way to treat disease. Longo also says that he will donate 100 percent of his shares in the company to research and charity.

Renewal

Longo’s USC lab is currently delving further into how the FMD dietary intervention affects regeneration and disease resistance. He has coined the term “juventology” to explore the question of how to stay young and not just healthy.

“That’s really what this fasting movement is about. How do you change the system, how do you trick and reset cells so that you’re going back, maybe not to 18 years old, but certainly to that state where everything was in place?” he said.

Longo, who hopes to live to 120, thinks that an L-Nutra fasting mimicking diet called Prolon, made for relatively healthy people and providing an average of 900 calories a day, can help with this resetting, even if it is done an average of only three times a year. “I think it’s got little to do with everyday food, in general, [and] more to do with the ability of a system to reset,” he said. “That’s the power of understanding the fundamental ability of organisms to repair themselves.”

However, this is not to say that Longo does not have recommendations about what, and how much, to eat when not fasting. In his recent book The Longevity Diet, he advocates following a diet supported by science and seen in most long-lived populations around the world that is mostly plant-based, low in protein and rich in unsaturated fats and complex carbohydrates. “It just has to be the right foods in the right amounts,” Longo said.

Fast Talk

In light of the focus on fasting, the USC Leonard Davis School hosted the First International Conference on Fasting, Dietary Restriction, Longevity and Disease. Top researchers from Harvard, MIT, the Salk Institute, the National Institutes of Aging and other institutions gathered for a two-day conference that offered education for doctors and the lay public, and that also provided an opportunity for participants to dialogue with other field leaders in an attempt to set standards — and reality checks — for the increasingly popular, and often improvised, practice.

“If you go out there and you pick the people that are fasting, I would say 95 percent of them are doing it wrong. Conferences like this are really important to make sure that we keep getting it right,” Longo said. “You really need to have lots of universities, lots of leaders, lots of clinical trials and lots of basic research. And I think that for the first time, this is happening.”

What’s Next

Indeed, several large clinical trials are now underway. One trial funded by the National Institutes of Health is looking at whether intermittent fasting is a safe and effective alternative to more standard methods of weight control, such as caloric restriction. Another National Institute on Aging (NIA) study is testing an intermittent fasting diet in obese people ages 55 to 70 with insulin resistance. According to the NIA, researchers will continue to explore many unresolved questions around determining the long-term benefits and risks of various eating patterns, including looking at which diets are feasible as a long-term practice, what specific biological effects on aging and disease are triggered by a particular eating pattern, what ways of eating are best for different age groups, and whether an eating pattern that’s found to help one person might not have the same effect on another.

“Other than genes, it is hard to think of something that can be more powerful than food in determining whether someone is going to make it to 100 or die before 50 years old,” Longo said.

The challenge for researchers and for society in general, he says, is to translate what works in the lab into real people’s lives. He says a new approach is needed, one that does not call for an across-the-board reduction in the amounts and types of foods people eat — which, studies show, most people cannot sustain.

“So, if you went to somebody and said, ‘You can do everything you did before, but I just ask you one thing: Reduce your animal protein intake by 40 percent, or undergo a vegan fasting-mimicking diet for 15 days a year.’ Now we start to become reasonable,” Longo said. “Let’s come up with something that doesn’t require people to change their habits, but it does require them to maybe once in a while make smaller changes.”

In other words… not so fast.

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