NMJ’s Medical Editor, Tina Kaczor, ND, FABNO , recently interviewed Valter Longo, PhD, Edna M. Jones professor in gerontology, professor in biological science, and director of the Longevity Institute, on his research in caloric restriction and fasting in cancer.

Longo is a member of the University of Southern California (USC) Norris Cancer Center and USC Alzheimer’s Disease Research Center. His laboratory is interested in understanding the fundamental mechanisms of aging by using genetics and biochemistry techniques. It also seeks to identify the molecular pathways conserved from simple organisms to humans that can be modulated to protect against multiple stresses and prevent or treat cancer, Alzheimer's disease, and other diseases of aging. The focus is on the signal transduction pathways that regulate resistance to oxidative damage and on the dietary changes that regulate them. Most projects in the lab include parallel molecular studies in model organisms and mammals, with several projects involving clinical trials and human population studies with focus on dietary restriction and its effect on disease prevention and treatment. Longo is a member of the University of Southern California (USC) Norris Cancer Center and USC Alzheimer’s Disease Research Center. His laboratory is interested in understanding the fundamental mechanisms of aging by using genetics and biochemistry techniques. It also seeks to identify the molecular pathways conserved from simple organisms to humans that can be modulated to protect against multiple stresses and prevent or treat cancer, Alzheimer's disease, and other diseases of aging. The focus is on the signal transduction pathways that regulate resistance to oxidative damage and on the dietary changes that regulate them. Most projects in the lab include parallel molecular studies in model organisms and mammals, with several projects involving clinical trials and human population studies with focus on dietary restriction and its effect on disease prevention and treatment.

Longo was born and raised in Genoa, Italy, and received his undergraduate degree from the University of North Texas in 1992, where he majored in biochemistry with a minor in jazz performance. He continued his studies at the University of California Los Angeles (UCLA) where he started his graduate studies in the pathology department but received his PhD in biochemistry in 1997. He completed his postdoctoral training in neurobiology at USC.

Kaczor: For those not familiar with your work, it may seem counterintuitive that caloric restriction can both prolong the life of cells/organisms as well as hasten the death of cancer cells. Can you explain how this seeming paradox works?

Longo: Fasting protects normal cells by causing entry into a non-dividing stress resistance mode, which we have shown to be similar in organisms ranging from yeast to humans. By contrast fasting makes it worse for cancer cells by generating an extreme environment with low glucose and growth factors and high ketone bodies, which weakens cancer cells. Each mutation in cancer cells makes them a little better at growing under standard conditions, but a little worse at surviving under extreme environments such as that caused by fasting.

Kaczor: The ubiquitous role of fasting in various cultures and religions around the world demonstrates that it is safe for humans. You published a review that detailed what you called “metabolic, molecular and cellular adaptations” from caloric restriction that ultimately may reduce the risk of cancer. From your work, what is the optimal amount of caloric restriction, and duration of that restriction, to achieve cancer preventative changes in humans?

Longo: I don’t think severe calorie restriction is appropriate since, in addition to many beneficial effects, it also causes severe weight loss. I believe that for now, a high micronourishment, mostly plant-based diet with some fish that allows a BMI of 21–23 and low waist circumference is the ideal diet. Brief periods of fasting followed by refeeding to remain at a steady weight may also be recommended.

Kaczor: Your latest publication demonstrated sensitization the cytotoxic effects of chemotherapeutics on mammalian cells in vitro through short-term fasting. This was apparent for some cancers that have a poor prognosis clinically, such as glioma. While the study was in vitro, many clinicians in integrative medicine will be eager to hear if this is feasible in humans. Cancer patients risk losing muscle mass, though, and maintenance of weight is the priority in cancer care. The question for clinicians is how long of a fast would be necessary to achieve possible sensitization of cancer cells to chemotherapies? Is caloric restriction enough to achieve similar cellular effects?

Longo: In both mice and patients, the great majority who fasted were able to regain their weight after returning to the normal diet. For the 2–3 days of fasting (water only) before chemo and 24-hour fast (water only) after chemo, the risk is minimal. However, patients with diabetes or metabolic disorders, or those who have lost more than 10% of their weight, should be carefully assessed before deciding whether fasting is appropriate for them.

Kaczor: Are there any agents, natural or pharmaceutical, that either enhance the cellular changes seen in caloric restriction, or, conversely any agents that may negate its benefits?