Editorial: Interview with Professor Valter Longo

Valter Longo received his PhD from UCLA, in the laboratory of Joan Valentine and Edith Gralla. During graduate school, he developed a novel method to study aging in yeast, which he called the Chronological Lifespan, and used it to identify first the role of the Ras-PKA pathway and then of the Tor-S6K pathway in aging and stress sensitization (Longo 1999; Fabrizio et al.2001). He is a professor of biogerontology and biological sciences at USC, where he also serves as Director of the Longevity Institute and directs the Cancer and Longevity Program at the IFOM Institute in Milan, Italy. The Longo Laboratory has focused on translating basic research in yeast and mice into interventions with the potential to prevent and treat major human diseases and optimize healthspan.

Q1: You are well-known for you work on aging? How did you get into that field?

That is all I have ever done, since I was a sophomore in college, when I started doing research on protein damage in the laboratory of Robert Gracy at the University of North Texas. A few years later, I was lucky to join the laboratory of one of the pioneers of aging and nutrition Prof Roy Walford at UCLA. But Walford was working with mice and humans, and at that time we had no idea what genes were regulating the aging process, so I left his lab and joined the laboratory of Joan Valentine and Edith Gralla where I worked exclusively with yeast. This was a great environment, we were surrounded by labs such as the Tamanoi lab, who had generated yeast mutants lacking components of ‘the sugar aging pathway’ (Fontana, Partridge and Longo 2010). The other great aspect of the lab was that it combined the genetics expertise of Edith Gralla with the oxidative chemistry knowledge of Joan Valentine. It was the right place in which to learn how genes and nutrition regulate cellular protection and aging in a simple organism, with the hope that these effects would be conserved (Longo 1999).

Q2: You use different model systems, from yeast to mouse to human cells. Do you think yeast still has a place in this research field?

Yes, undoubtedly. We still include yeast in many of our papers and often, if we have a new hypothesis, we first test it in yeast. Almost every clinical trial we are performing or plan to perform is based on research and discoveries we first made in yeast. For example, we would never be doing clinical trials on cancer patients exposed to a fasting diet in combination with chemotherapy if it wasn’t for our original discoveries of the role of Ras and other proto-oncogene-like genes in Saccharomyces cerevisiae (Longo 1999; Fabrizio et al.2001; Raffaghello et al.2008). We would also have not developed a prolonged fasting mimicking diet which we recently tested on adult subjects (Wei et al.2017) if it wasn’t for my early studies at UCLA showing that starving yeast lived much longer (Longo et al.1997). I remember that when I started working with yeast in a starvation (stationary) phase, everyone looked at it as an uninteresting. Someone even told me that at a major conference, a Nobel prize winner responded to someone's question by saying ‘we don’t work on stationary phase’ in an annoyed and dismissive way. I couldn’t understand it. I always thought it was even more interesting than the growth phase.

Q3: A lot of your work lately has been on dietary interventions, specifically on fasting. Can you explain briefly your main findings?

We are now using fasting as a way to understand and activate the programs that are part of the toolkit of many organisms and that can destroy damaged cells or cellular components to save but also generate energy (Cheng et al.2017). The evidence in multiple organisms indicates that starvation conditions may be the most powerful way to activate embryonic-like programs able to regenerate and potentially rejuvenate multiple systems and organs Brandhorst et al.2015). We have now used this idea to treat Alzheimer, diabetes, cancer and autoimmunities in mouse models (Choi et al.2016). We have also used it to extend the mouse lifespan and healthspan (Brandhorst et al.2015). We are now using it in a series of clinical trials: several small ones on fasting and cancer are completed and show positive and promising results and the larger clinical studies are still ongoing (Dorff et al.2016).

Q4: What do you think is the future direction of your research field? What are still the great scientific questions?

The major objective will be to understand how to allow most people to make it to 110 healthy or with only minor problems. Since we cannot do this study in humans, a challenge will be to identify organisms or combinations of organisms that will serve as good models for humans. More specifically for our field the question will be: Can an organism be reprogrammed to become younger or much younger? What are the mechanisms for that? Again, it will be important to do parallel studies in yeast, other simple model organisms, mice and humans.

Q5: What advice would you give to PhD students and postdocs who are now starting off their scientific careers?

• Find something you would do even if they did not pay you

• Dedicate all of your time to it

• Work with both a simple model organism and mice or human cells

• Do regular presentations of your work but not too many

• Start an experiment every day or as often as possible

• Don’t believe anything you hear and half of what you see

• Doubt your own results

• Don’t worry, be happy