Ask the Expert: Rafael de Cabo, PhD, on the benefits of several types of caloric restrictions and his 2023 Irving S. Wright Award

At the NIA, one of the 27 centers and institutes at the federal government’s National Institutes of Health, the goal of Dr. de Cabo’s work is to learn what altered dietary behavior will prevent age-related functional decline.To that end, his current research with mice and rhesus monkeys seeks to improve understanding of the molecular mechanisms underlying the beneficial effects of caloric restriction on aging. He is also making vital contributions to the development of interventions that could improve both healthspan and lifespan. He uses both whole body physiological and tissue-specific molecular approaches to explore how pharmaceutical and nutritional interventions affect the basic mechanisms of aging and age-related diseases.

Dr. de Cabo was the 2014 winner of AFAR’s Vincent Cristofalo Rising Star Award in Aging Research. After announcing him as the 2023 Irving S. Wright Award recipient, AFAR talked with him to glean insight into his work. His answers were edited for brevity and clarity.

What led you into your career in aging research?

When I was doing my PhD at Purdue University in about 1999, Richard Weindruch of the University of Wisconsin was a visiting speaker who presented some of the first data on calorie restrictions and aging in non-human primates. Based on that presentation and talking with him after, I really got curious about the whole aging process and how we could actually intervene to slow down the aging process. And then right after that, I think three or four weeks later, I saw an advertisement for a position at the National Institute on Aging with Mark Lane and Don Ingram, who were running the non-human primate experiment at NIA and were looking for a postdoc with interests in nutrition, aging, and antioxidants. My thesis was on nutrition and antioxidants. And I just recently got enamored with these primate studies. So I applied, I got an interview, and the rest is history. I've been here 23 years.

And what’s been the arc of your work during that time, and how has it led to pharmacological interventions?

Soon after I started at the NIA, we began to focus on developing caloric restriction mimetics, or CRMs . These are molecules that will mimic aspects of caloric restriction, but without the need to actually cut your consumption of calories. And out of that research, we worked on a set of molecules that are called sirtuin activators—resveratrol, SRT 1720 and SRT 2104—under a cooperative research and development agreement (CRADA) with GlaxoSmithKline. And some of those molecules were moved to clinical trials. We also tested metformin in male mice starting late in life, resulting in an extension of lifespan and healthspan. Our interventions program is still ongoing ans we are testing new molecules.

In parallel to the CRM work, we continue to dissect the potential mechanism by which caloric restriction works. We're focusing a lot of research on the length of fasting times necessary to produce the beneficial effects of calorie restriction. We know that most humans cannot go without calories for long periods. We're trying to understand the different aspects of the intervention that can be quickly translated to the clinic and used in combination with other therapies. There are lots of clinical trials now testing fasting interventions, and there are lots of caloric restriction studies. Other groups outside NIA are applying calorie restriction and CRMs, or time-restricted feeding and fasting, or fasting-mimicking diets in combination with other therapies.

What’s one message about caloric restriction work that you'd like to be able to communicate clearly to the general public?

In the last 25 years we've moved from having only one general intervention that works to a whole repertoire of tools that seem to work in different aspects of the biology of aging—and which should help to preserve function late in life. I don't know how quickly these will translate into the clinic and have broad application, but definitely steps are being taken to get there soon—or sooner than where we were 20 years ago. So I’m optimistic. But there are lots of things we need to understand before we can make a blanket statement that everybody should be doing this.

What's the research on caloric restriction at the moment that is most exciting?

Work on time-restricted feeding for people, or restricting their consumption of calories to a part of the day—because that seems to be working to help control metabolic diseases and improve health in the long run. And ongoing clinical trials that were initiated in the last few years should produce data soon to document whether these effects are applicable to the general population.

In the U.S. population, the eating window typically starts around 8 a.m. and finishes around 7 or 8 p.m. That’s 12 to 14 hours of feeding—and it is common for some people to get a snack from the fridge before going to bed. Now we know that if you restrict that window of feeding to between six and eight hours a day, it seems to have a beneficial impact on your health. The outcomes from some clinical trials demonstrate that, in a broad population study, you see beneficial effects consistent with what we’ve seen in animals, which is extremely promising.

How has your work contributed to other research in aging biology?

Twenty years ago, we showed we could make the blanket statement that caloric restriction affects some chronic diseases—but we didn't know what aspects of the restriction were responsible for it working. Now we know that a percentage of the beneficial effect of calorie restriction depends exclusively on the amount of food. And we know now that the length of fasting time, and the timing of the consumption of calories, are almost as crucial. We went from having a single intervention that we did not truly understand how it worked to having three aspects of that intervention that we can focus on really translating into the clinic.

Do you have a prediction where work to slow the process of aging will be in a decade?

I think that you're seeing it. The mean lifespan, which reflects the overall health of the population, is increasing. Since I was born to today, the onset of diseases has been later and the impact of those diseases is going down. Ten years from now, hopefully, we'll have less sarcopenia and less osteoporosis, and we’ll have lessened the impact of Alzheimer's and Parkinsonism. Those things are all moving in the right direction as we speak.

But are we going to be able to, as some people are saying, be able to reverse the aging process as a whole? As a hope, that is great. As a reality, that is not even close. We're talking about many, many years until we understand all the intricacies of the aging process well enough that we will be able to put the brakes on it.

And what about your plans for the next 10 years?

I'm super excited about the progress that we're making and will keep pushing to try to move the field forward at every opportunity. I’m also in the active process of recruiting people from different disciplines into the aging field. There are huge gains that we can make, for example, by bringing bioengineering into the aging field to improve bone health, to improve posture. If we have more people who are working on understanding the basic processes of aging, and how to translate them into the clinic to improve human health and human well-being—I think the more the merrier.