Laboratory studies have shown consistently that animals eating less food, or eating less often, can live longer. But scientists have struggled to understand why these kinds of restrictive diets work to extend lifespan, and how humans could best implement them. Researchers at The Jackson Laboratory (JAX) have now reported the results of a study through which they tracked the health of nearly one thousand genetically distinct mice fed a variety of diets, providing what they suggest are more clinically relevant insights that might inform on how diets can impact longevity.

The study in mice concluded that eating fewer calories—caloric restriction (CR)—had a greater impact on lifespan than intermittent fasting (IF), revealing that very low calorie diets generally extended an animal’s lifespan regardless of their body fat or glucose levels—both typically seen as markers of metabolic health and aging. Surprisingly, the mice that lived the longest on the restrictive diets were those that lost the least weight despite eating less. Animals that lost the most weight on these diets tended to have low energy, compromised immune and reproductive systems, and shorter lives.

“Our study really points to the importance of resilience,” said study lead Gary Churchill, PhD, Karl Gunnar Johansson Chair and professor at JAX. “The most robust animals keep their weight on even in the face of stress and caloric restriction, and they are the ones that live the longest. It also suggests that a more moderate level of calorie restriction might be the way to balance long-term health and lifespan.”

Churchill and colleagues reported on their findings in Nature, in a paper titled “Dietary restriction impacts health and lifespan of genetically diverse mice,” in which they noted, “Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.”

While caloric restriction extends healthy lifespan in multiple species, an alternative form of dietary restriction, intermittent fasting, may be “potentially more sustainable in humans,” the authors wrote. “In humans, compliance with CR is challenging, and interest has shifted to more permissive forms of dietary restriction (DR), such as time-restricted feeding and intermittent fasting (IF) that have proven to be effective in promoting organismal health.” However, the team noted, the effectiveness of intermittent fasting remains largely unexplored.

Human clinical studies investigating the effects of dietary restriction on health have largely focused on changes in body weight, adiposity, energy metabolism and cardiometabolic risk factors, the team continued. “There has been less exploration of the long-term effects of DR because studies in humans are limited by their small sample size and short duration.” And the safety and effectiveness of dietary restriction may depend on multiple factors, such as age and health, they further pointed out.

For their newly reported study the team investigated the effects of caloric restriction and intermittent fasting on multiple measures of health, as well as lifespan, in female diversity outbred (DO) mice. The study was designed to ensure that each mouse was genetically distinct, which allowed the team to better represent the genetic diversity of the human population. By doing so, the results are made more clinically relevant, which they suggest elevates the study to one of the most significant investigations into aging and lifespan to date.

“We used DO mice because findings in genetically diverse mice are more likely to generalize across species, and because DO mice present a wide range of physiological characteristics, including variation in body composition and other metabolic traits, that could serve as predictive markers of individual response to DR,” the team explained.

Churchill and colleagues randomly assigned the 960 female mice to one of five different diets: one diet of ad libitum feeding (AL) in which the animals could freely eat any amount of food at any time, two diets of caloric restriction at 20% or 40% of baseline (so the animals were provided with only 80% or 60%, respectively, of their baseline calories each day), and two in which the animals were not given any food for either one day (1D) or two days (2D) consecutively each week, but could eat as much as they wanted on the other days. The mice were studied for the rest of their lives with periodic blood tests and extensive evaluation of their overall health.

The results showed that overall, mice on unrestricted diets lived for an average of 25 months, those on the intermittent fasting diets lived for an average of 28 months, those eating 80% of baseline calories lived for an average of 30 months, and those eating 60% of baseline lived for 34 months. But within each group, the range of lifespans was wide; mice eating the fewest calories, for example, had lifespans ranging from a few months to four and a half years.

When the researchers analyzed the rest of their data to try to explain this wide range, they found that genetic factors had a far greater impact on lifespan than diets, highlighting how underlying genetic features, yet to be identified, play a major role in how these diets would affect an individual person’s health trajectory. “If you want to live a long time, there are things you can control within your lifetime such as diet, but really what you want is a very old grandmother,” Churchill said.

Moreover, the investigators pinpointed genetically encoded resilience as a critical factor in lifespan; mice that naturally maintained their body weight, body fat percentage and immune cell health during periods of stress or low food intake, as well as those that did not lose body fat late in life, survived the longest.

Commenting on their combined study findings, the team wrote, “Collectively, these results highlight a paradox: DR extends lifespan while decreasing body weight and fat mass, yet preserving body weight and fat mass is associated with longer lifespan. This paradox is a recurrent theme in this study.”

The reported study also casts doubt on traditional ideas about why certain diets can extend life in the first place. For example, factors like weight, body fat percentages, blood glucose levels and body temperature did not explain the link between cutting calories and living a longer life. Instead, the results indicated that immune system health and traits related to red blood cells were more clearly connected to lifespan. “Collectively, our study highlighted physiological resilience, in particular the maintenance of body weight, body composition and key immune cell populations, as major biomarkers for longevity and suggested that the pro-longevity effects of DR may be uncoupled from its effects on metabolic traits,” the investigators wrote.

Importantly, those findings mean that human studies of longevity—which often use metabolic measurements as markers for aging or youthfulness—may be overlooking more important aspects of healthy aging.

“While caloric restriction is generally good for lifespan, our data show that losing weight on caloric restriction is actually bad for lifespan,” Churchill explained. “So when we look at human trials of longevity drugs and see that people are losing weight and have better metabolic profiles, it turns out that might not be a good marker of their future lifespan at all.”

Commenting on the implications of the study, the team concluded that while DR-induced changes in metabolic traits can be beneficial for health, they may not necessarily translate into a major expansion in lifespan. “This insight has important implications for the choice of biomarkers in human dietary intervention studies, which frequently focus on metabolic health,” they wrote. The findings also more generally imply that the effects of DR on health and lifespan may be partially non-overlapping, such that “… certain lifespan-extending properties of DR may in fact be detrimental to other aspects of physiological health.”

The team also stressed that definitive investigation will be needed to investigate whether intermittent fasting or caloric restriction could extend human lifespan. “… whether IF and CR would extend lifespan in humans awaits definitive investigation.” They noted that the reported findings do suggest that human responses to DR will be “highly individualized based on genetic context … Despite the powerful effects of DR in this study, genetic background proved to be the more important factor in determining lifespan.”

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