Researchers studied the health of over a thousand mice fed a range of diets to determine if they would live longer. The project was meant to ensure that each mouse was genetically distinct, allowing the scientists to more accurately replicate the genetic diversity of the human population. This makes the study’s findings more therapeutically relevant, upgrading it to one of the most significant studies on aging and lifespan to date.
For than a century, laboratory tests have consistently demonstrated that if an animal eats less food or eats less frequently, it lives longer. However, scientists have struggled to understand why these types of restricted diets work to lengthen longevity and how to best apply them in humans. In a long-awaited study published in Nature, scientists at The Jackson Laboratory (JAX) and partners studied the health of almost a thousand mice on a variety of diets to get new insights into these problems.
The project was meant to ensure that each mouse was genetically distinct, allowing the scientists to more accurately replicate the genetic diversity of the human population. This makes the study’s findings more therapeutically relevant, upgrading it to one of the most significant studies on aging and lifespan to date.
Our study really points to the importance of resilience. 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.
Gary Churchill
The study revealed that eating fewer calories had a higher influence on lifespan than intermittent fasting, indicating that very-low-calorie diets generally prolonged mice’s lifetime regardless of body fat or glucose levels, both of which are commonly used markers of metabolic health and aging. Surprisingly, the mice who survived the longest on restrictive diets lost the least weight while eating less. Animals that lost the most weight on these diets had poor energy, weakened immunological and reproductive systems, and shorter lifespans.
“Our study really points to the importance of resilience,” said Gary Churchill, Karl Gunnar Johansson Chair and professor at JAX who led the study. “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 his colleagues assigned female mice to any of five different diets: one in which the animals could freely eat any amount of food at any time, two in which the animals were provided only 60% or 80% of their baseline calories each day, and two in which the animals were not given any food for either one or two consecutive days each week but could eat as much as they wanted on the other days. Then, the mice were studied for the rest of their lives with periodic blood tests and extensive evaluation of their overall health.
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 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 examined the remaining data to try to explain this wide range, they discovered that genetic factors had a far greater impact on lifespan than diets, highlighting how underlying genetic features that have yet to be identified play a significant role in how these diets affect an individual’s health trajectory. Furthermore, they identified genetically-encoded resilience as a critical factor in longevity; mice that naturally maintained their body weight, body fat percentage, and immune cell health during times of stress or low food intake, as well as those who did not lose body fat late in life, lived the longest.
“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.
The findings also called into question long-held beliefs about why particular diets can help people live longer lives. For example, weight, body fat percentages, blood glucose levels, and body temperature did not explain the link between calorie restriction and longer life. Instead, the study discovered that immune system function and red blood cell characteristics were more clearly linked to longevity. Importantly, these data suggest that human lifespan research, which frequently employ metabolic parameters as indicators of aging or youthfulness, may be disregarding more significant components 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.”
