Researchers conduct pivotal study into aging and lifespan to uncover new details about how diets might make people live longer — but also their negative side effects.
Recent research involving nearly one thousand genetically distinct mice examined the impact of various diets on lifespan, uncovering that lower caloric intake significantly enhances longevity compared to periodic fasting. The study’s pivotal findings suggest that genetic resilience and maintaining health during caloric restriction are crucial, potentially challenging existing theories on the biological markers of aging and longevity.
Groundbreaking Longevity Research
For nearly a century, laboratory studies have consistently shown that animals live longer when they eat less food or eat less frequently. However, scientists have struggled to understand why these restrictive diets extend lifespan and how they can be effectively applied to humans. Now, in a pivotal study published in the October 9 issue of Nature, researchers at The Jackson Laboratory (JAX) and their collaborators tracked the health of nearly one thousand mice on various diets to explore these questions further.
The study was meticulously designed to ensure each mouse was genetically unique, better mirroring the genetic diversity of humans. This approach enhances the clinical relevance of the findings, marking the study as one of the most significant contributions to the research on aging and lifespan to date.
Key Findings on Caloric Restriction and Lifespan
The study concluded that eating fewer calories had a greater impact on lifespan than periodic fasting, revealing that very-low-calorie diets generally extended the mice’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 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.
Genetic Factors and Lifespan Variability
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.
Surprising Insights into Longevity and Diet
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. Moreover, they 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.
“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.
Reevaluating the Markers of Aging
The study also cast 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 study found that immune system health and traits related to red blood cells were more clearly connected to lifespan. 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.”
Reference: “Dietary restriction impacts health and lifespan of genetically diverse mice” by Andrea Di Francesco, Andrew G. Deighan, Lev Litichevskiy, Zhenghao Chen, Alison Luciano, Laura Robinson, Gaven Garland, Hannah Donato, Matthew Vincent, Will Schott, Kevin M. Wright, Anil Raj, G. V. Prateek, Martin Mullis, Warren G. Hill, Mark L. Zeidel, Luanne L. Peters, Fiona Harding, David Botstein, Ron Korstanje, Christoph A. Thaiss, Adam Freund and Gary A. Churchill, 9 October 2024, Nature.
DOI: 10.1038/s41586-024-08026-3
