New research on mice suggests that while extreme caloric restriction may extend lifespan, genetic resilience plays a critical role.
For decades, researchers have explored the effects of caloric restriction on lifespan, observing that reduced caloric intake appears to enhance longevity across various species. However, the exact mechanisms underlying this phenomenon and its applicability to humans have remained somewhat elusive. Now, a recent study published in Nature, led by researchers from The Jackson Laboratory, has shed new light on the relationship between diet and lifespan, emphasizing the complex interplay between genetics and dietary habits. This study is among the most extensive to date, involving nearly a thousand genetically diverse mice subjected to varying degrees of caloric restriction and intermittent fasting [1].
While caloric restriction (CR) has long been associated with increased lifespan, the study found that its effectiveness is highly influenced by individual genetic factors; some mice on restrictive diets experienced a notable lifespan extension, while others saw minimal gains.
“Our study really points to the importance of resilience,” said Gary Churchill, Karl Gunnar Johansson Chair and professor at The Jackson Laboratory, 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 [2].”
Longevity.Technology: Caloric restriction has been shown to reduce oxidative stress and slow cellular aging, primarily by decreasing metabolic rates and reducing the production of reactive oxygen species, which can damage DNA and accelerate aging. Additionally, CR often enhances autophagy, a process where cells remove damaged components, promoting cellular health and delaying age-related decline. So far, so well-known, but this research emphasizes that genetic factors significantly influence these outcomes, meaning the longevity benefits of CR aren’t guaranteed for everyone. Some individuals, due to their genetic makeup, may be more resilient and better able to maintain metabolic stability under caloric restriction, which translates to a longer, healthier lifespan. Meanwhile, others might face immune suppression or energy deficiencies if pushed too far into caloric restriction. Going forward, understanding these genetic interactions could pave the way for personalized diets that harness the longevity benefits of CR without compromising health, offering a promising direction for aging research and dietary recommendations.
The role of diet and caloric restriction
The study primarily examined two dietary approaches: intermittent fasting, in which mice fasted for one or two days per week, and caloric restriction, where daily intake was reduced to 60% or 80% of the baseline caloric amount. Female mice were divided across five groups, including a control group with unrestricted access to food. The researchers monitored these groups over their natural lifespans, assessing not only longevity but also overall health through periodic blood tests and other evaluations.
Results revealed that mice on the most restrictive diet (60% of baseline calories) lived an average of 34 months, while those on unrestricted diets lived an average of 25 months. Interestingly, within each dietary group, there was substantial variation in lifespan; some mice on the 60% diet lived over four years, while others survived only a few months [1]. This finding highlights the significant role of genetic factors in determining individual responses to dietary restriction.
Genetic resilience as a lifespan predictor
The researchers identified several key physiological traits that were strongly associated with extended lifespan. Mice that retained body weight during stressful conditions, particularly during the phenotyping period, exhibited longer lifespans. “Mice that were most resilient to weight loss had a longer lifespan,” the study noted, suggesting that the ability to maintain body mass under caloric restriction may be as important as the restriction itself [1]. Importantly, this study challenges the traditional view that metabolic markers such as low body weight and low glucose levels are definitive indicators of health and longevity. Instead, mice with moderate body weight who showed resilience under stress lived the longest.
Genetic diversity was central to the study’s design, with each mouse representing a unique genetic background. This approach enabled the researchers to draw broader conclusions that may be applicable to genetically diverse human populations.
“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,” remarked Churchill, reflecting the finding that genetic resilience, rather than caloric restriction alone, significantly influences longevity [2].
The limits of caloric restriction and intermittent fasting
Although caloric restriction was generally associated with increased lifespan, the study revealed limitations and potential drawbacks. Mice on the most restrictive diets, particularly those that lost significant weight, often displayed compromised immune and reproductive systems and experienced decreased energy levels. These mice also tended to have shorter lifespans compared with those that maintained moderate body weight despite reduced caloric intake.
“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 [2].”
Further, the study found that intermittent fasting had less impact on lifespan than caloric restriction; mice on intermittent fasting diets lived an average of 28 months, compared with 30 and 34 months for the 80% and 60% caloric restriction groups, respectively [1]. Notably, mice with higher body weights before starting the fasting regimen experienced no significant lifespan extension under intermittent fasting protocols. The researchers observed that intermittent fasting disrupted red blood cell populations in the two-day fasting group, indicating that fasting frequency may affect hematologic health.
Implications for future research and human health
The results of this study raise questions about the long-term effects of restrictive diets in humans, particularly in the context of genetic diversity. While CR has shown promise in extending lifespan, its effects may not be universally positive, as seen with the immune and reproductive issues in mice under severe restriction. Additionally, the study’s findings highlight the importance of looking beyond metabolic markers when assessing the effectiveness of antiaging interventions – factors such as immune health and red blood cell characteristics were more strongly correlated with lifespan than glucose levels or body fat percentages, and studies that rely on metabolic measurements as markers for aging could well be overlooking some of the more important aspects of healthy aging.
Future research may benefit from focusing on the genetic predictors of dietary responses, potentially enabling the development of personalized dietary interventions aimed at promoting longevity. In particular, researchers hope to better understand which specific genetic traits enhance resilience under caloric restriction, as these factors could inform targeted therapies for aging.
While this research notes that caloric restriction and intermittent fasting may have beneficial effects on lifespan, it makes it clear that the genetic component plays a pivotal role in determining outcomes. For humans, adopting a more balanced approach that incorporates moderate dietary adjustments tailored to individual genetic profiles may offer the most sustainable path to longevity.
[1] https://www.nature.com/articles/s41586-024-08026-3
[2] https://www.jax.org/news-and-insights/2024/october/study-probes-how-eating-less-can-extend-lifespan
