Caloric restriction (CR) has fascinated longevity researchers for decades, with species from yeast to primates showing extended lifespans under CR. But important questions remain. How exactly does CR work? Does meal timing matter, or is it simply about total intake? And how much do our genes influence the benefits?
These aren’t just academic curiosities. For anyone aiming to live longer and healthier, they get at the heart of a practical question: should we all be practicing extreme CR?
A large-scale study in mice, published in Nature last October, takes us closer to some answers.1 By directly comparing CR with intermittent fasting (IF) in a genetically diverse population of mice, the study offers one of the most detailed looks yet at how diet and genetics interact to shape both lifespan and healthspan. The results reaffirm that extreme CR can extend lifespan in a controlled lab setting—but they also make clear why it’s unlikely to be the most promising path for extending human life.
The lifespan-extending effects of CR
To test how different dietary patterns influence both healthspan and lifespan—and to probe possible mechanisms behind caloric restriction’s effects—researchers Di Francesco et al. tested nearly 1,000 genetically diverse female mice over their natural lifespans. Their goal was to directly compare the lifespan-extending effects of CR, in which total available food was limited, with IF, in which food is withheld entirely for designated periods before resuming normal eating. By examining both approaches in a genetically varied population, the researchers set the stage for a comprehensive look into the impacts of not only caloric intake, but also meal timing and genetic background.
At six months of age—roughly equivalent to 30 years of age for humans—the mice were assigned to one of five groups:
- Control: unlimited food access
- 20% CR: 20% fewer calories than baseline
- 40% CR: 40% fewer calories than baseline
- IF 1 day/week: one day of fasting each week
- IF 2 days/week: two days of fasting each week
Results revealed a dose–response relationship between calorie restriction and longevity: the greater the sustained calorie reduction, the greater the lifespan extension. Mice on a 20% calorie restriction lived 18.2% longer than controls, while those on 40% restriction had the largest gain—a 36.3% increase in median lifespan. This relationship was even more striking for maximum lifespan: the longest-lived mice in the 20% CR group lived 22.3% longer than their control counterparts, and the 40% CR group lived an astounding 38.4% longer.
The intermittent fasting groups also experienced some benefit—mice fasting one day per week had a median lifespan 11.8% longer than controls, and those fasting two days per week saw a 10.6% increase, suggesting that this pattern of eating may also extend lifespan, though to a lesser extent than sustained calorie restriction. Again, the pattern was echoed in maximal lifespan, for which one-day fasting group saw a 6.2% increase relative to controls, and the two-day fasting group saw a 14.9% increase.
However, it’s critical to note that gains observed in the IF groups coincided with unplanned calorie restriction, as IF mice did not fully compensate for fasting days with increased calorie intake on feeding days. The two-day fasting group, for example, consumed about 12% fewer calories overall than controls, suggesting that their longevity benefit may have been due as much to reduced total intake as to fasting itself. (CR groups also experienced a degree of IF, since the 40% CR group tended to consume most of their allotted weekend food within one day after it was provided on Friday afternoons—resulting in about 1.5 days without food—and the 20% CR group tended to consume most of their allotted weekend food within two days—resulting in about 0.5 days without food.) This observation, combined with the findings that CR protocols had significantly greater impact on lifespan than IF protocols, indicates that calorie restriction itself—not simply the timing of meals—was the dominant factor in extending life.
Extreme CR is unlikely to be the answer for human longevity
The results of this study show that calorie restriction clearly “worked” for enhancing lifespan—but would these benefits really translate to humans? And if so, at what cost?
A 40% caloric restriction in humans would mean dropping from a 2,000-calorie diet to just 1,200 calories—indefinitely—a level that is both physiologically taxing and socially impractical. Even in the most rigorous, long-term human CR study to date, the CALERIE trial, participants aimed for a 25% reduction but managed only about half of that.2 Likewise, two days of IF per week might seem to some like an achievable feeding pattern, but because mice have much faster metabolisms and shorter lifespans than humans, this two-day period in mice would be more akin to two weeks of fasting in people—a far greater physiological challenge that most would find impossible. These gaps underscore the difference between what can be achieved in a tightly controlled laboratory study and what is realistic in daily life.
But even if we pretend that such extreme interventions were more feasible for your average human, the results of this study raise questions about whether certain negative consequences of CR might compromise potential lifespan benefits in a “real-world” setting. The 40% CR group may have lived the longest, but their added years came with significant losses in lean body mass and marked shifts in immune cell composition that Di Francesco et al. note might “confer susceptibility to infection.” In the protected environment of a laboratory where risk of injury and infection are minimized, such changes may have little consequence for lifespan. However, in the real world, they could mean reduced resilience, slower recovery from illness, or greater vulnerability to infections—all of which can be deadly for older humans.
IF groups also showed concerning physiological changes. For instance, two-day IF resulted in disruptions in red blood cell characteristics, including an increase in red blood cell distribution width—a significant negative predictor of lifespan in this study that potentially reflects subtle but meaningful stresses on blood and oxygen transport. Of note, red blood cell distribution width measure in humans is also associated with higher risk of mortality and chronic disease.3
These results make one thing clear: while extreme CR can push lifespan to new heights in mice, the accompanying costs raise serious questions about whether it can ever be a viable path for humans. The more practical role for CR in humans may be how many apply it already: as a way to prevent gradual gains in adiposity over time through adherence to mild CR, rather than utilizing dramatic, sustained reductions in calories. Extreme CR, by contrast, may be better reserved for research settings as a tool for exploring the fundamental biology of aging—by identifying the pathways through which CR exerts its effects, scientists may uncover possibilities for safer, more targeted interventions.
The bottom line
Extreme calorie restriction can clearly extend lifespan in mice, but the trade-offs, risks, and impracticality make it an unlikely tool for extending human life. Its greatest value is as a research model for increasing our collective understanding of the biology of aging itself—an endeavor that someday might lead to more promising and practical lifespan-extending interventions.
Of course, this isn’t to say that diet has no place in efforts to achieve a longer and healthier life. As a smaller element of their study, Di Francesco et al. investigated how diet patterns stacked up against genetics in determining lifespan. They found that although genetics accounted for more variability in lifespan than diet assignment, the relative influence of diet increased as animals got older—suggesting that the dietary choices we make throughout our lives gradually accrue into increasingly significant impacts on lifespan.
Indeed, while extreme CR and IF may be unsustainable and come with downsides for body composition and immune function, more moderate engagement in these dietary strategies can be very effective in preventing excess fat accumulation and avoiding metabolic dysfunction, which in turn affects risk for several chronic diseases. (For those interested, I discussed the pros and cons of various fasting protocols in depth in a recent AMA.) So despite substantial doubt about the utility of extreme CR for human lifespan extension, there’s no question that diet—along with other lifestyle factors such as exercise, sleep habits, and stress management—remains a critical lever for promoting not just a longer life, but a healthier one.
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References
- Di Francesco A, Deighan AG, Litichevskiy L, et al. Dietary restriction impacts health and lifespan of genetically diverse mice. Nature. 2024;634(8034):684-692. doi:10.1038/s41586-024-08026-3
- Kraus WE, Bhapkar M, Huffman KM, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(9):673-683. doi:10.1016/S2213-8587(19)30151-2
- Hou H, Sun T, Li C, et al. An overall and dose-response meta-analysis of red blood cell distribution width and CVD outcomes. Sci Rep. 2017;7(1):43420. doi:10.1038/srep43420
