In Search of Longevity: Explaining Caloric Restriction Through a Wide Study

In one of the cutting-edge experiments, researchers from The Jackson Laboratory and collaborating scientists have looked into a very intricate aspect of diet, genetic diversity, and lifespan. Published in Nature on October 9, 2024, the study tracks the health span of nearly a thousand mice genetically distinct under four different dietary regimens. An important outcome here is how such a study challenges conventional wisdom around caloric restriction and its role in aging.

Understanding the Scope and Design of the Study

Traditional experiments would enroll genetically identical laboratory animals. In contrast, this study employed genetically diverse mice with as much genetic variation as is found in humans. The hope here was to obtain more clinically relevant results. This diversity enabled the team to explore how different people might react to caloric restriction based on their unique genetic makeup, making the study one of the largest and most significant investigations into diet, metabolism, and lifespan to date.

Five different diets were tested on the mice:

1. Unrestricted eating: Mice could eat as much food as they wanted at any time.

2. 60% caloric restriction: The mice were fed a portion equal to just 60% of their calorie supplies.

3. 80% caloric restriction: The mice were given an 80% level of their original calorie intakes.

4. Intermittent fasting with 1 day off: Mice received one water-free day each week; otherwise, they were allowed access to food at all times.

5. Intermittent fasting with 2 days off: Mice were deprived of water for 2 successive days and fed free on the other days.

Mice were observed from the time of birth until their death. Periodic blood tests and health examinations measured a variety of physiological changes in the mice. Lifespans were recorded and body weight, fat percentage, glucose, immunity and red blood cell function measured.

Key Findings: Resilience Over Weight Loss

Results indicated that mice surviving on very-low-calorie diet regimens actually survived longer than mice surviving under intermittent fasting plans, while the 60% calorie-restricted group presented the most extended average lifespan of 34 months. The mice that survived under unrestricted diets only lasted, on average, 25 months. However, all lifespans in groups varied hugely. While some mice could tolerate up to and including four and a half years in the most restricted diets, others in that same group may barely survive for a few months.

One of the most telling findings was that the mice that lost the most weight on these low-calorie diets tended to die young. Typically, the loss of weight and improved metabolic profiles, such as reduced glucose levels and lower body fat, are indicators of health and longevity. However in this experiment, the mice whose body weight they could keep stable while taking in less food had long lives. This metabolism study further revealed that serious weight loss in animals results in low energy, weak or dysfunctional systems immunological and reproductive systems, and a reduced lifespan. Therefore this means that the metabolic adaptation might not contribute directly to the effects of caloric restriction-induced longevity in the animals.

As the lead researcher, Gary Churchill, phrased it, "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."

The Role of Genetic Diversity

One of the impressive features of the study is its emphasis on genetic diversity.

What is clear is that there was huge variability within each dietary group; the level of genetic variation affects how well an animal can adapt to caloric restriction. More often than not, caloric restriction increased lifespan, but the actual impact of this increase varied widely based on genetics. This suggests that some individuals are more resistant to the stress of reduced food intake than others, and that resistance may be encoded in the genes themselves.

The researchers found that genetic factors influenced how well mice maintained their body weight, immune function, and red blood cell health during periods of caloric restriction. Mice that could keep these factors stable, regardless of their diet, lived the longest.

This perspective puts the myth of calorie restriction benefiting everyone in the same way into question. As Churchill famously said, "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."

New Views on Health Indicators and Longevity

This research also questions the common measures applied in measuring metabolic fitness and aging. Scientists and clinicians use markers to mark and tell how well an organism is aging by body weight, percentage of fat, glucose levels, and body temperature. Interestingly enough, this study found that these markers did not fully explain why the mice lived longer than others.

The researchers, however, found that the health and resilience of the immune system itself were better predictors of longevity, as well as other traits associated with red blood cells. Such findings might be calling for a paradigm shift in human aging studies -- one that moves from quantitative measurements of metabolism, such as glucose or body fat levels, towards the health and robustness of the immune system. It appears that longevity is the result of the immunity of stressed cells, especially the immune and red blood cells, and not merely through weight loss or improvements in metabolic profiles.

As Churchill has pointed out, "While caloric restriction is generally good for lifespan, our data show that losing weight on caloric restriction is actually bad for lifespan. 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.".

Thus, the results of the study could change the scientific view regarding diet, health, and aging of humankind. While all clinical trials regarding caloric restriction frequently emphasized the metabolic changes as indicators of improved health besides extended lifespan, it seems that such metabolic changes would not be crucial after all for longevity. Genetic resilience and ability to keep on the immune could therefore play the utmost role in determining how long someone would live rather than longevity due to race or ethnicity.

Results from these studies may open new avenues of research on aging, which derive points of interest not from metabolic health, but rather other physiologic traits, such as immune function, that may be involved. At the same time, it underscores the need for more personalized approaches to diet and health, given the evidence that suggests genetic factors contribute a large proportion in how an organism may respond to caloric restriction.

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The study conducted by Jackson Laboratory can be considered definitive in examining diet, genetics, and aging as interconnected elements. It was such a remarkable opportunity for the scientists to use genetically diverse mice to explore relationships that have never been studied before. Their findings are such that caloric restriction may extend life span but, as it turns out, the real key to life is genetic resilience and healthy immunity. This research sheds new light into future inquiries about human aging and opens an avenue for new, more personalized strategies for promoting long-term health and longevity.

Reference: Di Francesco, A., Deighan, A. G., Litichevskiy, L., Chen, Z., Luciano, A., Robinson, L., et al. (2024). Dietary restriction impacts health and lifespan of genetically diverse mice. Nature. https://doi.org/10.1038/s41586-024-08026-3

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