How Much of the Benefit of Calorie Restriction in Mice is Due to Incidental Fasting?

Both calorie restriction and intermittent fasting can extend life in short-lived species such as mice, the former producing a larger benefit. Both appear to produce benefits to health in humans, though nowhere near the same effects on life span. Mice in past calorie restriction studies tended to be fed at intervals, such as daily, that were in practice imposing periods of fasting as well as a lowered calorie intake. How much of the observed benefits are due to the metabolic changes imposed by reduced calorie intake versus the metabolic changes imposed by time spent fasting? A growing interest in intermittent fasting in the research community has led to the discovery that both reduced calorie intake during a fast and then the restoration of a higher calorie intake at the end of a fast appear to produce distinct benefits. Researchers here report on their efforts to split apart the effects of reduced calorie intake from duration of fasting in mice. The results are interesting.

Researchers began to realize that previous studies had unintentionally combined calorie restrictions with long fasts by providing animals with food just once a day. It was difficult, then, to distinguish the effects of one from the other. "This overlap of treatment - both reducing calories and imposing a fast - was something that everybody saw, but it wasn't always obvious that it had biological significance. It's only been in the past few years that people started getting interested in this issue."

Researchers designed four different diets for mice to follow. One group ate as much as they wanted whenever they wanted. Another group ate a full amount, but in a short period of time - this gave them a long daily fast without reducing calories. The other two groups were given about 30% fewer calories either once a day or dispersed over the entire day. That meant that some mice had a long daily fast while others ate the same reduced-calorie diet but never fasted, which differed from most previous studies of calorie restriction.

It turned out that many of the benefits originally ascribed to calorie restriction alone - better blood sugar control, healthier use of fat for energy, protection from frailty in old age and longer lifespans - all required fasting as well. Mice who ate fewer calories without fasting didn't see these positive changes. Fasting on its own, without reducing the amount of food eaten, was just as powerful as calorie restriction with fasting. Fasting alone was enough to improve insulin sensitivity and to reprogram metabolism to focus more on using fats as a source of energy. The livers of fasting mice also showed the hallmarks of healthier metabolism.

The researchers did not study the effect of fasting alone on lifespan or frailty as mice aged, but other studies have suggested that fasting can provide these benefits as well. While the mice that ate fewer calories without ever fasting did show some improved blood sugar control, they also died younger. Compared with mice who both ate less and fasted, these mice that only ate less died about 8 months earlier on average. "That was quite surprising. In addition to their shorter lifespans, these mice were worse in certain aspects of frailty, but better in others. So, on balance their frailty didn't change much, but they didn't look as healthy."



Fasting groups knew from a long time ago that it was easier to handle fasting than a prolonged calorie restriction, which in some cases leads to malnutrition.

In the other hand, modern diets are so calorie rich that what a lay person might consider calorie restriction might be just California calorie normalization.

The good news is that fasting is not that hard and doesn't require much will power. Just read some of the books fine 18-19 century. The authors casually mention the poor skipping eating for a couple of days and nobody is impressed.

Posted by: Cuberat at October 26th, 2021 6:15 AM

Diet and rapamycin
Calorie restriction (CR) and intermittent fasting (IF) extend both the lifespan and healthspan in diverse species. However, CR is of little benefit when started in old age [73,173-178]. Fasting inhibits the mTOR pathway in young but not old mice [179,180]. By contrast, rapamycin strongly inhibits mTORC1 at any age. It extends lifespan, whether started late or early in life [108,155,181], even if used transiently [109]. So, whereas CR is more beneficial early in life, rapamycin may be indicated later in life. In addition, the beneficial effects of rapamycin and CR may be additive, given that they are exerted through overlapping but distinct mechanisms [182-186]. Intermittent rapamycin and CR (24-48 hours after) can be combined, to avoid potential hyperglycemia. Physical exercise may be most beneficial starting immediately after rapamycin use, to take advantage of rapamycin-induced lipolysis as a fuel for the muscles. By itself, chronic rapamycin treatment does not compromise muscle endurance [187] and even prevents muscle loss

Posted by: Robert Read at October 26th, 2021 10:19 AM

I always wondered if murine models are much better than research in petri dishes.
I would imagine that the energy expenditure of mice in the wild is vastly different from mice living a semi sedentary life in box in a lab. Feeding themselves and trying not to become food in the process, reproducing, feeding offspring, living through changing seasons, etc. certainly produces CR like effects in the wild. So it might very well be that the always cited 'significant' life/health prolongation of lab mice is only observable due to the artificial life conditions in a lab. They don't make the CR group live longer, they make the control group's lives shorter.
And then there is the issue of mice's 'faster' than human's metabolism paired with their worse anti-oxidant and DNA repair systems which surely contribute to the effect size of CR/Fasting in mice.

If one looks at the vast amount of studies showing life/health prolonging effects in lab mice, one has to wonder if there is anything that doesn't prolong a lab mouse's life.
Somewhere else someone (jokingly?) answered that question with 'Yes, longer telomeres.'

Posted by: Jones at October 26th, 2021 10:47 AM
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