Questions and answers on animal experiments with reduced food intake

What is behind reduced food intake and why are its effects being studied at the Max Planck Institute for Biology of Ageing?

The health benefits of a balanced and healthy diet have been known for a long time [PMID: 29316987, PMID: 24069505]. Research has also shown that reducing food intake leads to a healthier and often longer life in many organisms - potentially also in humans [PMID: 20395504]. However, reduced food intake is by no means understood as permanent malnutrition. Instead, it is a reduced food intake with simultaneous avoidance of malnutrition [PMID: 15096581].

Reduced food intake thus offers a possible option for the treatment of age-related diseases in humans [PMID: 30185958]. However, one of the crucial questions is whether the comprehensive benefits of reduced food intake can be effectively triggered at any point in life. In flies, reduced food intake has been shown to significantly reduce mortality in both young and old animals, regardless of previous diet. On the other hand, switching flies with long-term reduced food intake to unlimited food intake led to an increase in mortality [PMID: 14500985]. However, studies on the effects of reduced food intake in older rodents have so far yielded contradictory results [PMID: 8994305, PMID: 18486188, PMID: 12586746, PMID: 15044709].

The question of the positive effects of reduced food intake, especially when it is started in old age, is therefore far from clear. Further research in this area is needed to understand the effects of reduced food intake as a possible therapy against age-related diseases.

What does reduced food intake mean for the diet of mice?

The effects of reduced food intake are being researched at our institute in mice, among other animals. Mice fed a reduced diet receive 60 percent of the food compared to their conspecifics who are allowed to eat at will [PMID: 31742247]. The reduction in food takes place gradually over a period of four weeks. The mice are given food enriched with vitamins and minerals to prevent malnutrition. They are fed this food once a day - in other words, they perform a kind of interval fasting.

To understand the food restrictions, one has to compare the feeding habits of wild mice with the diet of laboratory mice. The wild house mouse spends a large part of its time foraging at night at 20-30 different feeding sites, which can vary greatly in terms of the nutritional value of each food [DOI]. In contrast, mice in most laboratories can eat at will. Such feeding is also called ad libitum feeding. The mice have access to energy-rich food around the clock [PMID: 31993444].

However, it is not only fundamentally different from the natural foraging behaviour of house mice, but is also associated with some known negative effects on health and welfare. In particular, ad libitum feeding has been shown to cause obesity in laboratory mice and rats [PMID: 16207639]. In addition, it has been associated with premature mortality due to severe degenerative diseases and a higher incidence of spontaneous tumours [PMID: 8672867, PMID: 7713457, DOI].

Although the restrictions of food-reduced mice look very drastic at first glance, they probably more closely resemble the natural habits of mice compared to ad libitum diets and have a positive effect on the animals' health.

What experiments have taken place at the Max Planck Institute for Biology of Ageing?

Scientists at the Max Planck Institute for Biology of Ageing investigated the influence of a reduced food intake at different times in the life of mice. For the study, 800 female mice were subjected to a change in diet and examined for their health and lifespan [PMID: 31742247]. Initially, all mice were fed an ad libitum diet. At three months of age, corresponding to entry into adulthood, 400 mice were henceforth fed a reduced food intake, while the other 400 mice continued to be fed ad libitum. After about two years, some of the mice were again switched to a different diet.

At this point, 86 mice in the ad-libitum group and 16 mice on the reduced diet had died naturally. Half of the mice that had been on an ad libitum diet all their lives received a reduced food intake from then on, while the other half continued to eat at will. Conversely, half of the mice that had previously experienced dietary restrictions were switched to an ad libitum diet, while the second half continued to receive a reduced food intake [PMID: 31742247].

A total of 40 mice, ten from each of the four dietary groups, were euthanized during the experiment so that organs could be collected and molecular biology studies performed. Of the remaining 760 mice, the lifespan was determined, meaning they died of natural causes or were killed for animal ethical reasons to spare them unnecessary suffering [PMID: 31742247].

What are the effects of reduced food intake on the health of mice?

Reducing food intake leads to a healthier and often longer life for many creatures. Mice live longer and are healthier in old age if they are fed 60 per cent of the food compared to ad libitum at three months of age, i.e. when they enter adulthood, than conspecifics that are allowed to eat at will. Compared to animals that are fed around the clock and whose body weight increases steadily with age, these animals maintain their body weight throughout their lives [PMID: 31742247]. They generally show higher athletic fitness, improved learning ability and memory, and are better protected against age-related diseases such as diabetes or cancer.

The decisive factor for the positive effect of reduced food intake is when it is started.  If the mice do not begin with reduced food intake until they are seniors, their life expectancy remains largely the same. The body has a memory, so to speak, of the earlier diet [PMID: 31742247]. The dietary change in mice is therefore only healthier if it is started early and maintained until old age.

These findings could also be of enormous importance for humans. They suggest that healthy behaviour needs to be established earlier in life to improve health in old age and extend lifespan. The studies on mice provide clues as to the age at which it may still make sense for humans to change their diet.

What do we already know about the effects of calorie restriction on life expectancy in humans?

So far, we do not know whether calorie restriction can also extend lifespan in humans. Some people voluntarily reduce their food intake to age healthier and live longer, according to the International Calorie Reduction Society. Initial studies show that this voluntary calorie reduction has a positive effect on health, but also on mood, sexual behaviour or sleep of the test persons [PMID: 27136347]. However, such studies are often relatively short-term, i.e. at most over a few years, so that the effect of calorie restriction on lifespan is not known. In addition, the effects of external influences on the ageing process can never be excluded in humans. Thus, not only the genetic disposition of the respective living being plays a role in the ageing process, but above all external factors such as nutrition, environment and stress [PMID: 31690828].