Monday, March 2, 2009

Intermittent Fasting Reduces Mitochondrial Damage and Lymphoma Incidence in Aged Mice

Intermittent fasting may protect mitochondria from free radical damage.
Intermittent fasting may protect mitochondria from free radical damage.

According to the mitochondrial theory of aging, damage caused by oxygen free radicals leads to loss of mitochondrial function and cellular energy. This damage, in turn, eventually leads to aging-related pathologies such as cardiovascular and neurodegenerative diseases and cancer.

In many animals maximum lifespan and free radical damage to mitochondrial DNA are inversely correlated, meaning that the more damage their mitochondria suffer, the shorter their lifespan. This is why sufficient levels of antioxidants like superoxide dismutase (SOD), which protects from damage caused by reactive oxygen species (ROS), are so important.

It seems that intermittent fasting may be one way of increasing this protection. Descamps et al. studied the effects of alternate-day fasting on female mice that have high rates of fatal lymphomas, a type of cancer, as they age. According to the authors, these OF1 breeder mice can be considered a "senescence-accelerated mouse model", meaning that compared to non-breeder mice of the same age, these mice show more signs of clinical aging.

Intermittent fasting with or without caloric restriction?

At 8 months of age, the mice were split into two groups. The mice in the ad libitum (AL) group were allowed to eat when and as much as they wanted, while the alternate-day fasting (AF) group was given food only every other day. Note that this is the same as 24/24 hour cycle intermittent fasting in humans.

With studies on intermittent fasting, the first question to ask is whether the intermittent fasting group ended up eating less than the ad libitum group. If they did, it becomes difficult to say whether the results are due to periods of not eating or simply due to eating less. In other words, it may then well be that the reason behind the observed health benefits is caloric restriction instead of intermittent fasting.

Often restricting one's eating results in a decreased caloric intake, whether it's intended or not. Human studies on intermittent fasting frequently report that the subjects would have eaten less if they had not been instructed to make sure their total energy intake stays the same.

What makes this study particularly interesting is that there was no significant difference in energy intake and body weight between the two groups. On eating days, the alternate-fed mice ate nearly twice as much as the ad libitum group ate daily. In the first two months of the experiment, the alternate-fed mice weighed slightly less than the ad libitum mice, but after the third month there was no difference. At the end of the experiment the AF mice even weighed a little more than their counterparts, having gained 6% in body weight compared to 3% in the AL group.

Protection from cancer & free radical damage

After four months, 33% of the mice with free access to food had died of lymphoma, while all of the mice on an alternate-day fasting diet were still alive. The authors note that the AF mice "appeared as clinically healthy mice". Their basal levels of reactive oxygen species generation were 12% lower than in the AL mice still alive at the end of the experiment. When ROS generation was articially induced with succinate or succinate and adenosine diphosphate together, the levels in the AF group were 46.5% and 27% lower, respectively.

As the lymphoma progresses, the spleens of the mice become overweight. The spleen size of the mice in the AF group was 56% smaller, indicating the ability of alternate-day feeding to prevent spleens from becoming enlargened due to lymphoma.

Intermittent fasting also increased superoxide dismutase activity by 37% in spleen mitochondria and by 27% in the brain. Glutathione peroxidase and catalase, two other enzymes that protect from oxidative damage, were increased in the brain by 27% and 19%, respectively. In contrast, SOD activity in the liver was reduced by 29%.

Lipid peroxidation, which refers to the oxidative degradation of lipids, was reduced by 18% in the alternate-day fasting mice. This was associated with an increase of the ratio of glutathione (GSH) and glutathione disulfide (GSSG) in the spleen. As glutathione plays an important role in scavenging free radicals, the GSH/GSSG ratio is often used to determine the exposure of cells to oxidative stress.


Intermittent fasting without a reduction in body weight or total energy intake completely inhibited the development of a specific cancer (lymphoma) in female mice considered to be a model of accelerated aging. After four months, a third of the mice in control group had died, while all of the alternate-day fed mice were still alive and healthy.

This inhibitive effect was associated with lower reactive oxygen species (ROS) production and higher levels of enzymes protecting from free radical damage, including superoxide dismutase (SOD), glutathione and catalase.

For more information on intermittent fasting, see these posts:

A Typical Meal Paleolithic High-Fat, Low-Carb Meal of an Intermittent Faster
A Typical Day of Intermittent Fasting
Intermittent Fasting Improves Insulin Sensitivity Even without Weight Loss
Intermittent Fasting - Update after 5 Months

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