Lowering IGF-1 Through Dietary Restriction

Short-term fasting before and immediately after chemotherapy can minimize its side effects while at the same time making cancer cells more susceptible to therapy. In see.nf/fastingcancer I describe some preclinical studies, including a series of experiments showing that, in laboratory animals, fasting can determine whether 100 percent die or 100 percent survive.

In see.nf/fastingchemo I describe the clinical studies. Water-only fasting for a total of 72 hours before and after chemo appears to reduce the toxicity of the treatment without detectable harm. Fasting-mimicking diets were also tested.

In the DIRECT study (DIetary REstriction as an Adjunct to Neoadjuvant ChemoTherapy, 'Dietary restriction as an adjunct to neoadjuvant chemotherapy ), more than 100 breast cancer patients were randomized to the same plant-based calorie-, protein-, and carbohydrate-restriction fasting-mimicking diet (FMD) mainly consisting of soups, teas, and broths, for three days before and on the day of the chemotherapy cycle. Unfortunately, no difference in quality of life or chemotherapy side effects could be found between participants in the FMD group and the control group eating a normal diet. However, improvements were found in the per-protocol analysis that is, when adherence to the instructions was taken into account and only those subjects who had actually stuck to the diet plan were counted, they performed significantly better on a number of emotional and physical function measures. And isn't that what we really care about what happens when the diet plan is followed? The problem with per-protocol analyses is that the purpose of randomization, preventing bias, is lost. For example, it could be that patients who were doing better from the outset were more likely to comply with the requirements.

But apart from quality of life: Did the fasting-mimicking diet improve the effectiveness of chemotherapy? FMD appears to help against cancer in mice, and a number of promising case reports have been published, but what did the DIRECT study, in which this diet was actually tested, find? On the primary measure there was no significant difference: the complete response rate, the disappearance of all signs of cancer from the body. (That occurred in about 11 percent in the FMD group, and 13 percent in the control group.) At least in the FMD group, radiologic evidence of tumor shrinkage on MRI or ultrasound was found three times as often, though its long-term effect is uncertain. In the per-protocol analysis, an improvement in pathologic response was also found (no more cancer cells were found in tissue samples), although, as with any per-protocol analysis, this carries the possibility of selection bias. The lack of more convincing evidence for a benefit of the fasting-mimicking diet was attributed to poor adherence to the FMD eating plan, which in turn was mainly because some prepackaged dishes did not taste good. It was suggested that future studies might incorporate fresh foods.

Lowering IGF-1 Through Dietary Restriction

Is there anything we can change in our diet to achieve a similar benefit without having to fast? As I explain in detail in see.nf/fmdcancer, fasting works in part by lowering levels of insulin-like growth factor 1, a cancer-promoting growth hormone (see the chapter on IGF-1). Lower IGF-1 levels appear to regulate the differential protection of normal cells compared with cancer cells in response to fasting, since restoring IGF-1 can be enough to negate the protective effects. If you add chemo in a Petri dish to different cancers, it can wipe out half or more. Under nutrient deprivation, the same chemo dose in the Petri dish kills about twice as many cancer cells, but this effect disappears if you add IGF-1 back into the mix.

The downregulation of IGF-1 through fasting has been described as a way to 'deploy anti-aging genes against cancer. You may recall that lowering IGF-1 levels genetically or by other means leads to a markedly longer life span. But you can lower IGF-1 levels not only through fasting. Yes, with a few days of fasting you can cut it in half, but that is largely because you reduce protein intake. Protein intake is considered a key factor determining IGF-1 levels in humans, suggesting that you may be able to achieve part of the anti-cancer and anti-aging benefit that comes with eating less simply by consuming less protein.

In rodents, calorie restriction alone can lower IGF-1, but in humans it is not enough for them to eat less. For example, in the CALERIE study, two years of calorie restriction did not lead to a greater reduction in IGF-1 levels than in the control group. That is not surprising, since protein intake was not reduced. Not even severe calorie restriction lowers IGF-1 levels unless protein intake is reduced at the same time.

CRONies, who reduced their calories by 30 percent on average for six years, had similar IGF-1 values to others eating the full American standard diet. This is also not surprising, since the CRONies consumed 1.7 grams of protein per kilogram of body weight per day, double the recommended daily allowance (RDA) of 0.8 grams/kilogram. In contrast, vegans who consumed about the recommended amount of protein had about 25 percent lower IGF-1 levels in their blood. This was attributed to differences in protein intake, since intervention studies showed that IGF-1 levels rise with higher protein intake but how do we know it is not some other factor? By investigating it. And indeed, when the CRONies who had been consuming 1.7 grams/kilogram of protein lowered their intake to one gram or less, their IGF-1 level dropped by 25 percent within three weeks, to the level of the vegans.

Protein Restriction

Reduced protein intake seems to be a more feasible lifelong strategy than long-term strict calorie restriction, but there is debate about the relative contribution of protein restriction to the overall longevity benefit of calorie restriction. In insects, a longer life from restricting total food intake seems to be solely the result of lower protein intake, but in mammals the data are contradictory. Some evidence suggests that protein restriction alone does about half as much as calorie restriction in rodents, the average extension of maximum life span is 20 percent, while with calorie restriction it is about 40 percent. At the same time, however, there are also rodent studies showing that the life-span extension from food restriction seems to be independent of protein intake it was nearly identical when food was reduced by 40 percent, regardless of whether protein intake remained the same. Recently, the pendulum has swung in the other direction, because presumably the life-span benefit of calorie restriction is due to the lower protein intake. In this chapter I will examine how these discrepancies can be explained and what implications that has for human longevity.