The starvation hormone increases lifespan
In the last post, I discussed the growth-longevity trade-off in the context of intermittent fasting. In this post, I’ll discuss some further evidence for the connection between growth and lifespan.
A very neat paper shows that transgenic mice made to overexpress a certain hormone live much longer than wild type mice: The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. First of all, I’ll just emphasize something from the title of the paper, namely that fibroblast growth factor, or FGF-21, is the starvation hormone.
In mice, FGF21 is strongly induced in liver in response to prolonged fasts… FGF21 in turn elicits diverse aspects of the adaptive starvation response. Among these, FGF21 increases insulin sensitivity and causes a corresponding decrease in basal insulin concentrations; FGF21 increases hepatic fatty acid oxidation, ketogenesis and gluconeogenesis; and, FGF21 sensitizes mice to torpor, a hibernation-like state of reduced body temperature and physical activity. FGF21 also blocks somatic growth by causing GH resistance, a phenomenon associated with starvation. Transgenic (Tg) mice overexpressing FGF21 are markedly smaller than wild-type mice and have a corresponding decrease in circulating IGF-1 concentrations despite having elevated growth hormone (GH) levels…. In liver, FGF21 inhibits the GH signaling pathway… Thus, FGF21-mediated repression of the GH/IGF-1 axis provides a mechanism for blocking growth and conserving energy under starvation conditions. [my emphases]
So, it can be seen from this passage how growth and lifespan are opposed. FGF-21 causes better insulin sensitivity and increased fat burning, both known to be associated with better health and longevity, and it interferes with the growth hormone signaling pathway.
Here are the survival curves for the mice, transgenic vs. wild type:
Median survival time in the mice was increased by 36%, and maximum survival was even longer, as around 30% of the transgenic mice were still alive at the time the paper was written.
According to an accompanying article written by one of the most prominent aging researchers around, Cynthia Kenyon, FGF-21 is produced by the liver after 12 hours of fasting.
All in all, we see that a hormone produced by fasting inhibits growth pathways and extends lifespan. Worth noting also is that FGF-21 also increases insulin sensitivity and promotes the production of ketones. Low-carbohydrate diets do this also, suggesting that they may promote longevity as well. And exercise, especially resistance exercise, strongly increases insulin sensitivity.
Could regular use of intermittent fasting increase longevity in humans? In my opinion, very likely it will. What is needed now are studies to see how and to what extent FGF-21 is increased in humans in response to fasting.
Finally, as further evidence of the growth-longevity trade-off, we should note that, in humans, growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes. Also in humans, functionally significant mutations in the insulin-like growth factor receptor are more common in centenarians.
How to Fast Without Fasting
Intermittent fasting, discussed many times on this site, is a potent anti-aging and health-promoting intervention. It lowers insulin and glucose levels, and therefore can be used to treat diabetes and for fat loss. Nevertheless, fasting requires going without food, which many people are unwilling — or possibly unable, in some cases — to do. Is there a workaround? Yes… here’s how to fast without fasting.
The effects of fasting
What does intermittent fasting do that’s so beneficial? It appears that the main way that short-term fasting benefits health is by lowering insulin levels. The mobilization of fat stores — lipolysis — that greatly accelerates during fasting appears to be due to lower insulin levels, and not to changes in blood glucose (sugar) levels.
Besides increasing lipolysis or fat-burning, lowering insulin levels also greatly increases the rate of autophagy, the cellular self-cleansing process that rids cells of junk and that is so important to fighting aging.
Fasting also increases the production of ketones, which benefit metabolic and brain health.
So how can you get these effects of fasting without fasting?
You do this through restricting carbohydrates.
Carbohydrate restriction gives many of the benefits of fasting
Carbohydrate restriction, i.e. a very low carbohydrate ketogenic diet (VLCKD), or in this case, a zero-carbohydrate diet, was found to account for about 70% of the metabolic response to fasting. That is, merely refraining from eating carbohydrates gives most of the benefits of fasting in terms of lower glucose and insulin.
In another study, a group of volunteers fasted for 84 hours (3.5 days), or fasted for that length of time and received a lipid infusion such that they got all the calories they needed. The scientists found that there were no differences in “plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations” between fasting and non-fasting conditions.
The authors conclude, “These results demonstrate that restriction of dietary carbohydrate, not the general absence of energy intake itself, is responsible for initiating the metabolic response to short-term fasting.” [My emphasis.]
Now, I might not go so far as these scientists as to say that the entire response to intermittent fasting is due to absence of dietary carbohydrate. Another study cited above found that carbohydrate restriction accounted for about 70% of the response to fasting, not 100%.
There may be other parameters that the study didn’t observe, IGF-1 for example, or increased rates of autophagy. But it’s clear that restricting carbohydrates accounts for a lot of the changes seen in intermittent fasting.
I suspect that the additional benefits of fasting come from lack of protein intake.
Radically restricting carbohydrates results in the production of ketones, and ketones stimulate autophagy, which is one of the important benefits of fasting. So here’s another way that reducing carbs effectively imitates fasting.
Intermittent fasting also works by reproducing many of the effects of calorie restriction, the most robust life-extending intervention known.
And in turn, restriction of carbohydrates is the most effective way to mimic calorie restriction.
The conclusion must be that carbohydrate restriction confers most of the benefits of intermittent fasting.
What if you combine a very-low carbohydrate diet with bouts of intermittent fasting? That’s exactly what I do, and it should give synergistic benefits.
If you start from a base of low-carb eating, and then fast for a period of time, this should more strongly induce ketosis and lower insulin levels, and more strongly increase the rate of autophagy and lipolysis (fat-burning).
How to implement a low-carbohydrate diet + intermittent fasting
The main source of dietary carbohydrates are refined grains and starches. These should be omitted entirely, so that means no bread, tortillas, pasta, breakfast cereal, rice, anything with sugar such as soda.
Large sources of carbohydrates are also found in starches such as potatoes.
Green leafy vegetables, while they contain carbohydrates, are such poor sources of them and so high in fiber that they may be eaten freely.
The main source of calories would consist of meat, eggs, cheese, cream, butter, yogurt (unsweetened, natch). If you drink alcohol, be moderate and stay with red wine and plain highballs, which have no sugar.
Don’t eat anything after dinner, and then again not until 16 to 18 hours have passed, say until 10 A.M. to noon the following day. That’s your fast.
You could do that daily, although if you lift weights, don’t begin a fast until at least 24 hours after your workout. When you lift weights, muscles are primed for growth, and need nutrients to do so. If you want to get those gains, you must feed your muscles.
On my current schedule of approximately twice a week workouts, I can still manage several 16-hour fasts a week.
Hopefully, I’m getting potent anti-aging and health-giving synergy between my low-carbohydrate way of eating and intermittent fasting.