Modifying Growth (IGF-1) Signals to Extend Lifespan - Better Aging Series Part 10

In the previous article in this series, I discussed how the the GH / IGF-1 axis promotes growth and helps a young body mature. (You can find the rest of the articles here: 1, 2, 3, 4, 5, 6, 7, 8.) This offers an advantage in reproduction when animals are in the prime of their life, and therefore it likely emerged through natural selection. But when an animal ages beyond that window of reproductive potential, the aggressive promotion of growth becomes detrimental to longevity by increasing risk for insulin resistance and cancer. In contrast, animals and humans with suppressed growth promotion appear to be protected from these diseases. Therefore, inhibiting this growth axis after the reproductive window has emerged as an intriguing target to slow aging.

In this post we’ll address a few potential lifestyle modifications that may be effective for inhibiting the GH / IGF-1 axis, and discuss why lifestyle modification may be better than suppression of this pathway via drugs.

When done properly, fasting has potential to augment health and slow the aging process. One way it may affect aging is by reducing IGF-1.

In research that I participated in back in the year 2000, patients diagnosed with prostate cancer were put on a comprehensive lifestyle program including a vegan diet. While the intervention did not reverse the cancer, it did show a significant modulation in gene expression and suppression of the genes involved in the IGF-1 pathway (IGF1R, PIK3C2A, and FOXA2):

In summary, high-quality protein sources, especially dairy, can promote IGF-1. A vegan diet omits dairy and, overall, has a lower protein intake compared to other dietary patterns, and there is evidence that it downregulates the IGF-1 pathway. Furthermore, in support of the notion that lower protein intake supports better aging, we can revisit this quote from leading fasting and aging expert, Valter Longo:

This sounds like a slightly modified Mediterranean diet, which is a dietary style I am very favorable towards, and one that has strong evidence demonstrating that it permits health and longevity.

The ketogenic diet, first introduced in 1921 as a treatment for epilepsy in children who do not respond to medications, features a very low intake of carbohydrates and very high intake of fat. Under this condition, the liver starts to produce a fuel source called ketones. This dietary style is also known to be effective as a weight loss regimen, which I described in a previous blog article.

Several studies have demonstrated that ketosis lowers IGF-1. In one study, patients with rheumatoid arthritis underwent a 7-day ketogenic diet. Although its effects on inflammatory markers were modest, the diet was associated with decreased IGF-1 – an effect that was also noted in some of the epilepsy studies mentioned above. Unfortunately for the epileptic children on this dietary regimen, the decreased IGF-1 also appeared to stunt physical growth and development. For post-reproductive adults, however, this is not as serious of a concern, and may, in fact, be a benefit.

We evolved on a planet with a daily cycle of dark and light. Processes in our body synchronize with the light cycle, and this function is referred to as our circadian rhythm. For instance, hormones that regulate energy fluctuate over a 24 hour period matching energy availability to energy needs. This is of particular interest to us here because many of the mechanisms shown to slow down aging are tied to energy metabolism.

The good news is that we have some control over our these rhythms through the choices we make. My guess is that when we make smart decisions about how we live to support a healthy circadian rhythm over the lifespan, two things happen. First, we maintain healthy circadian function for a longer time within the lifespan, and second, we quite possibly impact lifespan itself in a positive way.

Modern lifestyle encourages us to eat at random times, skip physical activity, and cut back on sleep, and most importantly, get a strange pattern of light exposure (as far as our genes are concerned). All these factors weaken the strength of our circadian rhythm temporarily. Like many things, we can get away with more when we’re younger without experiencing immediate feedback indicating the consequences of our actions. If one’s rhythm strength naturally declines with age, it’s even more reason to observe good circadian practices as we get older. That means, for example, not turning on the television or playing with your phone if you wake up in the middle of the night. It’s like giving your body a signal that’s it’s daytime at the wrong time of day, and this pattern may accelerate the rate with which you age. Learn more about circadian rhythms here.

We must acknowledge the important physiological role IGF-1 plays, even as we age. As I addressed in the first article on this subject, ‘growth’ has a role beyond sexual development; it’s also important for regeneration. For example, the stress induced by exercise stimulate signals that regenerate tissue. It’s this yin and yang relationship that keeps the body strong. Indeed, we do not remain healthy without adequate stress and subsequent regeneration. Therefore, while there is good evidence that aggressive growth promotion is risky, it’s also risky to suppress it entirely.

This suggests that we should perhaps seek to inhibit – but not eliminate – IGF-1 signaling. This incidentally may be a good reason to favor lifestyle modifications that increase IGF-1 sensitivity over pharmaceutical interventions that suppress this growth and regeneration pathway. Medications that inhibit GH / IGF-1 signaling (e.g., pegvisomant) may do too good of a job, resulting in adverse effects such as loss of muscle mass, increased body fat, reduced bone mineral density, and declines in cognition.

Perhaps there will come a time where we will have identified a way to use growth hormone to sustain youthful regeneration capability while eliminating the disease-promoting, lifespan-limiting effects. In the meantime, private aging clinics might try to sell programs that theoretically limit these consequences, but until I see replicated published data demonstrating safety with efficacy, I would not choose to use growth hormone to age better. Likewise, while the longevity data is compelling, I would also refrain from using GH / IGF-1 axis inhibiting drugs, opting instead for lifestyle strategies that promote growth pathway sensitivity.

Personally, I currently adhere to a Mediterranean diet, fast regularly, and enter into extended periods of ketosis (a week to weeks at a time) periodically. I don’t, on the other hand, restrict protein at this point of my life.