The really fun thing about discussing signaling networks (the inputs that let cells make decisions based on their environment) in aging is the wide range of ways that these pathways exert their influence. See my previous blog on myostatin for an example of this. Cells are like a computer—they take inputs (nutrition, hormones, toxic molecules) and use their existing programming (epigenetic state) to make decisions. Components that control one process, such as regulating body size, can play roles in completely different processes. Today, I’ll discuss an example involving Insulin-like growth factor 1 or IGF1, a close relative of Insulin (a hormone that regulates blood glucose levels). While IGF1 was initially discovered due to its effect on blood glucose, it has since turned out to exert profound effects on a wide variety of processes that also include body size, longevity and cancer.
IGF1 is released by the liver in response to secretion of human growth hormone and promotes growth of muscles, bones and other parts of the body. IGF1 levels are often elevated during pregnancy, puberty and after some forms of exercise. People who have too little IGF1 signaling may develop dwarfism (such as Laron syndrome, discussed below), while too much IGF1 can lead to various forms of gigantism and increased risk of age-related diseases.
IGF1 is important for control of body size in more than just humans: an excellent example of the importance of IGF1 signaling in determining body size comes from dogs. As we all know, dogs vary greatly in size. In fact, the difference between the smallest and largest dog is nearly two orders of magnitude (that is, the largest dog weighs 100 times more than the smallest dog). A study in the journal Science in 2007 mapped the source of this variation back to one gene: IGF1. It turns out that small dogs have a variant of the IGF1 gene that results in less efficient production of the IGF1 protein, resulting in lower IGF1 levels and smaller body size.
IGF1 is an important molecule in development, as demonstrated by its key role in size determination; however IGF1 does much more than just determine how large an animal or human will be. IGF1 signaling has cropped up as a central player in fundamental studies on the genetic basis of aging. Using the small roundworm, Caenorhabditis elegans, scientists discovered that IGF1 signaling has a profound effect on aging. Like in dogs and people, IGF signaling plays a role in worm development. When IGF signaling is lost (in this case by losing the receptor, called DAF2 in the worm), juvenile worms enter into a developmental state characterized by small size and a greatly extended lifespan (the dauer). When IGF1 signaling is lost later in development, these worms develop into adults, but still display a long lifespan (2x longer than worms that have normal IGF signaling). This discovery was one of the first to identify a gene linked to extending lifespan, and represents an important milestone the modern field of aging. (For more on genes associated with lifespan extension, check out our recent blog on Centenarians).
Loss of IGF1/DAF2 signaling in worms results in smaller body size and extended lifespan. The same holds true for larger organisms such as mice. Does reducing IGF1 signaling during aging extend lifespan in humans? Unfortunately, the jury is still out on this. Studies lowering IGF1 in adult mice have shown mixed results, however, two other lines of research discussed below further support the role of IGF1 as major factor in aging in mammals.
The first arises from the same phenomenon that alters size in dogs: differences in IGF1 levels in small dogs due to a genetic mutation. As it turns out, this mutation affects both body size and longevity, that is, small dogs (that make less IGF1) tend to live longer than large dogs that make more IGF1. Second, people with Laron syndrome or Laron-type dwarfism have naturally reduced IGF1 levels. Laron syndrome results from a dysfunction of the growth hormone receptor, resulting in reduced levels of insulin and IGF1 levels. These individuals are typically short in stature (less than four feet) and have a reduced risk of cancer and diabetes; however there have not been comprehensive studies on whether these individuals have an extended life span.
Despite the evidence for a negative role of IGF1 in longevity, there are people who seek to increase their IGF1 levels. IGF1 is a performance enhancing drug (it builds muscle) that is popular in bodybuilding circles. This is concerning, since many studies link excessive or aberrant IGF1 signaling to cancer, with elevated IGF1 increasing both the risk and severity (metastatic potential) of cancer. In researching this article, I couldn’t help but be struck by the number of quasi-legal nutritional supplements peddling IGF1 or odd sources of IGF1 (deer antler spray anyone?).
Once more we here at SAGE STRONGLY DISCOURAGE TAKING IGF1 IN ANY FORM UNLESS PRESCRIBED BY A DOCTOR FOR AN ACTUAL MEDICAL CONDITION.
So to summarize, alteration of IGF1 signaling changes body size in worms, mice, dogs and people and can alter either the risk of several diseases of aging, or lifespan in these animals. Understanding how this signaling pathway is regulated is a major focus in aging, cancer, diabetes and obesity research. Unfortunately, clinical trials focused on blocking IGF1 signaling to treat cancer have failed so far. Despite these initial failures in cancer, targeting this gene and the pathways that it activates still holds great potential in altering the risk of all of these conditions and improving peoples’ lives as they age.