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. 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.
People who have too little IGF1 signaling may develop dwarfism (such as Laron syndrome), while too much IGF1 can lead to various forms of gigantism and increased risk of age-related diseases. 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. 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 (twice as long as 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.
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 further support the role of IGF1 as major factor in aging in mammals. The first arises from the differences in IGF1 levels in small dogs. 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.