06 Mar 2008

Only one in 10,000 people gets to be serenaded with the “Happy Birthday” song for the 100th time. For some of them, reaching that magic number may have more to do with genetics than clean living. In this week’s PNAS, researchers led by Nir Barzilai and Pinchas Cohen at the Albert Einstein College of Medicine, New York, report that loss-of-function mutations in the insulin-like growth factor receptor are overrepresented in a cohort of centenarians. The finding suggests that toning down this signaling pathway might become one ticket to longevity in humans.

Suppressing insulin signaling leads to impressive increases in lifespan in invertebrates (see ARF related news story) and may even protect against neurodegeneration. Shutting down the insulin receptor homolog, DAF-2, for example, prevents amyloid-β aggregation in C. elegans (see ARF related news story). In mammals, too, there are hints that insulin signaling may be linked to longevity, since increased insulin sensitivity is associated with longer lifespan in animals on caloric restriction diets (see ARF related news story). Even the insulin-like growth factor (IGF) pathway, an evolutionary upgrade, may be related to longevity in mammals. Mutations in IGF receptors increase lifespan in female mice, albeit at the expense of growth—the mutations are associated with dwarfism (see ARF related news story and Bonkowski et al., 2006). However, the role of insulin/IGF signaling in human longevity remains unclear.

To address this, first author Yousin Suh and colleagues assembled and analyzed a genetically homogenous group of people with family histories of extreme longevity. The cohort comprised 384 Ashkenazi Jews (286 women, 98 men) with an average age of 97.7 years, and age- and sex-matched controls without a family history of long life. The researchers found that female offspring of the centenarians who had long-lived relatives have significantly higher serum IGF1 than offspring from age-matched controls (they did not rely on IGF1 measurements from the centenarians themselves, because those levels do not correlate with plasma levels at younger ages). Female offspring were also 2.5 cm shorter, on average, than control offspring, which would be consistent with reduced IGF1 signaling, suggesting that the elevated IGF1 is a compensatory effect.

With this in mind, Suh and colleagues screened for mutations in the IGF1 pathway genes. They found no difference in the IGF gene itself, but substantial polymorphisms in the IGF1 receptor (IGF1R) gene, including two non-synonymous mutations in the coding region. When they genotyped the whole cohort (centenarians and controls), they found nine centenarians who carried either one of the mutations (Arg-407-His, or Ala-37-Thr). IGF1 and height data were available for six of those carriers and revealed that they all had significantly higher plasma levels of the growth factor and were all slightly, though not significantly, shorter than controls. Functionally, these mutations seem to be important, because when lymphoblasts from the carriers were tested, they had reduced expression of IGF1R and also reduced phosphorylation of the downstream kinase Akt, indicative of reduced IGF signaling. Interestingly, increased Akt activity has been linked to mild cognitive impairment (see ARF related news story) and AD pathology (see Griffin et al., 2005), and while it is not clear if any of these centenarians are free of dementia, they were required to be living independently at age 95 to qualify for the study.

The authors note that though the role of the growth hormone/IGF axis is well established as a modulator of lifespan in animals, its role in humans has been controversial. Drugs that increase IGF1 release have even been tried in clinical trials for AD, but to no avail (see ARF related news story). “The identification of new non-synonymous mutations in the IGF1R gene that result in reduced IGF signaling among centenarians suggests a similar role for this pathway in modulation of human lifespan as observed in model organisms,” write the authors. They acknowledge, however, that these particular variations occur at very low frequency in human centenarians. Perhaps other genetic variations in the IGF1 pathway may predispose to a long life, as well.—Tom Fagan