Fight Aging!

A few genetic and metabolic commonalities have been uncovered in studies of the longest-lived families over the past decade, a part of the broader search for longevity genes and mechanisms in humans. Some of these involve the activity and levels of insulin-like growth factor IGF-1, something that is well studied by that part of the research community focused on the intersection of aging, genetics, and the operation of metabolism. Changes in IGF-1 biochemistry show up in many species and many interventions that alter life span, but despite an ocean of data gathered by various researchers, the sheer complexity of these metabolic processes ensures that there is still room to argue over how and why (or even if) IGF-1 influences lifespan.

For example, take a look at the introduction to the paper I'm going to point out today, wherein the authors skim over a set of contradictory results that show either higher and lower IGF-1 levels to be associated with human longevity, or no association at all:

Data on IGF-I system in relation to longevity are still controversial. Bonafè et al. previously found that subjects with at least an A allele of the IGF-I receptor (IGF-IR) gene (G/A, codon 1013) had low levels of free plasma IGF-I and were more represented among long-lived people. In contrast, Paolisso et al. found [evidence suggesting] a higher IGF-I bioavailability which contributed to the observed improved insulin action in centenarians. An overrepresentation of heterozygous mutations in the IGF-IR gene associated with high serum IGF-I levels and reduced activity of the IGF-IR has been reported in Ashkenazi Jewish centenarians compared to controls. In addition, in humans positive associations between circulating total IGF-I levels and cancer mortality have been found in many studies, while low total IGF-I levels have been associated with an increased risk for cardiovascular diseases and diabetes. On the other hand, Rozing et al. showed that offspring of familial nonagenarians displayed similar IGF-I and IGFBP-3 levels compared to their partners.

These conflicting results probably reflect the complexity of the IGF-system. We recently developed an IGF-I kinase receptor activation (KIRA) assay to assess circulating IGF bioactivity. This assay determines IGF-I bioactivity [and] unlike the traditional IGF-I immunoassays [it can be used] to measure the overall IGF-IR activation in blood.

So the authors here suggest that other researchers have been measuring values that don't reflect the true and complicated operation of the IGF-1 system, and produce an assay of their own that supposedly does better - by measuring a better proxy for the actual activity of IGF-1 and accounting for more confounding factors. The results from their data are as follows:

Low circulating IGF-I bioactivity is associated with human longevity: Findings in centenarians' offspring

Centenarians' offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay ... In conclusion: 1) centenarians' offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians' offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process.

If you look back in the Fight Aging! archives you'll find some discussion on how IGF-1 might influence life span in various species, such as through hormetic mechanisms relating to the mitochondria:

Signs of progress in understanding the mechanisms of induced longevity through altered insulin/IGF-1 signaling are shown in this paper. This is one of the most-studied class of longevity mutations in lower animals, despite there being some debate over whether it is relevant to mammal biochemistry. Here, the basic mechanism is explained as being hormetic, centering on the mitochondria: researchers elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial [reactive oxygen species (ROS)] signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways.