It’s not easy being wee: Does IGF-1 deficiency slow down the brain?

If you want a long life, be short. While larger species tend to have longer average lifespans than smaller species, within a species it’s the smaller organisms that live longer: little dogs outlive big dogs, and big mice die young.

Much of the genetically determined variation in body size can be ascribed to differences in the growth hormone (GH) signaling pathway: less growth hormone in early life confers a smaller body size and a longer lifespan as well. Snell and Ames dwarf mice both exhibit GH deficiencies as a result of their respective mutations, and they’re consequently smaller and longer-lived than their control littermates.

It has been proposed that downregulation of insulin-like growth factor 1 (IGF-1) signaling pathway, which is downstream of GH, is responsible for the lifespan extension in GH-deficient mutants. Defects in IGF-1 signaling cause lifespan extension in nematodes and flies (see here and here for recent findings in C. elegans), and the idea that mammalian lifespan is under genetic control that conforms to the paradigm established in worms is beginning to be widely accepted. In my own opinion, the evidence is pretty good, as epitomized in this study of IGF-1 pathway components in the Snell mouse.

But there’s a whole other side to IGF-1 deficiency: IGF-1 levels drop with age, and because the hormone has neuroprotective effects, this decrease is speculated to be responsible for age-related decline in neural function. Is this a paradox? Can downregulation of the same pathway both extend lifespan and harm the brain?

Taking the affirmative side on the latter half of the question, but more or less ignoring the first half, Sonntag et al. inform us that lowering IGF-1 in the adult rat decreases cerebral glucose utilization, a proxy for brain activity:

…we developed a unique model of adult-onset GH/IGF-I deficiency by using dwarf rats specifically deficient in GH and IGF-I. The deficiency in plasma IGF-I is similar to that observed with age (e.g., 50% decrease), and replacement of GH restores levels of IGF-I to that found in young animals with normal GH levels. The present study employs this model to investigate the effects of circulating GH and IGF-I on local cerebral glucose utilization (LCGU). Analysis of LCGU indicated that GH/IGF-I-deficient animals exhibit a 29% decrease in glucose metabolism in many brain regions, especially those involved in hippocampally dependent processes of learning and memory. Similarly, a high correlation between plasma IGF-I levels and glucose metabolism was found in these areas. … our results provide important data to support the conclusion that deficiencies in circulating GH/IGF-I contribute to the genesis of brain aging.

To buy the final sentence of the abstract, you have to believe that the decreased brain glucose utilization they observe actually means decreased brain function. I am going to throw up my hands at this point and say that this is well outside my field, but since at least one very clever neuroscientist friend of mine is fond of pointing out over a pint or two that measurements of spectroscopic proxies of brain function aren’t the same as measurements of brain function per se — even as he gets flown around the world on the strength of his fMRI studies — I’m willing to venture the objection that before one concludes that a given treatment causes functional defects, one should perform a functional study or two.

Which the authors of this paper didn’t get around to doing. We’re left wondering whether the decrease in brain glucose use in adult-onset low-IGF-1 rats actually results in cognitive impairment.

I wouldn’t ordinarily harp on the absence of an experiment that could simply be part of the next planned parcel of results from this group — except that it turns out that dwarf animals aren’t generally thought to have any functional problems with their brains, let alone premature brain aging. Starting from the premise that IGF-1 is neuroprotective and that this represents a paradox, the authors offer a peculiarly byzantine explanation for their persistence in pursuing their hypothesis:

Paradoxically, previous studies using transgenic GHRKO or mutant animals suggest that severe growth hormone deficiency maintains cognitive function in aging animals. Although the basis for this effect is not clear, we have proposed that deficiency in growth hormone and IGF-I early during development may impair maturation of specific organ systems, resulting in a complex array of developmental changes that mask the specific effects of growth hormone and IGF-I deficiency. [emphasis mine]

To restate the argument, if only to test my understanding of it: Lifelong IGF-1 deficiency so impairs an animal and deranges its development that specific neurological damage will be hidden, and cognitive function will appear to be entirely normal, which is why dwarf animals are cognitively intact. Hence (the argument proceeds), we must employ an adult-onset model of GH/IGF-1 deficiency, so that the resulting normally developed animals will lack the “masking” effects found in the dwarfs, and reveal the deleterious specific effects of age-related GH/IGF-1 decreases. When we do so, we observe decreases in markers of brain function, which we should conclude are concomitant with decreases in brain function per se, even though animals with low IGF-1 levels throughout life enjoy both long lives and perfectly normal brains.

Right.

Granted, the glucose utilization figures and other endpoints measured do show impressive decreases from control. Also, it’s hard to believe some of the competing explanations for the data, e.g., rather than diminishing brain function, adult-onset IGF-1 deficiency suddenly makes the brain so much more efficient that it simply needs less glucose and ATP (though the “I” in “IGF” does stand for “insulin-like”, so one can imagine an effect on glucose uptake/metabolism). For the moment, however, in the absence of the cognitive-functional data, I won’t make the final leap.

Still, it’s worth keeping in mind the possibility IGF-1 deficiency might not be entirely salubrious, despite its positive effect on lifespan. We’ll continue to follow the story and sift through the evidence on all sides.