Depression of the IGF-1 signaling axis is a well-known genetic means of extending lifespan in multiple organisms, ranging from worm to fly to mouse. There are, however, examples of IGF-1 playing a beneficial role in preventing specific kinds of age-related decline — for instance, in our earlier discussion of IGF-1 in the brain, or in this recent paper from Li et al., in which the authors demonstrate that overexpression of IGF-1 in late adulthood can slow cardian diastolic contractile dysfunction, a specific type of age-related decline in the heart:
Aging is associated with hepatic growth hormone resistance resulting in a fall in serum insulin-like growth factor-1 (IGF-1) level. However, whether loss of IGF-1 contributes to cardiac aging is unclear. This study was designed to examine the effect of cardiac overexpression of IGF-1 on cardiomyocyte contractile function in young (3 mo) and old (26-28 mo) mice. Cardiomyocyte contractile function was evaluated including peak shortening (PS), time-to-90% PS, time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (± dL/dt). … SERCA activity was measured by 45Ca2+ uptake. Aging induced a decline in plasma IGF-1 levels. Aged cells exhibited depressed ± dL/dt, prolonged TR90 and a steeper PS decline in response to increasing stimulus frequency compared with young myocytes. IGF-1 transgene alleviated aging-induced loss in plasma IGF-1 and aging-induced mechanical defects with little effect in young mice. … Expression of SERCA2a (but not NCX and PLB) and SERCA activity were reduced with aging, which was ablated by the IGF-1 transgene. Collectively, our data suggest beneficial role of IGF-1 in aging-induced cardiac contractile dysfunction, possibly related to improved Ca2+ uptake.
The comparison here is between wildtype mice and those with an extra transgenic copy of IGF-1, so we’re left hanging on a couple of important points.
Most urgently: Do IGF-1 deficient mice suffer from increased cardian diastolic contractile dysfunction as they age? These animals exist, so the experiment would be straightforward. I don’t know of any evidence of heart problems in IGF-1-deficient mice, and certainly even if such problems do arise, the net result on lifespan is still positive.
Nonetheless, to play devil’s advocate, I would point out that a tiny cage in an animal facility encourages a sedentary lifestyle that might be particularly easy on a prematurely weakened heart, concealing any problems from the casual observer. I would therefore caution the reader against over-interpreting the absence of evidence as evidence of absence. Could targeting Igf-1 axis work to extend lifespan in people? Perhaps, but if the therapy was systemic, a longer life might possibly come at the cost of a weakened heart and a limit on physical activity.
The idea that this (or any) signaling axis might have opposing effects in different tissues is an important one for biologists of aging and lifespan-extension enthusiasts alike: Just because a given mutation extends lifespan doesn’t mean that everything about that lifespan is going to be better. And in the end, something kills long-lived Igf-1 mutants too…perhaps with a couple of well-placed tissue- and temporally-specific Igf-1 receptor transgenes, the end of life could be further delayed.