IGF-1 and Longevity

Those lucky enough to just be born with genetically lower levels of the hormone IGF-1 are more likely to live to age 90 and beyond. For example, there’s one IGF-1-lowering gene variant that adds about 10 years to your life expectancy if you inherit it from both parents. This longevity benefit of lower IGF-1 levels is borne out in population studies like this one, out of the Albert Einstein’s Institute for Aging Research, where higher IGF-1 levels predict death and disease, while lower IGF-1 levels appear to predict longer survival, better cognitive function, and better overall functional status. Not all studies painted such a rosy picture, though. A meta-analysis of a dozen population studies suggested a U-shaped curve. Both high and low IGF-1 concentrations were associated with a shorter lifespan, prompting editorial titles such as “IGF-1: Panacea or Poison?”

The correlation between low IGF-1 levels and mortality may be a case of reverse causation. Instead of lower IGF-1 levels leading to life-threatening disease, life-threatening disease may be leading to low IGF-1 levels. Indeed, both acute and chronic illness can lower IGF-1 levels to potentially create the spurious appearance of harm. To tease this out, rather than relying on snapshot-in-time studies, we can prospectively follow people over time to see which comes first, use interventional trials to directly put it to the test, as well as New subscribers to our e-newsletter always receive a free gift. Get yours here: https://nutritionfacts.org/subscribe/.

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employing so-called Mendelian randomization methods to study what happens when people are effectively randomized at birth to just genetically have lower or higher life-long IGF-1 set-points.

For cognitive function, the prospective data are mixed with no effect either way in a drug trial to change IGF-1 levels in Alzheimer’s patients or an Alzheimer’s Mendelian randomization trial. However, Mendelian randomization studies do implicate IGF-1 as a culprit in causally increasing the risk of osteoarthritis and type 2 diabetes. That may help explain why the risk of type 2 diabetes appears to be increased by animal protein intake but decreased by the intake of plant protein.

In 2014, a meta-analysis found that animal protein intake was associated with lower stroke risk, though, which was used to try to explain why a study found vegetarians have higher rates of stroke. A larger meta-analysis that covered twice as many people subsequently found no such animal protein benefit and, in fact, a protective effect of plant protein. Likewise, six subsequent studies on the vegetarian question found only neutral or beneficial effects of healthy plant-based diets on stroke risk.

As for physical function, prospective disability data is mixed, and Mendelian randomization results suggest no effect of IGF-1 activity on physical capacity in old age. A randomized controlled trial in which postmenopausal women injected themselves with IGF-1 for a year found no change in lean mass or muscle strength compared to those who injected a placebo, nor any change in bone mineral density.

Whether higher protein intakes help maintain bone mass as we age is a separate question. Randomizing older women to years of an extra 30-gram protein supplement had no effect on bone mass or strength, but in those who had a recent osteoporotic hip fracture, a 20-gram a day protein supplement reduced further bone loss over the subsequent year. Sadly, a meta-analysis of seven such protein supplementation studies found no overall bone benefit, and the most important question—whether this translates into the prevention of fractures—has yet to be tested.

In terms of longevity, protein restriction alone can improve survival, but it is possible to separate out the effects of IGF-1 and protein intake. As I noted earlier, those winning the genetic lottery to have lower IGF-1 levels without even having to work at it are more likely to survive into their 90s, survive through their 90s, and have a longer lifespan overall. There are also interventional studies showing a reduction in overall protein intake down to recommended levels and/or switching from animal to plant protein sources has a variety of metabolic benefits. However, the prospective study by Longo and colleagues that found the positive association between decreased protein intake and decreased mortality in middle age appeared to flip into a negative benefit at around age 65. This could be due to reverse causation (frail adults may be more likely to be malnourished, for instance), but the researchers recommend a protein intake of a gram per kilogram of body weight per day after age 65, preferably from plants.