Insulin and IGF-1 in Human Aging and Longevity

The area of cellular metabolism surrounding growth hormone, IGF-1, and insulin is arguably the most studied set of mechanisms linking the operation of metabolism and the pace of aging. It is impacted by calorie restriction, an intervention that reliably slows aging. The longest lived engineered mice are those in which growth hormone signaling is disabled, and there is an equivalent human population with a similar inherited mutation to study. Many of the early attempts at producing long-lived nematode worms involved manipulation of IGF-1/insulin signaling. A greater number of centenarians than younger individuals appear to have favorable IGF-1/insulin signaling, suggesting some survival advantage.

But is this of any practical use when it comes to producing therapies that treat aging and meaningfully lengthen human life spans? After going on for thirty years of study, one has to think that the answer might be no. There is no way forward to radical life extension of decades and restored youth via mimicking calorie restriction, or trying to make metabolism more like that of long-lived people. Most people with the same biochemistry as centenarians die long before reaching that point - the survival advantage doesn't have to be large for centenarians to exhibit a larger proportion of a given trait than the general population. Human growth hormone mutants don't seem to live any longer than the rest of us. And so forth.

These and other, similar points have long led me to think that altering metabolism to age slightly more slowly - via IGF-1 signaling or other aspects of the response to calorie restriction - is just not a good use of research and development funds. It will not help those already aged in any meaningful way. It is a poor strategy for the research community to be undertaking, and it is a major problem that this strategy remains the dominant recipient of resources and attention. If enormous funding is to be invested in this field, let it go towards true rejuvenation research based on repair of the causes of aging, not tinkering with metabolism to produce minor adjustments in aging.

Centenarians are considered the best human model to study biological determinants of longevity having reached the very extremes of the human lifespan. Several studies compared circulating insulin and IGF-1 levels in centenarians with those of younger controls. Metabolic age-dependent remodeling is a physiological process occurring in the whole population. Aging is frequently associated with a decline in glucose tolerance secondary to an increased insulin resistance, but an exception occurs in long-lived people. Researchers found that insulin resistance increased with aging and declined in subjects older than 90 years. Indeed, long-lived subjects showed a higher insulin sensitivity and a better preservation of beta-cell function than younger subjects.

Data on the IGF-1 system in relation to longevity are still controversial in long-lived subjects. One team described an increased plasma IGF-1/IGFBP-3 ratio in healthy centenarians compared to elderly subjects. They hypothesized that this elevated ratio was indicative of a higher IGF-1 bioavailability which contributed to the improved insulin action in centenarians. In contrast, others reported that subjects with at least an A allele of the IGF-1 receptor gene had low levels of free plasma IGF-1 and were more represented among long-lived people.

These conflicting results probably reflect the complexity of the IGF-1 system and ethnic differences in enrolled populations. In addition, centenarians have often been compared to a control group of younger subjects. Therefore, in most of these studies it was not possible to conclude if IGF-1 differences between both groups were related to a different lifespan or reflected a physiological age-dependent IGF-1 decline.

While it is well known that enhanced insulin sensitivity and low insulin levels are associated with an improved survival, there is evidence showing that attenuation of the growth hormone/IGF-1 axis may have beneficial effects in extending lifespan in humans. However, it is still unknown which are the optimal IGF-1 levels during life to live longer and healthier. In addition, IGF-1 receptor sensitivity and activation of the post-receptor pathway were not evaluated in the majority of the study enrolling long-lived subjects. Therefore, it is not possible to define the real activation status of the IGF-1 receptor signaling through the mere dosage of circulating IGF-1 levels. This renders more difficult the identification of pharmacological or environmental strategies targeting this system for extending lifespan and promoting healthy aging.

Nonetheless, striking similarities have been described concerning the endocrine profile between centenarians and subjects after a calorie-restricted diet. The endocrine and metabolic adaptation observed in both models may be a physiological strategy to increase life span through a slower cell growing/metabolism, a slower loss of physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. These mechanisms seem to be, at least in part, mediated through the modulation of the growth hormone/IGF-1/insulin system.