Highlights
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Low IGF-I levels have not been consistently associated with human longevity. •
Humans with more stable circulating IGF-I levels over time show better survival. •
A low protein intake and low IGF-I in the very old may reduce life expectancy. •
Reduced paracrine IGF-I-mediated effects may play an important role in longevity.
Abstract
Age is a major determinant of circulating Insulin-like Growth Factor-I (IGF-I) levels. In healthy populations levels of IGF-I markedly differ between individuals, but total IGF-I, IGFBP-3, and their ratio within one individual show only small changes with age over time. In many experimental models an increased longevity has been found with downregulation of the growth hormone (GH)/IGF-I system. However, a relationship between low IGF-I and longevity is often only observed in female animals. In contrast, in humans low IGF-I has not consistently been found to be associated with longevity. Low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize longevity through a process that may involve regulation of circulating IGF-I. Changes of IGF-I levels over time in an individual may provide more insights about the relevance of IGF-I for lifespan of that individual than measuring IGF-I once at baseline. For each individual there probably is a specific optimal age-dependent ‘setpoint’ for the GH/IGF-I system which co-determines survival. Local (paracrine) IGF-I actions may induce effects independently from systemic circulating IGF-I. Therefore, in order to obtain an overall view about the role of IGF-I in the endocrinology of aging it is necessary to study both paracrine and systemic (endocrine) IGF-I-mediated effects.
Introduction
Age is a major determinant of circulating Insulin-like Growth Factor-I (IGF-I). IGF-I increases from very low levels directly after birth to a clear peak level at puberty. After this peak at puberty, a sharp decline occurs in the third decade followed by a more gradual decrease from the third to the eighth decade [1]. The main regulators of IGF-I synthesis are growth hormone, nutrition, and the immune system [2]. Growth hormone (GH) secretion is believed to play a major role in the changing circulating levels of IGF-I during aging, although in the majority of studies no correlation was found with the endogenous GH secretion in healthy adults 1, 3.
In the circulation, most IGF-I is bound to at least six different binding proteins (IGFBPs), of which IGFBP-3 binds the majority of IGF-I. It is thought that the activity of IGF-I is modulated by these IGFBPs and their proteases [4]. The IGFBPs bind IGF-I non-covalently on a 1:1 M basis, and due to their affinity and a molar concentration which is around 50% higher than that of IGF-I, less than 1% of IGF-I is present in the circulation in a free form. Analogous to free testosterone and free thyronine (T3), free IGF-I is considered to be the biologically active hormonal form of total IGF-I [5].
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Section snippets
The decline of IGF-I with age
Borofsky et al. previously demonstrated that with aging, most of the variability of total IGF-I occurred between individuals rather than within individuals [6]. They showed that within individuals, there was only a modest decline in total IGF-I during a 5 year period [6] (Figure 1). In line with this, it has recently been reported that within one individual total IGF-I, IGFBP-3, and their ratio show only small changes with age over time [7].
Although both total IGF-I and IGFBP-3 decreased across
Low IGF-I and longevity in experimental models
One of the prevailing concepts in the literature is that reduced circulating IGF-I levels are relevant and favorable to increase longevity by improving stress defenses and delaying the onset of age-related pathological conditions 10, 11. In many experimental models (Caenorhabditis elegans, Drosophila, and several strains of mice) an increased longevity has been found to be related to downregulation of the GH/IGF-I system [12]. However, longevity in experimental models is often only observed in
Low IGF-I and longevity in humans
Understanding of how IGF-I is exactly involved in longevity and pathological conditions in humans is an important topic of ongoing research. In contrast to findings in many animal studies, reduced IGF-I activity/relatively low IGF-I activity has not consistently been found to be associated with longevity in humans. Reduced IGF-I activity/relatively low IGF-I activity has even been associated with inflammation and an increased risk of developing cardiovascular disease, diabetes, osteoporosis and
IGF-I, protein intake and mortality
A recent study performed in NHANES III showed that participants aged 50–65 years with a high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death during the following 18 years [22]. It was found that IGF-I was an important moderator of this association: for every 10 ng/mL increase of IGF-I, the mortality risk of cancer among subjects 50–65 yrs was increased by an additional 9% in the high protein group compared to the low protein group [22]. In contrast,
Changes of IGF-I in time and longevity
Recently, it has been suggested that in order to fully understand the effects of IGF-I on longevity, one must measure the trajectory of IGF-I levels in time, i.e. the way IGF-I changes over time [18]. In other words, changes of IGF-I levels over time in an individual may provide more insights about the relevance of IGF-I for health- and lifespan of that individual than measuring IGF-I levels one-time (at baseline of the study). It has been hypothesized that, irrespective of the actual level of
Circulating IGF-I receptor stimulating activity and longevity
One of the major functions of IGFBPs is to modulate the biological activity of circulating IGF-I. Aging is usually characterized by a decrease in the circulating concentrations of IGFBP-3 and simultaneously an increase in the concentrations of IGFBP-1, IGFBP-2 and IGFBP-4 [28]. In most studies investigating the possible relationship between IGF-I and longevity, immunoassays were used to assess circulating total IGF-I levels. However, the commonly available IGF-I immunoassays use an extraction
Paracrine IGF-I and longevity
Physical exercise may be vital to the maintenance of the GH-IGF-I axis with aging. It may help to restore loss of activity of the endocrine/paracrine system with aging 33, 34. Recently it was reported that combined sprint and resistance training is able to abrogate age differences in somatotropic hormones [35]. Mechano growth factor (MGF), a locally produced isoform of IGF-I, has been hypothesized to be important for the maintenance of skeletal muscles with aging 33, 36.
Pregnancy-associated
Conclusions
In conclusion, although in many experimental models an increased longevity has been found with downregulation of IGF-I activity, in humans low IGF-I has not consistently been found to be associated with longevity. In order to fully understand the effects of IGF-I on longevity in humans, nutritional intake, the trajectory of circulating IGF-I levels across life time and paracrine effects of IGF-I should be taken into account. The measurement of IGF-I receptor stimulating activity by the IGF-IR
Conflict of interest statement
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