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. Author manuscript; available in PMC: 2017 Jun 14.
Published in final edited form as: Cell Metab. 2016 Jun 14;23(6):980–989. doi: 10.1016/j.cmet.2016.05.014

The somatotropic axis in human aging: Framework for the current state of knowledge and future research

Sofiya Milman 1,2, Derek M Huffman 1,3, Nir Barzilai 1,2,4
PMCID: PMC4919980  NIHMSID: NIHMS791172  PMID: 27304500

Summary

Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life and health-span across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicates that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases. We propose that studies in humans and animals need to consider differences in sex, pathway function, organs, and time-specific effects of GH/IGF-1 signaling in order to better define the role of the somatotropic axis in aging. Agents that modulate signaling of the GH/IGF-1 pathway are available for human use, but before they can be implemented in clinical studies that target aging and age-related diseases, researchers need to address the challenges discussed in this review.

Introduction

A growing body of evidence points to the importance of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling pathway in the regulation of aging and disease. Although the beneficial effects of attenuated GH/IGF-1 signaling on lifespan and some aspects of healthspan in invertebrates (Kenyon et al., 1993) and rodents (Brown-Borg et al., 1996; Ikeno et al., 2003) have long been recognized, only recently have similar benefits been observed in humans (Guevara-Aguirre et al., 2011; Milman et al., 2014; Suh et al., 2008; van der Spoel et al., 2015). GH and IGF-1 levels change throughout the human lifespan. Circulating GH/IGF-1 levels peak in the 2nd decade of life, a time of considerable cell proliferation and linear growth, but then rapidly decline until the 6th decade, at which time levels plateau (Yamamoto et al., 1991). The effect of this age-related decline in the somatotropic hormones on health in humans is complex and remains unresolved, though there is consensus among scientists that GH replacement is not a viable treatment option in the older adult population.

Data is accumulating from dwarf humans (Guevara-Aguirre et al., 2011) and individuals with exceptional longevity (Milman et al., 2014; Suh et al., 2008; van der Spoel et al., 2015) about the potential beneficial effects of attenuated somatotropic signaling on human lifespan and healthspan, yet results of epidemiological studies remain inconclusive. This ambiguity stems from several shortcomings of epidemiological studies, such as failure to account for sex, age, organ-specific effects and function, rather than levels of GH/IGF-1. Although it is possible to target the GH and/or IGF-1 signaling pathway in humans with pharmaceutical agents, many important questions remain unanswered. At what point in the lifespan and for what duration and magnitude would attenuating the GH and/or IGF-1 pathway impact aging? Does an early decline in somatotropic hormones reflect premature aging or enhanced adaptation to and protection from the consequences of aging? Are there organ-systems in older adults that might suffer detrimental effects from reduced IGF-1 signaling? How are these effects expected to differ between males and females? Is it a reduction in GH, IGF-1 or both that is necessary to achieve these effects? What is the contribution of environmental factors, such as nutrition, to the function of the somatotropic axis? We focus our review on the current state of knowledge about the role of the somatotropic axis in human aging and present some supporting data from animal studies in an effort to establish a framework to guide future research in addressing the knowledge gaps in this area of science.

Regulation of the GH/IGF-1 pathway in humans

GH is secreted from the anterior pituitary gland in pulses, in response to stimulation by growth hormone releasing hormone (GHRH), ghrelin, and dietary stimuli such as protein. GH secretion is inhibited by IGF-1 in a feedback loop, as well as by somatostatin, and other neuroendocrine signals, including insulin (Ceda et al., 1985), which act by binding to their respective receptors. While GH is a major regulator of hepatic IGF-1 expression, IGF-1 is also regulated and secreted by other organs in an autocrine/paracrine manner(Stewart and Rotwein, 1996). Insulin has also been shown to potentiate hepatic IGF-1 secretion in response to GH via up-regulation of GH receptors (Leung et al., 2000). IGF-1 initiates complex intracellular signal cascades through binding to the high-affinity IGF-1R on the cell surface(Holly and Perks, 2012) and activating the phosphorylation of the insulin receptor substrate (IRS) molecules, the (phosphoinositide 3-kinase) PI3K-Akt pathway, and the mitogen activated protein kinase (MAPK) signaling cascade, controlling multiple functions including the mechanistic target of rapamycin (mTOR) activity and FoxO translocation (Taniguchi et al., 2006). IGF-1 is bound to a family of six structurally related binding proteins, termed IGF-binding proteins (IGFBP-1 to 6) that sequester IGF-1 in high-affinity complexes. Hepatic production of IGFBP-1 is under the negative control of insulin and it is inversely correlated with IGF-1 levels, while IGFBP-3 production is under positive regulation of GH (Holly and Perks, 2012). IGFBP-1 circulates in small concentrations, whereas IGFBP-3 is the most abundant of these binding proteins. In circulation, most IGF-1 is bound to IGFBP-3 as part of a 150 kD ternary complex involving a third protein, the acid-labile subunit (ALS)(Holly and Perks, 2012). This highly regulated process protects IGF-1 and IGFBPs from rapid degradation or elimination from the serum and keeps the circulating concentrations of biologically active, un-complexed ‘free’ IGF-1 at relatively low levels (Baxter, 2000; Rajaram et al., 1997). Of note, some of the IGFBPs exhibit actions that are independent of IGF-1 and impact functions such as glucose metabolism (Kim et al., 2007; Muzumdar et al., 2006) and cell-cycle (Cobb et al., 2009). With aging, the amplitude and frequency of GH pulses decline, resulting in decreased circulating IGF-1 levels (Rudman et al., 1981). However, the impact of this decline on autocrine production of IGF-1 by brain and peripheral tissues in humans is unknown.

Human “models” of GH/IGF-1 attenuation and aging

Humans with genetic variations or mutations within the GH/IGF-1 pathway serve as models for understanding the relationship between the somatotropic axis, health, and longevity. Individuals with non-functional GH receptor (GHR), resulting from a mutation in the GHR gene (Laron dwarfs), manifest a significantly reduced risk of developing cancer, stroke, and type 2 diabetes mellitus (T2DM) (Guevara-Aguirre et al., 2011; Steuerman et al., 2011). Nonagenarian female carriers of genetic polymorphisms that attenuate the action of the GH/IGF-1 pathway exhibit longer survival (van Heemst et al., 2005). Likewise, individuals with exceptional longevity are enriched with functional mutations in the IGF1R gene, which confer partial IGF-1 resistance (Suh et al., 2008; Tazearslan et al., 2011). Variants in AKT1 and FOXO3A genes, which are elements of the GH/IGF-1 signaling pathway, have been identified in long-lived individuals from several different cohorts of diverse ethnic backgrounds, although their functional role has not yet been defined (He et al., 2014; Pawlikowska et al., 2009). Furthermore, centenarians exhibit a higher than age-predicted level of a specific microRNA, hsa-miR-363*, which regulates AKT1 and IGFBP-5 (Gombar et al., 2012). This indicates that posttranslational regulation of the GH/IGF-1 axis may also play a role in longevity. However, since carriers of these variants have been exposed to reduced activity in various signaling or downstream effectors of this pathway throughout the lifecourse, the question of whether these beneficial effects require developmental exposure or could be alternatively achieved by pharmacologic interventions at later ages remains unresolved.

Humans with exceptional longevity serve as models of successful aging. Aging is the major underlying risk factor for numerous diseases, including cardiovascular disease (CVD), cancer, diabetes mellitus type 2 (T2DM), and dementia. Yet, centenarians demonstrate a significant delay in the onset of most age-associated diseases and frequently escape from disease altogether (Andersen et al., 2012). Circulating IGF-1 levels have been inversely correlated with survival in those with lifespan extending into the tenth decade and beyond. Our group demonstrated that lower IGF-1 levels can predict extended survival in Ashkenazi Jewish female nonagenarians and nonagenarians of both sexes with a history of cancer (Milman et al., 2014). In Dutch nonagenarians of both sexes, the hazard of death was 27% lower among those with IGF-1/IGFBP-3 ratios in the first quartile compared to those in the fourth quartile (van der Spoel et al., 2015). Furthermore, those with the lowest IGF-1/IGFBP-3 demonstrated higher scores on performance of activities of daily living (ADL) (van der Spoel et al., 2015). Such evidence suggests that diminished function of the GH/IGF-1 axis may be beneficial to human aging and promotes longevity by conferring protection against age-related diseases and dysfunction.

GH/IGF-1 axis and age-related diseases

A number of human studies now support the notion that attenuation of GH/IGF-1 signaling may protect from age-related diseases and functional decline. This evidence is more robust for several site-specific cancers, but remains equivocal when it comes to cardiovascular disease, T2DM, and neurodegenerative conditions. On the other hand, age-related osteoporotic bone loss is offset by higher circulating IGF-1 levels, but this effect may be sex and age specific. Below, we review the available evidence from human and animal studies that associate the GH/IGF-1 axis with age-related diseases and mortality.

Neoplastic diseases

Epidemiological evidence reveals that higher levels of circulating IGF-1 are associated with future increased risk of multiple cancers in human populations (Cao et al., 2015; Key et al., 2010; Renehan et al., 2004; Rinaldi et al., 2010). Mechanistically, IGF-1 is believed to promote malignancy by activating downstream signaling via the IRS/Akt/MAPK pathway, which promotes cell growth and proliferation (Novosyadlyy and Leroith, 2012). The evidence linking IGF-1 and cancer in humans is strongest for breast (Key et al., 2010; Renehan et al., 2004) and prostate cancer (Cao et al., 2015; Renehan et al., 2004; Rowlands et al., 2009), while moderate evidence exists for a relationship with colorectal cancer (Rinaldi et al., 2010). However, the association of IGF-1 and lung cancer is equivocal (Cao et al., 2012; Renehan et al., 2004). Additionally, IGFBP levels have been related to cancer risk. Higher IGFBP-3 level has been linked to breast cancer (Renehan et al., 2004), whereas lower IGFBP-1 was associated with reduced risk for prostate cancer (Cao et al., 2015).

The role of GH per se on cancer risk in humans is less clear. Patients with acromegaly, characterized by excess GH secretion, have been noted to have an increased risk of multiple cancers, including colon, thyroid, and prostate (Boguszewski and Ayuk, 2016), while Laron dwarfs appear to be protected from malignancy (Guevara-Aguirre et al., 2011; Steuerman et al., 2011).. However, alterations in GH signaling are also accompanied by concurrent changes in IGF-1 and insulin levels. This relationship has made it challenging to characterize the independent contribution of GH to aging and diseases of aging, though recent generation of animal models with extrahepatic targeted deletion of GH receptors (GHR) represent a significant step forward in overcoming these limitations to better clarify the role of GH (Jara et al., 2016; List et al., 2015).

Numerous studies in rodents have demonstrated the importance of GH, IGF-1 and insulin to tumorigenesis (Ikeno et al., 2003). Indeed, caloric restriction (CR), which reduces GH/IGF-1 and insulin levels in rodents (Breese et al., 1991), potently retards tumor transformation and progression (Huffman et al., 2007; Reddy et al., 1987). Moreover, replacing GH or IGF-1 completely abrogated the protective effects of CR on carcinogenesis (Hursting et al., 1993). Furthermore, pre-clinical studies employing IGF-1R antibodies have proven effective in retarding cancer progression (Fahrenholtz et al., 2013; Galet et al., 2013), though its use as a monotherapy in clinical trials for advanced stage cancers were not as successful (Fuchs et al., 2015; Robertson et al., 2013). GH may impact tumor growth, independent of circulating IGF-1, since deletion of hepatic Igf1 did not reduce prostate tumor progression in mice (Anzo et al., 2008), although the LID model used to generate this deficiency is also markedly insulin resistant (Haluzik et al., 2003). Human cancer cell lines, and in particular metastatic melanoma cell lines, express GHR, with some lines displaying increased proliferation in response to GH (Sustarsic et al., 2013). Whether these effects on cancer progression are directly mediated by GH or via GH-stimulated local production of IGF-1 remains to be determined. It should also be noted that whole body, rather than tissue-specific modulation of IGF-1 or its receptor, impact on GH secretion and insulin sensitivity, may explain some differences in findings between systemic and tissue specific models.

Several analyses of cancer-associated mortality and circulating IGF-1 levels in humans have revealed a U-shaped relationship, with both lowest and highest levels of IGF-1 associated with greater hazard of cancer-related mortality (Burgers et al., 2011; Svensson et al., 2012). Yet, not all studies have confirmed this association, with many finding no link between IGF-1 and cancer-specific mortality (Friedrich et al., 2009; Saydah et al., 2007; van Bunderen et al., 2010). However, it is important to note that several of these studies have analyzed data from individuals over a wide age range, beginning as young as 20 years old (Friedrich et al., 2009; Saydah et al., 2007), without regard for the possibility that the relationship between IGF-1 and mortality may differ significantly according to age group. One study identified a positive correlation between self-reported protein intake and circulating IGF-1 level in people age 50–65 from the National Health and Nutrition Examination Survey III (NHANES III), with consumers of a high protein diet having a 4-fold increased risk in cancer mortality over 18-years of follow-up compared to those who consumed a low-protein diet (Levine et al., 2014). However, protein consumption did not correlate with IGF-1 levels in individuals age 66 and older in that study (Levine et al., 2014).

Cardiovascular disease

The relationship between cardiovascular disease, cardiovascular-associated mortality and IGF-1 levels in humans is conflicting. Higher levels of circulating IGF-1 have been positively correlated with risk for congestive heart failure (Andreassen et al., 2009), but not consistently across studies (Vasan et al., 2003). No significant association has been found between IGF-1 and future risk for cardiovascular events, such as myocardial infarction or stroke (Andreassen et al., 2009; Kaplan et al., 2007; Ricketts et al., 2011). On the other hand, several population studies have found about 1.5–2 times increased risk for cardiovascular mortality among individuals with lower circulating IGF-1 levels (Friedrich et al., 2009; Juul et al., 2002; Laughlin et al., 2004; Svensson et al., 2012). Analysis of data from NHANES III did not find a significant association between IGF-1 levels and cardiovascular mortality (Saydah et al., 2007), whereas a population study of older individuals in the Netherlands and a meta-analysis revealed a U-shaped relationship between IGF-1 and cardiovascular mortality (Burgers et al., 2011; van Bunderen et al., 2010). Further, while data is far more limited, one study reported high IGFBP-3 was associated with greater risk of death from ischemic heart disease (Juul et al., 2002).

Animal studies examining the role of GH and IGF-1 signaling on the vasculature and myocardium have proven to be equally complex. GH transgenic mice have cardiac hypertrophy and increased fibrosis (Bollano et al., 2000), similar to humans with acromegaly who have excess circulating GH and IGF-1 (Lopez-Velasco et al., 1997), while GHRKO mice have generally normal cardiac function and less fibrosis with aging (Egecioglu et al., 2007). On the other hand, Lewis dwarf rats, which have GH and IGF-1 deficiency, have increased incidence of stroke and arterial stress (Csiszar et al., 2008; Ungvari and Csiszar, 2012). However, because these models cannot distinguish from concomitant changes in circulating IGF-1, a model was generated with targeted disruption of GHR in cardiomyocytes (Jara et al., 2016); yet, no alteration in cardiac performance was observed in this model. In contrast, cardiac specific deletion of IGF-1R in adult mice was shown to impair diastolic function, while adult onset IGF-1 deficiency mice demonstrated multiple impairments in cardiovascular function (Bailey-Downs et al., 2012; Li et al., 2008). Collectively, these data suggest that IGF-1R signaling is most critical to cardiac structure and function (Moellendorf et al., 2012).

Animal models suggest that IGF-1 may protect from endothelial dysfunction and reduce pro-inflammatory signaling, thereby contributing to protection form cardiovascular disease (Higashi et al., 2012). In contrast, others have observed that whole-body haploinsufficiency or conditional deletion of the IGF-1R gene in endothelial cells resulted in beneficial effects on endothelial nitric oxide synthase (eNOS) phosphorylation (Abbas et al., 2011) and vascular wall repair (Yuldasheva et al., 2014). Interestingly, Ames hypopituitary mice, which are deficient in circulating GH/IGF-1, manifest delayed aging, yet they exhibit increased vascular oxidative stress (Csiszar et al., 2008). While these studies, particularly the recent inclusion of conditional models, have shed greater insights into the role of GH versus IGF-1 signaling on the cardiovascular system, it should be noted that the vast majority of studies have been performed in young, male rodents. Moving forward, age and sex differences, as well as timing of deficiencies, should be carefully considered in order to more clearly define the role of GH and IGF-1 signaling on the developing and aging myocardium and vasculature.

Diabetes Mellitus Type 2

The somatotropic axis is intricately linked to the insulin pathway and thereby glucose homeostasis. The insulin and IGF-1 signaling pathways are evolutionary conserved among species. Reduced signaling through these pathways results in lifespan extensions in both invertebrate and mammalian models. Unlike mammals, invertebrates have a single orthologue of the IGF-1 and insulin receptor that binds insulin-like peptides (Russell and Kahn, 2007). In mammals on the other hand, signaling through the IGF-1R and insulin receptor (InsR) converge at the PI3K-Akt and MAPK pathways (Novosyadlyy and Leroith, 2012; Russell and Kahn, 2007; Taniguchi et al., 2006). IGF-1 and insulin can each bind to the IGF-1R and InsR, although each ligand binds to its own receptor with 100 to 1,000 fold greater affinity (Novosyadlyy and Leroith, 2012). Furthermore, IGF-1R and InsR can combine to form heterodimers known as IGF-1R/InsR hybrids, and the expression of these hybrid receptors can account for a significant proportion of total receptor stoichiometry in some tissues, including heart, muscle and brain (Bailyes et al., 1997). Physiologically, IGF-1 has been shown to have similar effects as insulin both in the periphery (Hawkins et al., 1996) and in the brain (Muzumdar et al., 2006) to regulate glucose homeostasis, though centrally-acting IGF-1 proved more potent than insulin in regulating peripheral glucose fluxes in aging (Huffman et al., 2016).

Despite the integration of the two systems, prospective studies in humans that look at the risk of developing diabetes mellitus type 2 (T2DM) in association with the GH/IGF-1 axis are sparse. A prospective study of middle-aged men and women found that IGF-1 levels above the median were associated with 50% lower odds of developing impaired glucose tolerance or T2DM (Sandhu et al., 2002). Another study that looked at the risk of developing T2DM in middle-aged women did not find an association between T2DM and serum total IGF-1 level, but did note a negative association between IGFBP-1 level and T2DM (Rajpathak et al., 2012). This study also noted an increased risk for T2DM in women in the highest quintile of IGFBP-3 compared to those in the lowest quintile (Rajpathak et al., 2012). The results of these cohort studies differ substantially from the findings in the Laron dwarfs (Guevara-Aguirre et al., 2011), in whom lifelong inactivity of GH and deficiency of IGF-1 is protective from T2DM, although the absence of GH action may be largely responsible for this protection. Indeed, while haploinsufficiency for the IGF-1R results in impaired glucose tolerance (Holzenberger et al., 2003), mice deficient in GH and IGF-1 (GHRKO) are more insulin sensitive (Al-Regaiey et al., 2005).

Neurodegenerative diseases

The association between circulating IGF-1 levels and cognitive function in humans remains an issue of current debate. One cross-sectional analysis showed that higher circulating IGF-1 level was positively correlated with cognitive function in older men, but not women (Al-Delaimy et al., 2009). Similarly, a separate analysis revealed an association between mild cognitive impairment and IGF-1 among individuals in the lowest quartile of IGF-1 levels (Doi et al., 2015). The results of prospective studies have been less inconsistent, with some suggesting poorer cognitive performance and increased risk of Alzheimer’s disease in individuals with lower IGF-1 levels (Okereke et al., 2007; Westwood et al., 2014). Meanwhile, another prospective study conducted in men revealed no association between cognitive function and circulating IGF-1 level (Green et al., 2014). On the contrary, a recent analysis of men older than 40 revealed that individuals with circulating IGF-1 levels in the top quintile at baseline demonstrated poorer processing capacity and global cognitive scores after an average of 8 years of follow-up (Tumati et al., 2016). Interestingly, a year-long supplementation trial with GH in postmenopausal women had no affect on memory (Friedlander et al., 2001). Despite the conflicting results related to circulating GH and IGF-1, the paracrine effect of locally-produced GH and IGF-1 in the CNS remains an important caveat for which little is currently known, and therefore should also be considered.

Studies in rodents focused on the IGF-1 axis have been most well studied, and have revealed that IGF-1 levels in circulation, CSF and brain tissue decline with advancing age in some strains, while expression of the IGF-1R in various regions of the CNS either increases, decreases, or remains unchanged (Ashpole et al., 2015; Huffman et al., 2016). Evidence regarding the role of local GH and IGF-1 in cognition is limited, but expression of GH and IGF-1 in the hippocampus of dwarf mice was found to be paradoxically increased, suggesting that maintenance of adequate IGF-1 levels in the brain may be critical to normal cognitive function in these mice (Sun et al., 2005). In addition to local production, the brain receives peripheral input of IGF-1 via a transport mechanism in the choroid plexus involving the low-density lipoprotein receptor-related protein 2 (LRP2) and the IGF-1R (Fernandez and Torres-Aleman, 2012), but some evidence suggests that IGF-1 input from CSF into the brain is impaired with aging (Muller et al., 2012). However, IGF-1 replacement targeting the CNS in aged rodents, can improve learning and memory. The exact mechanisms involved in this effect are not clear, but appear to involve the cerebrovascular system, neurovascular coupling, regulation of N-methyl-D-aspartate (NMDA) receptors, synaptic function, and synaptic plasticity (Ashpole et al., 2015; Sonntag et al., 2005; Toth et al., 2015). IGF-1 may also influence cognition in aging via its effect on neurogenesis (Lichtenwalner et al., 2001). In contrast, some evidence in nematodes suggests that insulin/IGF-1 signaling may actually inhibit regeneration in aging neurons (Byrne et al., 2014). Similarly, knocking out the IGF-1R in the rodent brain has been linked to protection against various neurological conditions and functions (Chaker et al., 2015; Gontier et al., 2015). Thus, the role of IGF-1 in the brain is highly complex and to fully understand it will likely require a better appreciation of not only the site(s) of action, but also its specific role in the context of the aging central nervous system.

Osteoporosis

Decreased bone mineral density (BMD) that results in bone fragility, termed osteoporosis, leads to increased risk of fracture and often presents as a manifestation of aging. Both GH and IGF-1 regulate bone metabolism through endocrine and paracrine/autocrine signaling. GH induces IGF-1 production by osteoblasts. IGF-1 affects osteoblast differentiation and bone mineralization. Parathyroid hormone also contributes to IGF-1 gene transcription in bone. Although the role of GH/IGF-1 axis on bone mineral density maintenance has long been accepted, the relative contribution of GH and IGF-1 to skeletal acquisition remains difficult to interpret, particularly as it may differ between the sexes (Liu et al., 2016). Several cross-sectional studies conducted in older populations have found a positive correlation between IGF-1 levels and BMD specific to women or men only (Janssen et al., 1998; Langlois et al., 1998). Prospective analysis confirmed a similar association in women (van Varsseveld et al., 2015). Low IGF-1 level has been linked to increased risk of future fracture in men and women, although not all studies have shown consistent sex-specific effects (Ohlsson et al., 2011; van Varsseveld et al., 2015; Yamaguchi et al., 2006).

Interestingly, recent evidence in a mouse model of inducible IGF-1 deficiency suggests that low IGF-1 levels early, but not later in life, led to reductions in cortical bone structure and strength in both males and females, though shifts in trabecular bone were only observed in males (Ashpole et al., 2016). Similarly, Gong et al observed that IGF-1 deficiency, despite an excess of GH, led to compromised skeletal integrity and accelerated bone loss (Gong et al., 2014). In contrast, restoration of endocrine IGF-1 was insufficient to restore skeletal integrity in the absence of GHR, suggesting that both GH and IGF-1 are required for normal skeletal development and integrity (Wu et al., 2013). Therefore, in designing age-delaying strategies targeting the GH/IGF-1 axis, it will be critical to consider the importance of both hormones, as well as ramifications of age, sex and other factors on the skeletal system.

All-cause Mortality

Defects in the somatotrophic axis have been linked to longevity in invertebrate and rodent models (Bokov et al., 2011; Brown-Borg et al., 1996; Kenyon et al., 1993; Xu et al., 2014). While several models of combined GH and IGF-1 deficiency have been linked to improved longevity in males and females, the effect of isolated IGF-1 or IGF-1R deficiency has often been sex-specific, with females, rather than males, demonstrating improved survival (Holzenberger et al., 2003; Xu et al., 2014). Despite lower IGF-1 being predictive of extended survival in individuals with exceptional longevity (Milman et al., 2014; van der Spoel et al., 2015), its association with all-cause mortality in the general population remains inconsistent. Several assessments in older adult cohorts have found increased hazard of death among people with lower IGF-1 levels (Roubenoff et al., 2003; van Bunderen et al., 2010), although a study in men did not find consistent results (Maggio et al., 2007). A population-wide study found no association between IGF-1 levels and all-cause mortality (Saydah et al., 2007). There was also no association between the rate of IGF-1 decline over time and mortality in a cohort aged 77 and older (Kaplan et al., 2012). A number of analyses conducted in middle aged and older populations demonstrated a positive association between IGF-1 levels and mortality, with several revealing a U-shaped relationship (Andreassen et al., 2009; Burgers et al., 2011; Svensson et al., 2012).

Unraveling the Inconsistencies

As exemplified above, much of the knowledge about the affects of the GH/IGF-1 axis on age-associated diseases and aging in humans remains inconsistent. Several aspects of this controversy could potentially be unraveled by employing innovative study approaches in human populations. In addition, novel animal models can help to expand our understanding of GH/IGF-1 related mechanisms that impact human aging and disease. In the following sections we highlight several important issues that should be addressed through epidemiological, clinical and basic research. We also propose methodologies that can be employed to clarify some of the uncertainties. Only after these issues are better addressed can clinical trials that target the somatotropic axis be considered as a strategy to delay aging and its diseases.

Consideration of temporal factors that mediate the effect of GH/IGF-1 on disease and lifespan

Aging researchers recognize that the effect of a hormone may differ dramatically in a youthful organism compared to an older one. The concept of antagonistic pleiotropy, which posits that some factors may have been evolutionarily selected due to beneficial effects for growth and reproduction, yet could have harmful effects later, may be highly relevant to the somatotropic axis. Indeed, whereas sufficient levels of GH/IGF-1 are beneficial for the development and growth in the young, they may be detrimental to an aging organism by attenuating putative stress resistant pathways and accelerating malignancy. Whether a “switch” from beneficial to harmful exists for GH and IGF-1, and at what point in the lifespan it occurs remains unknown. IGF-1 is required for normal brain development (Liu et al., 2009) and appears to play an important role in cardiovascular health and bone acquisition, but persistently high circulating IGF-1 levels throughout mid and late life may come at the expense of greater risk for malignancy (Renehan et al., 2004). Therefore, when analyzing data on IGF-1 it is important to stratify analysis by age rather than pool all ages. Statistically adjusting for age does not satisfy this need because it assumes a linear relationship between age and IGF-1, whereas the true relationship may actually be positive during youth and inverse thereafter.

Other important questions center on the duration of exposure to increased or diminished GH/IGF-1 levels that is required for the onset of the beneficial age-associated effect and in what organ-systems these pathways should be targeted. Furthermore, lower IGF-1 levels may serve as either a protective mechanism during aging or a sign of accelerated aging. Low circulating IGF-1 level can be induced by illness, malnutrition, and debilitation; thus in cross-sectional analyses poor health status would be linked to lower IGF-1. Thus prospective studies in humans and animals are necessary to answer many of these questions.

Sexual dimorphism in GH/IGF-1 action

It is now becoming increasingly recognized that the effects of GH, and particularly IGF-1, on physiology, disease and survival are sex-specific (Bokov et al., 2011; Holzenberger et al., 2003; Milman et al., 2014; Xu et al., 2014). This has been observed to varying degrees in lifespan studies utilizing IGF-1R+/− animals (Bokov et al., 2011; Holzenberger et al., 2003; Xu et al., 2014), as well as disease-specific analyses in rodent models and humans (Liu et al., 2016; Milman et al., 2014; Wang et al., 2006). Going forward, sex stratification should be employed in all studies looking at the effects of the somatotropic axis in aging and disease. Furthermore, uncovering the mechanism(s) involved in these sexually-dimorphic effects on aging phenotypes should be a priority for future investigations in humans and animal models in order to enable tailored approaches to modulate these pathways in males and females. This can be further enhanced by studies addressing the potential role of sex steroids on the response to GH, IGF-1 and insulin signaling, with specific consideration of both developmental and later life exposure to androgens and estrogen.

Addressing the apparent paradoxical effect of GH/IGF-1 in different organs and diseases

IGF-1 functions both as a circulating endocrine hormone and as a paracrine/autocrine signaling molecule. Detectable circulating IGF-1 levels may not be reflective of the concentration of IGF-1 at the tissue level, where it may be locally produced and exert paracrine and autocrine function. In fact, Ames dwarf mice, which are deficient in circulating GH and IGF-1, among other hormones, have elevated levels of hippocampal GH and IGF-1 (Sun et al., 2005). Similarly, some cohorts of Laron dwarfs who exhibit GH insensitivity appear to have normal cognitive function, presumptively resulting from local production of IGF-1 in the brain (Kranzler et al., 1998). Based on this evidence we propose that declining circulating levels of IGF-1 may lead to greater local tissue production of IGF-1 as a result of loosened negative feedback that may be exerted by circulating IGF-1. This may explain how different organ systems that have varying IGF-1 requirements may maintain optimal function despite systemic decline in circulating IGF-1.

Alternatively, the beneficial health effects of higher circulating IGF-1 may be age dependent. As mentioned above, GH and IGF-1 regulated bone accrual was observed only in younger animals, but not in the older rodents (Ashpole et al., 2016). Thus, the age-associated decline in GH/IGF-1 levels may results in protection from malignancies without compromise of the musculoskeletal system in the aged individuals. Furthermore, the effect of IGF-1 on disease incidence or progression may differ depending on the underlying health of the organ in question. Gaining a better understanding of the production and regulation of tissue specific IGF-1 in humans is important for clarifying the physiology. Although some experiments may be prohibitive in humans, studies conducted in other model organisms may inform our understanding.

Genetic and functional approaches to resolve epidemiologic uncertainty

While lower IGF-1 levels are strongly associated with protection from various types of cancer and increased risk of osteoporosis, the effect of attenuated IGF-1 function on CVD, T2DM, dementia, and mortality remains inconclusive. This uncertainty, in part, results from observational studies that pool diverse groups of people based solely on the circulating IGF-1 phenotype (e.g. level of circulating IGF-1), not accounting for the individual genotypes that might impact on the response to this ligand. This approach would have resulted in the cohort of centenarians harboring functional IGF-1R mutation(s), which causes elevation in the IGF-1 level, to be grouped together with all other individuals with elevated IGF-1 levels, despite evidence that carriers of this mutation demonstrate IGF-1 resistance and decreased IGF-1 function (Suh et al., 2008; Tazearslan et al., 2011). These functional differences are not reflected in simple measurements of IGF-1 levels, but can be deduced from the genome coupled with functional assays and models. Transgenic animal models that harbor mutations or genomic variants identified in humans would help characterize the function of these genetic elements and assist with proper characterization of subjects, as was demonstrated by our group (Tazearslan et al., 2011). Thus future epidemiologic or experimental studies should consider phenotyping other components related to the IGF-1 response in addition to IGF-1, which should result in more accurate subject characterization and study conclusions. This novel approach will foster a more physiologically relevant assessment of the role of IGF-1 in age-associated diseases and longevity.

Unique populations serving as human “models”

Understanding the role of GH/IGF-1 on aging by utilizing human “models,” as described above, is unparalleled. Through studying the genetic make-up of centenarians, who are prototypes of healthy aging, one can uncover the effects of genomic variations that modulate the GH/IGF-1 system on healthspan and lifespan without following an individual for a lifetime. Furthermore, by studying the offspring of centenarians, who inherit, at least partially, the centenarian genome, permits one to validate prospectively the effect of these candidate genes against an age-matched control group.

Contribution of environmental factors to the regulation of the somatotropic axis

Certain environmental factors have also been shown to influence IGF-1 levels. Animal protein intake has been linked to higher circulating IGF-1 levels in individuals age 50–65 years (Levine et al., 2014). On the other hand, prolonged fasting was associated with reduction in IGF-1 levels, although moderate caloric restriction of 9% in humans has not been shown to reduce circulating IGF-1 (Fontana et al., 2016). Hormone replacement therapy in women may also modulate IGF-1 and IGFBP levels (Posaci et al., 2001). These factors should be considered in future studies.

Future Directions

Therapeutic modalities that attenuate GH/IGF-1 signaling

A number of available therapeutics that have been designed for human use can block the signaling of the GH/IGF-1 pathway. These include somatostatin analogs, growth hormone receptor antagonists and anti-IGF-1R antibodies. The effect of these agents on health and lifespan is currently being investigated in several different experimental models. Future studies conducted in humans and animal models should focus on elucidating the highlighted uncertainties that currently surround the association between GH/IGF-1 axis and aging. Only after these questions have been answered can we consider therapeutic trials in aging humans.

Consideration of other health-related outcomes

The impact of modulating GH/IGF-1 signaling on human health should not only consider effects on diseases per se, but also on health-span, robustness against common stressors encountered with aging and maintenance of independent function. Indeed, data from rodent models of GH and/or IGF-1 deficiency suggest improved stress resistance (Wang and Miller, 2012). Furthermore, evidence from long-lived humans indicates that lower IGF-1/IGFBP-3 ratio is related to improved performance of activities of daily living (ADLs) (van der Spoel et al., 2015). On the other hand, recent data from long-lived c. elegans daf-2 mutants suggests that a significant proportion of their lifespan is spent in suboptimal functional status (Bansal et al., 2015). Thus, these important outcomes should also be considered.

Here, we have laid out a framework for research that is needed to address the knowledge gaps surrounding the somatotropic axis and its impact on aging. Animal models can specifically be utilized to help clarify questions arising from human studies, where human studies would not be feasible. However, the utility of rodents as a model of IGF-1 and age-related disease should consider important limitations, including the fact that mortality is typically attributable to malignancy and renal disease in rats and mice, where IGF-1 may have harmful effects with age. In contrast, aging humans commonly suffer from cardiovascular disease, dementia, T2DM and osteoporosis, ailments where the role of IGF-1 is less defined. Finally, little is known about the role of other IGF axis components on aging biology, including IGF-2, despite the fact that circulating levels of this related ligand are several fold greater than IGF-1 in humans. Beyond its importance to development, evidence suggests a potentially important role in malignancy and cardiovascular disease, but its relevance to other diseases is not known. Certainly, the fact that adult rodents lack circulating IGF-2 has impaired progress in our understanding of this hormone (Bergman et al., 2013).

Conclusion

Genomic studies in humans and animals reveal a beneficial impact of attenuated IGF-1 action on several age-related diseases and lifespan; thus, bringing into question the assertion that the decline in circulating IGF-1 levels during aging are inherently detrimental. Despite the aforementioned evidence from dwarf humans and individuals with exceptional longevity, the results from epidemiological studies have not provided the same degree of clarity on these relationships. The inconsistencies among human study results are disease-specific, with reduced incidence of site-specific cancers clearly associated with low IGF-1 levels, while relationships with CVD, T2DM and cognitive decline are less consistent. These discrepancies partially stem from research methodological factors, including the lack of sex and age stratification in the analysis, functional and organ-specific characterization of the GH/IGF-1, and limited information regarding the degree of modulation observed in these pathways. An interdisciplinary approach will be required in order to better characterize the role of GH/IGF-1 in humans. Such an approach will require an increased emphasis on controlling for factors highlighted above in human investigations, while utilizing studies in model organisms to better recapitulate the pleiotropic actions of these hormones across cells and systems. Such efforts will be necessary to successfully translate approaches to modulate the GH/IGF-1 axis to promote healthy aging in humans.

Acknowledgments

This work was funded by 1K23AG051148-01 (S.M.), American Federation for Aging Research (S.M., D.M.H.), R00AG037574 (D.M.H.), Grants from the National Institutes of Health (P01AG021654) (N.B.), The Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072) (N.B.), the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation for Medical Research) (N.B.), NIH R37 AG18381 (Barzilai Merit Award), and NIH/NIA 1 R01AG044829 (PIs-Veghese/Barzilai).

Footnotes

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