Growth Hormone, Not IGF-1 Is the Key Longevity Regulator in Mammals

There are extraordinary examples of evolutionary conservation in biology, one of which is revealed in aging biology. A robust case in point are three interrelated endocrine systems that have been linked to longevity: the growth hormone (GH), insulin (INS), and insulin-like growth factor (IGF) pathways. As far down the evolutionary ladder as yeast, there is strong evidence that a carbohydrate regulatory system exists and that if perturbed, life-span extension is observed (1). As one moves up the rungs of the ladder to nematodes and fruit flies, both insulin and IGF become important in the maintenance of metabolism (Figure 1). Like yeast, when levels or activity of ligand, receptor or cognate signaling factors in these pathways are disrupted (ie, nematode age-1, daf-2; Drosophila InR, chico), an extension of life span is observed (2–6). In the mammalian system, the endocrine system becomes more complex with the addition of GH, a hormone that controls circulating IGF-1 levels and thus has somatic actions yet also exhibits key metabolic functions that are independent of IGF-1 (7–9). Disturbing the GH pathway by severely reducing plasma levels or by receptor disruption significantly extends health span and life span in mice (10–13). Elevating these findings to the more advanced mammals, humans, as with many biological tenets has added complexity for a variety of reasons.

Figure 1.

Growth hormone (GH) is a multifunctional hormone in mammals that drives growth and metabolism. Reduced GH signaling results in enhanced cellular stress resistance and altered metabolism promoting delays in aging processes, lowering age-related disease incidence and progression, and extending life span. Disrupted insulin and insulin-like growth factor (IGF)-like receptor signaling in invertebrates and yeast promotes life-span extension via altered metabolism and cellular defense. Created with BioRender.com.

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What is troublesome is that IGF-1 is very often cited as the key determinant of longevity in mammals. This is most likely due to the large body of evidence supporting the role of insulin and IGF-1 in longevity of yeast, worms, flies, and their presence in mammals. There is no question that IGF-1 is a major player in life-span determination in invertebrates. However, in mice, the data linking growth hormone with health-span and life-span regulation is far more robust yet often overlooked even though it regulates circulating IGF-1 production and secretion. The actions of these two closely linked hormones are not identical and sometimes opposite of one another.

Growth hormone is a pituitary-derived hormone that has both somatic and metabolic functions. The somatic actions of GH are mediated in part via the stimulation of liver IGF-1 secretion and its subsequent actions on bone, cartilage, and muscle. Somatic growth is driven by components of this pathway; therefore, body size differences are obvious in many GH/IGF-1 mutant mice as well as dogs and horses (14–18) and humans (19,20). Individual contributions of each hormone to body growth have been determined using knockout mice (21). This study estimated that GH accounted for 14%, IGF-1 contributed 35%, and the overlapping actions of both contributed to 34% of total postnatal growth in mice. Thus, in mammals, an intact GH/IGF-1 axis is required for normal growth (22). Along with growth, the proliferative drive (neoplastic growth, cancer) stimulated by growth-related hormones is also a consideration with little relevance in invertebrates. High levels of GH and IGF-1 are associated with tumor promotion and accelerated aging (23–28).

The metabolic activity of GH includes but is not limited to actions on glucose regulation, lipolysis, and oxidative metabolism. The actions of GH on glucose regulation and insulin signaling are well known. This hormone is considered a diabetogenic factor in that it counteracts the actions of insulin and promotes insulin resistance. GH elevates plasma glucose concentrations by stimulating gluconeogenesis and glycogenolysis and inhibiting glucose uptake at the tissue level. Humans and transgenic mice with elevated plasma GH levels exhibit hyperinsulinemia, hyperglycemia, and/or insulin resistance (29,30). Greater than 50% of humans with supraphysiological GH levels become diabetic and develop micro- and macrovascular complications associated with hyperglycemia. Whereas GH-deficient and GH-resistant animals exhibit low glucose, low blood insulin, and increased insulin sensitivity (31–34). In contrast to GH, IGF-1 has insulin-like effects and directly stimulates glucose uptake in skeletal muscle (35,36). Hepatocytes (liver) and adipocytes represent additional tissues of significance in glucose homeostasis and insulin signaling that are affected by GH directly, whereas these tissues lack IGF-1 receptors. Importantly, many of the actions of IGF-1 on glucose regulation are indirectly mediated via GH suppression indicating the overall contribution of GH on this key aspect of health and longevity in mammals.

Growth hormone has profound effects on lipid metabolism by promoting lipolysis and thus reducing fat mass; and the impact of GH on adiposity is distinct from that of IGF-1 (37,38). Differential effects of GH and IGF-1 are also observed on lipid parameters (39). High total serum cholesterol and triglyceride levels are observed in GH transgenic mice, mice treated with GH, and in humans with acromegaly, whereas IGF-1 treatment does not affect lipid levels (39–42). GH also increases apolipoprotein E, whereas IGF-1 does not (39). Thus, GH appears to directly affect aspects of lipid metabolism that affect health while IGF-1 lacks a direct action.

The role of GH on aspects of oxidative metabolism and stress resistance have been previously reviewed and indicate direct effects that would intuitively counter health and life-span extension (43). Evidence for the role of GH and GH receptor deficiency on immune metabolism and function are also emerging indicating GH signaling in the control of inflammation in aging (44,45).

A few key papers have examined the specific role of reduced IGF-1 signaling on life span in mice. An early report described studies in IGF-1R heterozygous mice indicating a 26% increase in life span (46). However, the wild-type mice in these studies only lived 18 months and these authors later reported that genetic background specifically affected the results as the life extension was very limited on a C57Bl/6 background (11% in females, no extension or shorter-lived in males; (47)). An additional study supported this finding demonstrating that male IGF-1 receptor heterozygous mice do not live longer than wild-type mice (nor do they exhibit differences in end-of-life pathology), and the extension of longevity in females was very modest (less than 5%; (48)). These investigators concluded that a reduction in circulating IGF-1 levels in mice plays little if any role in delayed aging and longevity.

Germane to this discussion, GH action is responsible for 70%–90% of circulating IGF-1 (49,50). Hepatic IGF-1 receptor gene deletion resulted in mice of normal body weight, length, and development. However, liver-specific GH receptor gene deletion produced mice with decreased body size, low IGF-1, impaired glucose metabolism, and hepatic steatosis (51). A reduction in IGF-1 signaling does not alter life span at nearly the levels observed in reduced GH signaling mutants (5% vs 40%–70%, respectively). In complete agreement, a metanalysis including 42 survival studies examined reduced somatotropic signaling (GH, IGF-1, insulin receptor substrate [IRS]) and found that mice with mutations that alter GH signaling exhibited greater relative reductions in mortality compared to those with mutations that affected either IGF-1 or IRS (52). This report concluded that reductions in GH signaling “robustly” increase median life span, exhibit low heterogeneity in the life-span response (5.6% vs IGF-1 34.1% and IRS 47.2%), and are not sex- or control strain-dependent (52). In contrast, reductions in IGF-1 signaling preferentially extend life span in females and short-lived strains of mice. Moreover, life span is not increased in transgenic mice expressing a GH antagonist where levels of circulating IGF-1 are decreased, and insulin levels and sensitivity are not altered (53). Overall, this evidence supports our work and others that strongly propose that reduced GH rather than the secondary reduction of IGF-1 provides beneficial effects on aging and is the key to longevity in mammalian systems perhaps through stress resistance, reduced inflammation, and insulin sensitivity.

In humans, these signaling pathways are relevant to biological aging with life-span implications that reveal more intricate relationships. Briefly, it is clear that genes within the somatotropic axis and downstream targets of these pathways influence aging and longevity (54–63). For example, studies of centenarians show that enhanced insulin sensitivity is strongly correlated with longevity and that exceptional longevity is associated with reduced IGF-1 (61,64–67). There are also differences in long-lived families indicating that less GH is secreted and is under tighter regulation (68). However, while neither lifelong GH deficiency nor GH resistance consistently extends human life span, they do result in major protection from diabetes, cancer, atherosclerosis, and other age-related diseases (69–74).

We also know that in the case of GH excess in both humans (acromegaly) and mice (transgene expression), life span is severely reduced (75–81). Edema, arthralgia, symptoms of carpal tunnel syndrome, and insulin resistance are among the detriments experienced by individuals administered GH (82). In GH transgenic mice, signs of premature aging are abundant and early death is related to kidney dysfunction and tumor development and progression (83–85). In contrast, IGF-1 transgenic mice do not experience such severe pathological changes as GH transgenic mice (86). Perhaps the natural age-related decline in plasma GH levels (14% per decade during adult human life) and the concomitant decrease in IGF-I that occurs in mammals is a protective mechanism to decrease metabolic activity and cellular division and increase autophagy (87,88).

Although IGF-1 is likely the major determinant of life span in invertebrates, it is GH that affects multiple physiological processes that significantly affect longevity in mammals. Keys that factor into the influence of growth hormone on longevity may be the major role it plays metabolically in vertebrate organisms stemming from the wide expression of GH receptors centrally and peripherally and its regulation of circulating IGF-1 levels among others. In addition, growth hormone’s influence on aging trajectories and longevity is not limited to early- or late-life actions (89,90).

The example provided is indicative of the need to read the literature, know the history, understand the physiology, and cite supportive work. Aging is a very complex field and we have so much more to learn! Let’s strive to discover more about these fascinating hormones and their role in aging biology.

What does it mean to be a Fellow of the Gerontological Society of America? To me, fellowship status in an association is the recognition by your scientific colleagues, your community of peers, that your contributions to the field have been impactful. Contributions not based solely on one’s research productivity but on your service, untold efforts, and time, that aimed to benefit the larger community composed of colleagues, trainees, as well as the public. That said, I believe that one’s training and experiences should be shared to connect and educate various groups, develop, and foster science communication, elevate our understanding of aging through research, all of which will improve/benefit our relationships between scientists, policymakers, and the lay public and reveal how important studying aging biology and gerontology is for all. Thus, I am appreciative of fellowship status in the Gerontological Society of America. My only issue with fellowship—is the word “fellow”—it is an antiquated, exclusive term.

Funding

This work was supported by the National Institutes of Health (AG067734 to H.M.B.-B.); and UND.

Conflict of Interest

None declared.

Author Contributions

H.M.B.-B. is the sole author of the manuscript. H.M.B.-B. drafted the text and created the accompanying figure.

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