Antagonistic pleiotropy: the example of cardiac insulin-like growth factor signaling, which is essential in youth but detrimental in age

KEYWORDS:

• Aging
• IGF-1
• insulin
• heart
• healthspan
• longevity

1. Introduction

Aging is a progressive and multi-faceted degenerative process afflicting virtually every cell and organ system across the human body [1,2]. Hence, age is by far the leading risk factor of morbidity, frailty, disability and death. Various theories and hypotheses have been suggested to explain the complex phenomenon of aging, with the aim to develop anti-aging therapies that might promote health and protect from age-related chronic diseases. The antagonistic pleiotropy theory is amongst the widely accepted theories for the evolutionary origin of aging [3], which argues that genes and molecular pathways that are beneficial for organismal fitness early in life often cause aging and age-related diseases late in life. The reasoning behind this is that modern civilization and its amenities, like unlimited access to nutrient resources as well as medical progress, drove human lifespan beyond evolutionary pressure and, hence, genes were selected without consideration of their consequences during aging. A more refined version of this theoretical framework later suggested that a trade-off exists between reproductive fitness and longevity. This idea, also known as the disposable soma theory [4], proposes that aging might emerge due to steering finite cellular energy resources away from maintenance and repair – which are essential to neutralize internal and external noxious events during the course of life – toward growth and reproduction. (For further details on the evolutionary theories of aging, we refer the readers to more comprehensive reviews on the topic [5,6].)

In this context, insulin-like growth factor-1 (IGF-1), which plays a key role in mediating growth and metabolism, has been implicated in regulating the rate of aging in a wide range of organisms [7]. In fact, low IGF-1 signaling is linked to extended longevity in worms, fruit flies and even mice [8]. However, the impact of reducing IGF-1 signaling on age-related diseases appears to be more complex. With the exception of cancer, inhibition of IGF-1 signaling has been shown to both improve and exacerbate experimental models of chronic human diseases [8]. Similarly, both supra- and infraphysiological levels of IGF-1 are associated with a higher risk of mortality and morbidity in humans [9,10]. Indeed, acromegaly – a condition characterized by an excessive production and activity of the growth hormone/IGF-1 axis – is accompanied by an increased mortality as well as by a large spectrum of cardiovascular diseases, including cardiac hypertrophy and dysfunction, valve disease, arrhythmias, hypertension and atherosclerosis [11]. By contrast, extremely low levels of IGF-1 in Laron dwarfs is associated with marked obesity, skin wrinkling, low bone density and reduced lean body mass [12], despite reduced risk of cancer and diabetes [13]. In sum, these observations demonstrate that modulating IGF-1 levels can result in both detrimental and beneficial effects.

2. Cardiac IGF-1 signaling: a case study of antagonistic pleiotropy

The controversy around the impact of IGF-1 manipulation might be resolved by a variety of different interpretations: (i) the impact of IGF-1 is context-dependent, meaning that depending on the life stage and health condition, IGF-1 might be beneficial or harmful, (ii) like any other essential molecule, IGF-1 has a narrow dynamic equilibrium and, thus, both its deficiency and hyperproduction are inherently detrimental, and/or (iii) circulating levels of IGF-1, that are commonly measured in cohort studies, do not necessarily reflect IGF-1 signaling activity in target tissues, meaning that a linear relationship does exist between IGF-1 and health, but is not accurately determined. All these hypotheses are testable using cell-specific manipulation of IGF-1 receptor (IGF-1R) signaling (not IGF-1 itself), along with a long-term follow-up of health and survival, at least in animal models.

Focusing on cardiac myocytes, as a prime example for which both harmful and beneficial effects have been reported in response to IGF-1 signaling manipulation [14,15], we examined the lifelong impact of such local, cell-targeted modulation of IGF-1 signaling [16]. Increasing IGF-1 signaling specifically in cardiac myocytes by overexpressing the human IGF-1R stimulated cardiac growth, leading to superior cardiac function and exercise capacity in young mice. However, later in life, aged IGF1-R transgenic mice (IGF-1R^tg) exhibited signs of accelerated aging in the form of maladaptive cardiac remodeling, characterized by increased left ventricular fibrosis, impaired relaxation and contractile dysfunction, coupled to left atrial dilation and lung congestion. Despite robust early-life cardiac benefits, the deleterious cardiac phenotype of aged IGF-1R^tg mice led to increased late-life mortality and shorter lifespan, lending support to the antagonistic pleiotropy theory of aging. Along similar lines, reduced cardiac IGF-1R signaling in mice harboring a dominant-negative p110α isoform of phosphoinositide 3-kinase (dnPI3K) – a key IGF-1R downstream effector – led to delayed cardiac growth and weaker cardiac function at a young age. Young mice expressing dnPI3K had even compromised cardiopulmonary functional capacity and an abnormally high risk of mortality in early life. In stark contrast, dnPI3K mice surviving to older age exhibited delayed cardiac aging, as indicated by superior cardiac systolic and diastolic functions, improved cardiac reserve capacity, reduced cardiac hypertrophy and extended longevity.

Mechanistically, the inverse relationship between cardiac IGF-1R signaling and cardiac health in aging appeared to be driven by its inhibitory effect on autophagy [17], which is a homeostatic process essential for protein and organelle quality control, particularly in post-mitotic cardiac myocytes [18,19]. Indeed, IGF-1R^tg mice exhibited reduced autophagic flux, which preceded the development of mitochondrial dysfunction and culminated in impaired myocardial bioenergetics and heart failure. Conversely, improved cardiac health upon reducing cardiac IGF-1R signaling in aged dnPI3K required active autophagic flux, as inhibiting autophagy using the lysosomotropic agent hydroxychloroquine abolished the cardioprotective effects of dnPI3K in these long-lived mice. Lending further support to this notion, reinstating autophagy in transgenic IGF-1R^tg mice using the autophagy inducer spermidine preserved cardiac function and protected them from imminent heart failure [20]. Taken together, these observations strongly suggest that an early benefit due to increased cardiac growth might occur at the expense of reduced autophagy-dependent cardiomyocyte maintenance later in life, which results in an accelerated age-related decline in cardiac structure and function.

3. Expert opinion

Altogether, these findings have major implications for the design of cardioprotective anti-aging interventions with respect to the onset of the treatment as well as to the choice of therapeutic agents. For instance, the use of IGF-1R monoclonal antibodies or any other approach that attenuates downstream signaling of IGF-1R using, for example, PI3K inhibitors should be reserved to grown up adults only, when cell growth is no longer a priority, but rather homeostatic and cell quality control mechanisms must be favored for organismal homeostasis. In this regard, it might be worth testing as to whether approaches combining IGF-1R inhibition with other inducers of autophagy can improve efficacy or at least circumvent the adverse effects associated with IGF-1 signaling inhibition [21,22]. Caloric restriction mimetics, like spermidine and nicotinamide, for which no antagonistic pleiotropy has thus far been described might be worth considering [23]. In fact, both compounds have shown anti-aging properties, which has been linked to autophagy, including in the context of cardiovascular disease [24–26]. However, it remains unknown whether IGF-1 is involved in their mechanisms of action and whether co-administration of spermidine or nicotinamide with IGF-1R antibodies would have any synergistic or additive cardioprotective effects.

Another important issue that should be considered is the complex, and potentially non-linear, relationship between the circulating levels of ligands and receptor activity in target tissues. For instance, we observed no correlation between plasma IGF-1 concentrations and IGF-1R signaling activity (such as phosphorylation of proteins in the AKT-mTORC1-S6K pathway) in the heart, irrespective of the animal model used [16]. Indeed, plasma levels of IGF-1 were almost identical in wild-type and transgenic mice with increased IGF-1R signaling (Figure 1). This has major implications on the reliability of circulating IGF-1 levels as a surrogate measure of IGF-1 signaling pathway activity, and might explain some inconsistent results in the field [27]. Thus, even though tissue samples might be limited and more challenging to acquire compared to plasma, especially in humans, direct assessment of IGF-1R signaling remains the most reliable method to determine the activity of this pathway. Of note, even local measurements of IGF-1 levels might be misleading and complex to interpret due to IGF-1R internalization and compensatory feedback mechanisms [28]. For instance, cardiac-specific IGF-1R^tg mice, which have clearly increased IGF-1 signaling, exhibit low IGF-1 levels in the heart (Figure 1).

Figure 1. Systemic and local changes in IGF-1 levels upon IGF-1 receptor overexpression in the mouse heart. Relative levels of plasma (left) and cardiac (right) abundance of insulin-like growth factor-1 in young wild-type (WT) and IGF-1 receptor-overexpressing mice (IGF-1R^tg), specifically in cardiac myocytes. Statistical significance assessed using Welch’s t test (ns, non-significant; ***p < 0.001) in GraphPad Prism 9. Bars and error bars show means and SD, respectively, of the indicated number of mice on the bars. Plot generated with data from [16].

Regardless, it may be interesting to investigate cell type-specific IGF-1 inhibition in other tissues than the heart to extend the notion of antagonistic pleiotropy to other organs. At least in case of adipose tissue, it appears that IGF-1 promotes both lipolytic and anti-lipolytic actions in a context-dependent manner (i.e. depending on whether the animals are fed or starved) [29,30]. Furthermore, the central nervous system, which – like the heart – is primarily composed of terminally differentiated cells, is known to require adequate IGF-1 levels for normal development and function [31], yet IGF-1-induced inhibition of autophagy promotes the accumulation of inclusion bodies that are commonly associated with neurodegenerative diseases [27].

4. Summary and conclusions

Taken together, our recent work on the cardiac effects of IGF-1R signaling highlights an example of antagonistic pleiotropy [16]. Thus, genetic overactivation of IGF-1R signaling improves cardiac function in young mice, but causes premature heart failure during aging. Conversely, genetic inhibition of IGF-1R signaling reduces cardiac fitness in young mice, yet avoids signs of age-related heart failure and extends healthspan and lifespan in old mice. The detrimental effects of IGF-1R overactivation on the aged heart can be overcome by autophagy induction, while the positive effects of IGF-1R inhibition are associated with autophagy induction. Apart from supporting the antagonistic pleiotropy theory of aging, these findings might have direct implications on the future development of cardioprotective anti-aging therapeutics, particularly in terms of the timing of treatments.

Declaration of interest

Dr Madeo has financial interests in TLL – The Longevity Labs GmbH and Samsara Therapeutics. Drs Abdellatif and Sedej are involved in patent applications related to the cardiometabolic effects of caloric restriction mimetics. Dr Kroemer has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. Dr Kroemer has been consulting for Reithera. Dr Kroemer is on the Board of Directors of the Bristol Myers Squibb Foundation France. Dr Kroemer is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. Dr Kroemer is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Dr Abdellatif acknowledges the support received from the Austrian Society of Cardiology (Präsidentenstipendium-ÖKG), Medical University of Graz (StartFund), the European Commission (H2020-MSCA-IF), BioTechMed-Graz (Young Researcher Group) and the Austrian Science Fund (FWF; P34926). GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. Dr Sedej is supported by the FWF (grants P27637-B28 and I3301-MINOTAUR) and BioTechMed-Graz (flagship project INTERACD+). Dr Madeo is grateful to the Austrian Science Fund FWF (F3012, W1226, P29203, P29262, P27893, P31727) and the Austrian Federal Ministry of Education, Science and Research as well as the University of Graz for grants ‘Unkonventionelle Forschung-InterFast and Fast4Health’ and ‘flysleep’ (BMWFW-80.109/0001-WF/V/3b/2015), Field of Excellence BioHealth Graz, NAWI Graz and the BioTechMed-Graz flagship project ‘EPIAge.’