The Relaxin-3 Receptor, RXFP3, Is A Modulator Of Aging-Related Disease

Abstract: During the aging process our body becomes less well-equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous neurometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders. 

Keywords: relaxin-family peptide receptor 3; aging; G-protein-coupled receptors; DNA; damage;GIT2 

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1. Introduction

Aging is arguably one of the most complex molecular biological processes. The majority of eukaryotic organisms undergo the aging process as progressive levels of cellular and tissue damage accumulate across the organism’s lifetime. While bewilderingly complex, aging can be deconstructed as a molecular biological process to reveal a core series of functions that represent a consistent signature that lends itself to potential generic therapeutic interventions. To this end, considerable research has suggested that through the targeting of these key signature features a tractable ability to control the aging process may be engineered. Here we discuss how such a novel target may have been recently identified.

1.1. Aging and Aging-Related Disorders

The increase in the world’s elderly population has caused an increased prevalence of aging-related chronic disease conditions, such as neurodegenerative disorders (e.g., Alzheimer’s disease (AD)), cardiovascular disease, arthritis, chronic kidney disease, and Type II Diabetes Mellitus (T2DM) [1]. Aging is a degradative neurometabolic process affecting every organ, and it drives the progression of a multitude of diseases. Aging is a complex multi-factorial process and, while some contributing factors may be unique to each individual, there are many common etiological factors across populations [1,2]. Aging is typified by the accumulation of molecular damage, causing progressive loss of an organism’s optimal function, eventually leading to systemic dysfunction and death [1,3].

Aging and many aging-related disorders involve perturbed energy balance [3]. Regulation of glucose metabolism, via the canonical insulinotropic system, has been shown to be a crucial regulator of the rate of aging [4]. The alteration of energy-controlling organelles and a signifificant reduction in glucose uptake are a sign of metabolic dysfunction. In times of stress or temporary depletion of glucose supplies, cellular energy metabolism will reflexively shift from glucose to adipose or protein metabolism to guarantee energy production. This metabolic change can cause oxidative stress [5], as the catabolism of these alternative energy sources is less energy efficient and yields lower ATP. The Harman free radical/oxidative stress theory stipulates that physiological iron and other metals in the body cause reactive oxygen species (ROS) accumulation in cells, as a by-product of normal redox reactions. ROS are essentially by-products of a variety of pathways that are involved in aerobic metabolism. The accumulation of oxidative stress constitutes one of the most realistic hypotheses of aging and neurodegenerative disorders [1]. This oxidative stress in turn can cause DNA damage, in the form of double-strand breaks (DSBs). While the DNA damage repair (DDR) process functions to repair these DSBs, it is well established that with age, DDR is impaired and can no longer perform this function optimally. This leads to the induction of mutations and/or chromosomal aberration, which in turn can cause cell death, and, in extreme cases, cancer and neurodegenerative disorders [2]. With aging there is a reduced ability to cope with cellular stresses, causing the body to become more prone to a wide variety of pathologies [6]. The central nervous system (CNS), comprised of post-mitotic tissue, is profoundly affected by DDR deficiencies. DDR dysfunction in mature neural tissues is linked to both premature aging and neurodegenerative disorders, such as AD [7]. 

Aging as a natural pathological process is slowly developing and coordinated by the interaction of multiple signaling systems across several somatic tissues. This complexity makes it a difficult process to therapeutically target. Chadwick et al. [2] demonstrated that such complex systems possess some degree of organization, with some proteins possessing a greater regulatory network function than others. These are the so-called ‘keystones’ (alternatively termed ‘hubs’). Targeting these proteins facilitates regulating these complex disorders, in contrast to controlling the process at every molecular point. One such keystone recently identified is GIT2 (G protein-coupled receptor kinase interacting transcript 2), an ADP-ribosylation factor GTPase-activating protein (Arf-GAP), and a class A G-protein-coupled receptor (GPCR) interacting protein [2,8,9]. GIT2 was identified as an important protein linked to several aspects of the aging process, through latent semantic indexing (LSI). As GIT2 is a potentially important keystone in aging, it might represent a crucial therapeutic target. However, canonical therapeutic targets are receptors, ion channels, kinases, and phosphatases, hence GIT2, being a scaffolding protein, does not represent an effective druggable target [10]. It was recently demonstrated that, in addition to regulating intermediary cell metabolism events such as calcium mobilization, GPCRs can also effectively regulate the expression profiles of multiple signaling proteins via slower signaling modalities outside of the traditional G-protein-dependent functions [11]. This suggests that GPCRs can be used to regulate the expression of specifific signaling proteins, to improve therapeutic activity [1,9]. GPCRs are also interesting drug candidates due to their high diversity, targetability, and involvement in nearly every physiological process. Our ongoing research has also demonstrated that the signaling functions of these receptors are far more nuanced than previously conceptualized [2,10]. This signaling complexity facilitates the creation of novel, signal-selective GPCR therapeutics. Previous research, using GIT2 knock-out (KO) mice to investigate expression relationships in the context of metabolic aging, identified a consistently downregulated GPCR, the relaxin-family peptide receptor 3 (RXFP3), in the CNS, pancreas, and liver [10]. This association, therefore, suggests perhaps that GIT2 may act as a novel aging-specific signaling adaptor for the RXFP3 receptor. 

1.2. Relaxin-Family Peptide Receptor 3

RXFP3, previously known as GPCR135, was deorphanized through the identifification of its endogenous ligand relaxin-3 (RLN3), also known as insulin-like peptide 7 (INSL7). This class A rhodopsin-like receptor, together with its relaxin peptide family and their receptors, is a branch of the insulin superfamily, which consists of insulin and insulin-like growth factor 1 and 2 (IGF1 and -2) [12]. This receptor, originally named the SALPR (somatostatin- and angiotensin-like peptide receptor [13]), is primarily expressed in the CNS [14–16]. There are currently four members in the relaxin family of GPCRs, i.e., RXFP1- 4. In contrast to RXFP1 and RXFP2, RXFP3 and its closely related family member RXFP4 couple to Gαi, causing inhibition of cAMP production through a pertussis toxin-sensitive mechanism [12]. RXFP3 and RXFP4, also resemble each other in structure, where both are classical type I peptide receptors with short amino (N)-terminal domains, and both are evolutionarily related to somatostatin and angiotensin receptors. In addition, the endogenous ligands for these two receptors are RLN3 and insulin-like peptide 5 (INSL5), respectively, which both play a role in neuroendocrine signaling [17]. 

While RXFP3 has been classifified as a class A rhodopsin-like receptor, it appears that it is not in its entirety a canonical rhodopsin-like GPCR. As detailed by van Gastel et al. [10], RXFP3 does not contain a typical transmembrane domain 3 (TM3) Aspartate-ArginineTyrosine ‘DRY’ motif but instead has a Threonine-Arginine-Tyrosine ‘TRY’ motif. This natural variation of this classical GPCR activation motif may demonstrate altered activation state kinetics, with an augmented level of ligand-independent constitutive activity. Furthermore, the highly conserved ExxxD motif, which is vital for RLN3 binding, has been identified at the second transmembrane domain on the extracellular side [18]. 

The relaxin peptides are small (approximately 60 amino acids long), and similarly to insulin, share a common two-domain structure with an α- and a β-chain in their mature form [12]. The α-chain appears to be important for receptor–ligand binding affinity, while the β-chain of RLN3 is mainly responsible for the binding and activation of RXFP3 [19]. RLN3 is the most recently identified relaxin family peptide, with the presence of the characteristic RxxxRxxI/V relaxin-binding motif found in the β-chain of all relaxin peptides; however, the remainder of the sequence displays low homology with other relaxin-family peptides. RLN3 is the only member of the relaxin family with a sequence conserved across species [20,21], and this neuropeptide is believed to be the ancestral peptide of the family [20,22]. The RLN3/RXFP3 system demonstrates strong indications of ligand-receptor co-evolution, where nearly all amino acids have been subject to purifying selection for both genes and display a near-perfect parallel in both mammals and teleosts [23], both in structure and function [20,23]. Teleosts possess two rln3 paralogs (rln3a and b) and multiple rxfp3-type genes, which are not all orthologous to mammalian RXFP3 [23]. However, it has been shown that intracellular loops 1 and 3 are important in terms of selection, indicating that a large part of the selection for these GPCRs concerns downstream receptor signaling and not just selection for ligand binding [23]. 

Further investigation of the functions of this receptor has uncovered that RXFP3 might play a vital role in several aging-related disorders, as a connection has been found to several hallmarks of aging, such as oxidative stress and DNA damage response [24], similar to the aging keystone GIT2 [6,7]. In addition, research by other groups has elucidated possible roles for RXFP3 in stress responses [25], anxiety [26], depression [26,27], feeding [15,28–30], arousal [28], and alcohol addiction [31]. Given the plethora of possible physiological activities of RXFP3, we will next assess how RXFP3 functionality may intersect with several of the classical hallmark processes involved with the aging process (Figure 1)

Figure 1. The human RXFP3 receptor functionally intersects with multiple hallmarks of aging. The RXFP3 receptor has been shown by multiple researchers to be associated, at the molecular signaling level, to activities that constitute many of the classical hallmarks of aging. In doing so the RXFP3 potentially represents, in conjunction with its synergistic relationship with the GIT2 signaling adaptor, a novel systems-level therapeutic target for the multidimensional interdiction of the pathological aging process. 

2. Intersection of RXFP3 Signaling with the Hallmarks of Aging 

While the aging process is a complex network of biological processes unique to every individual, there are various common molecular components of the aging process. These components, or so-called ‘hallmarks of aging’, manifest during normal healthy aging, accelerate pathological aging when aggravated and retard normal aging when relieved [32]. López-Otín et al. [32] described nine such hallmarks contributing to the aging process: (1) genomic instability; (2) telomere attrition; (3) epigenetic alterations; (4) loss of proteostasis; (5) deregulated nutrient sensing; (6) mitochondrial dysfunction; (7) cellular senescence; (8) stem cell exhaustion; and (9) altered intercellular communication. Due to the overlap and simultaneous occurrence of these alterations in aging, it is difficult to estimate the relative contribution of each hallmark. In the following section, the involvement of the RXFP3/RLN3 signaling system in multiple processes underpinning several hallmarks of aging will be described. 

2.1. Metabolic and Mitochondrial Dysfunction

Metabolic syndrome (MetS), which is mainly observed in late-middle-aged and older adults, is typified by insulin resistance and leads to major impairments including adipose lipogenesis, defective glycogen synthesis, and glucose uptake in skeletal muscle. Dysfunction of adipose tissue caused by MetS is widely recognized as a signifificant hallmark of the aging process [33]. While many older individuals seem to maintain a healthy body mass index (BMI), they are still prone to abdominal obesity, increasing their likelihood of developing MetS [34,35]. Furthermore, aging-related alterations in metabolic pathways and body fat distribution seem to be the active participants in a vicious cycle that is a possible accelerating factor in the aging process, as well as for the onset of many diseases [36]. For cellular metabolic pathways, glucose is the most utilized source of cellular energy and is typically produced from ingested dietary carbohydrates, but it can also be created within the body itself by gluconeogenesis. Glycolysis is the primary mechanism of energy generation in a wide variety of cells and tissues [37]. This mitochondrial process ultimately aims to generate, from glucose metabolism, adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NAD). However, along with this positive effect of mitochondrial energetics, these organelles are also the primary source of ROS, which have been implicated in one of the best-characterized theories of aging, i.e., the oxidative stress theory [38,39]. ROS can cause damage by irreparably affecting the structure of many molecules of the body that are potent controllers of natural aging, e.g., the telomeric regions of DNA [39]. 

It has been shown that even modest levels of metabolic dysfunction can exert profound effects on CNS tissues [3,40,41]. This is likely due to different factors, i.e., high energetic requirements of the CNS, combined with a high sensitivity of post-mitotic neuronal tissues to metabolic stress [6,42]. One of the key organs responsible for maintaining an effective interaction between neurological activity and energy balance is the hypothalamus. This small but vital part of the brain is involved in the aging process, as it coordinates both peripheral and central functions associated with neuroendocrine functionality, through the hypothalamic-pituitary-adrenal (HPA) axis [43]. The RXFP3/RLN3 system is highly expressed in different regions involved in the HPA axis, such as the paraventricular nucleus, indicating involvement in metabolic control [15,44–46]. Administration of corticotropin-releasing factor (CRF) has been shown to result in the activation of RLN3-containing neurons in the nucleus incertus, further supporting its functional role in the HPA axis [47]. DeAdder et al. [48] demonstrated that glucose-deprived brain slices display increased cell death and damage, while treatment with RLN3 returned these levels to baseline. Furthermore, blocking the receptor using the RXFP3 antagonist, B1-22R eliminated the effect of RLN3 treatment. Moreover, the addition of L-NIL, a NOSII inhibitor, partially eliminated the RLN3 treatment effect. This indicates the involvement of NO synthase in the protective function of the RLN3/RXFP3 system in glucose deprivation [48].

In recent years it has become apparent that mitochondrial dysfunction may be one of the central factors that allow metabolic changes to impact the aging process [49,50]. For the RXFP3 signaling system, it is interesting to note that the identified aging keystone factor GIT2 has also been shown to be a potent regulator of mitochondrial functionality [10,51,52]. Given this data, it is not surprising that natural protective mechanisms, e.g., in times of oxidative stress such as in ischemic stroke, that include mitochondrial and respiration support can be affected by relaxin (relaxin-2 (RLN2) and RLN3) peptides [53]. GIT2 has also been shown to be sensitive to ischemic events in multiple tissues [54]. Thus, single nucleotide polymorphism analysis of large patient cohorts identified GIT2 as a marker that confers susceptibility to early-onset MI myocardial infarction), hypertension, or chronic kidney disease. 

2.2. Oxidative Stress 

Oxidative stress refers to an imbalance between the generation of ROS and antioxidants, in favor of ROS, leading to disruption of redox signaling and control and eventually molecular oxidative attack [55]. ROS comprise unstable oxygen radicals (e.g., superoxide radicals and non-radical molecules such as hydrogen peroxide) that, at moderate concentrations, have important intracellular signaling functions, e.g., for the control of nerve transmission and immune regulatory processes. Moreover, low levels of oxidative stress by ROS even appear to be beneficial to organisms. Among others, Doonan et al. demonstrated that it may indeed prolong lifespan in yeast and C. elegans [56,57], demonstrating the role of ROS in triggering cell proliferation and survival in response to normal stress conditions and physiological signals [57]. Oxidative exposure of cells occurs naturally as ROS are continually produced during normal aerobic metabolism via the electron transport chain in mitochondria, which is not only a source of ATP, but also ROS [58]. However, ROS are not produced in an unregulated manner, with rates of ROS production typically being extremely low (~0.1 nM H2O2 formed min−1 mg−1 mitochondrial protein, ~0.01% of metabolic rate) [56]. Nevertheless, ROS levels may increase in damaged or aged mitochondria which causes the accumulation of ROS beyond physiological levels [56]. When their production overwhelms the capacity of antioxidant systems, they can cause irreversible molecular damage to macromolecules (e.g., lipids, proteins, and nucleic acids) and accumulated cell disruption, affecting multiple cellular functions, which over time is associated with cellular senescence and aging [6,58]. 

Van Gastel et al. [24] identified superoxide dismutase 1 (SOD1), sirtuin 1 (SIRT1), Ras GTPase-activating, and peroxiredoxin 6 (PRDX6) among the proteins functionally interacting with RXFP3, indicating a role in oxidative stress responsiveness. Loss of PRDX6 expression has previously been observed in aging cells and was shown to increase ROS production [59]. Furthermore, slight overexpression of RXFP3 resulted in an increased expression of PRDX6, indicating a synergistic role in the response to aging and oxidative stress [24]. Similar to PRDX6, SOD1 is also upregulated with RXFP3 overexpression [24]. Deletion of SOD1 in yeast and mouse models leads to increased oxidative stress and DNA damage. Elevated oxidative stressors, such as hydrogen peroxide, regulates the nuclear localization of SOD1. This process is associated with the Ataxia-Telangiectasia-mutated (ATM)/mec1 serine/threonine protein kinase (Mec1) regulation of gene expression to prevent oxidative stress-related DNA damage [60]. Similar to SOD1, the SIRT1/FoxO axis is important for the regulation of the response to metabolic and oxidative stress through the overexpression of antioxidants [61]. Recent evidence has also demonstrated that relaxin-3, acting via RXFP3, possesses the capacity to attenuate oxidative damage induced by glucose deprivation in cultured brain slices, through the manipulation of the nitric oxide generation system [48]. The specificity of this effect of relaxin-3 at the RXFP3 was demonstrated by selective inhibition through the action of the RXFP3 antagonist, B1-22R [48]. Taken together it seems that RXFP3-associated signaling complexes (often referred to as receptor somes [10,24]) could act as a sensor for oxidative stress and regulate the cellular response to it. 

2.3. DNA Damage

The amino acid sequence of RXFP3 displays multiple phosphorylation sites for kinases involved in DDR (i.e., ATM/PRKDC at serine 269 and 360: https://scansite4.mit.edu/, accessed on 12 April 2022). This could explain its association with GIT2 in aging and neurodegeneration. As discussed, DNA damage is one of the hallmarks of the aging process [32]. It has been demonstrated that many advanced aging disorders are linked to mutations in DDR proteins, e.g., a mutation occurs in ATM causing Ataxia-Telangiectasia (AT) [62]. ATM plays a central role in the maintenance of genome stability and phosphorylates proteins involved in the canonical DDR process. The phosphorylation preferentially takes place on serine (S) or threonine (T) residues preceded by glutamine (Q), the so-called SQ/TQ motifs [63]. This is required for normal DNA damage repair [63]. Interestingly, some researchers have demonstrated that ATM protein kinase is a sensor for ROS in human cells, concluding that ATM can be directly activated by oxidation [64]. RXFP3 contains two SQ motifs, which strongly suggests the potential involvement of RXFP3 as a sensor for oxidative stress, leading to aging. RXFP3 also contains a phosphorylation site for PRKDC. PRKDC binds to SxQ motifs, which in the case of RXFP3 x is a leucine (L), found in the receptor sequence in extracellular loop 2. In classical class A GPCRs these ATM and PRKDC sites would be located in the intracellular domain, whereas in RXFP3 they are located in the extracellular loops. However, it is highly likely that in this case, the sites are still accessible to intracellular ATM/PRKDC. Recently it has been hypothesized that GPCRs can be inserted inside-out in intracellular membranes such as the nucleus, endoplasmic reticulum, or mitochondria [65–67]. This would mean that the extracellular loops are accessible by intracellular ATM/PRKDC. Moreover, it has also been shown through surface accessibility topological predictions that these three sites are likely to be accessible to soluble hydrophilic factors. It has also been demonstrated that the majority of GPCRs are held in intracellular vesicles as a receptor reserve for plasma membrane recycling [68], and the TRY motif likely increases the amount of intracellular retained receptors [69].

Besides the phosphorylation sites for ATM and PRKDC, it was found that activation of RXFP3, through its endogenous ligand RLN3, increased PRKDC phosphorylation while resulting in a decrease of histone H2AX (H2AX) and breast cancer type 1 susceptibility protein (BRCA1) phosphorylation [24]. H2AX phosphorylation is one of the first molecular indicators of DNA damage that can then be repaired through the activity of BRCA1. Co-immunoprecipitation, using selective affinity purification of an N-terminally haemagglutinin-tagged RXFP3, also indicated the interaction of RXFP3 and activated PRKDC, highlighting the importance of RXFP3 in DNA damage repair through PRKDC [24].

2.4. Epigenetic Alterations

Epigenetic alterations to nucleic acids are a component of the normal cellular signaling landscape. Alterations to patterns of epigenetic profiles across the aging process are potentially one of the key factors for controlling individual healthy aging trajectories [70–72]. As aging is linked with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodeling, and non-coding RNAs, the potential therapeutic control of these mechanisms is a potentially effective strategy for interdicting the generation of pathological aging phenotypes. It has been shown that the methylation status of RXFP3 can be associated with aging-related changes in several cancers, including endometrial and cervical malignancies [73–75]. Alterations to the methylation status has also been shown for several other receptors with respect to these specific cancers, e.g., orexin-2 receptor [76], C-X-C chemokine receptor type 4 [77], and the P2X purinoceptor 7 [78]. It is interesting to note, however, that with respect to the role of RXFP3 in the aging process, Huang et al. [79] identified coordinated changes in RXFP3 epigenetic regulation along with CIDEA (cell death activator CIDEA), which has also been implicated in metabolic pro-aging molecular signaling activities [80].

2.5. Nutrient Sensing 

The complex and intricate aging process is implicitly associated with the glucometabolic system. Indeed, many of the first aging-regulating genes discovered in species such as C. elegans were nearly all associated with the insulinotropic system [81,82]. Given this, it is also interesting to note that the metabolic underpinning of nearly all diseases is now apparent, demonstrating the importance of therapeutic intervention in these systems [83–92]. From an intervention standpoint, simple lifestyle modifications have subsequently demonstrated that caloric restriction (CR) can be effective in controlling the glucometabolic system to attenuate the incidence and magnitude of aging-related disease [93–99]. Thus, it is clear that the ability of cells and tissues to sense fuel sources for energy metabolism is critical for the maintenance of homeostasis across the lifespan [100]. The main components of signaling pathways sensitive to the changes in nutrient availability include insulin, TOR (target of rapamycin), AMPK (50 -AMP-activated protein kinase), and the sweet-taste receptor system [86,101,102]. Impairments of these signaling pathways can trigger various metabolic disorders. Thus, disrupted functioning of AMPK can reduce the stress resistance capacity of cells as well as engendering the development of insulin resistance [103,104]. Activation or suppression of metabolic sensors might increase lifespan in various organisms and improve aging-related indicators in humans [105–107].

While a considerable amount of nutrient sensing is controlled by factors directly linked to the insulinotropic system, there are multiple other systems (including GPCRs) that also regulate the functionality of this longevity-regulating paradigm. In this light, it is interesting to note that RLN3 is an insulin-like peptide that has also been shown to be a controller of nutrient sensing and catabolic metabolism [108–110]. Demonstrating a further nuance of the positioning of the RXFP3 system, it has also been shown that regulation of food intake is also associated with psychosocial changes, suggesting that RXFP3 can act as a nexus between generic stress responses and cellular protection mechanisms to combat the deleterious effects of nutrient deprivation [29]. To further investigate this, it would be interesting to investigate such a proposal through the implementation of RXFP3 antagonist introduction or tissue-selective RXFP3 expression attenuation or silencing with short hairpin RNA or CRISPR/Cas9 approaches. 

2.6. Cell Senescence

Aging-related diseases are caused by the progressive degradation of the integrity of communication systems within and between organs. This process is associated with a decreased efficiency of receptor signaling systems and an increasing inability to cope with stress, leading to apoptosis and cellular senescence [111–113]. Cellular senescence is a natural process during embryonic development but more recently it has been shown to also be involved in the development of aging-related disorders and is now considered to be one of the major hallmarks of aging. Advances in the molecular understanding of GPCR signaling complexity have expanded their therapeutic capacity tremendously [114–118]. Thus, emerging data now suggest the involvement of GPCRs and their physically associating adaptor proteins in the development of cellular senescence [119–121]. With the proven efficacy of therapeutic GPCR targeting, it is reasonable to now consider GPCRs as potential platforms for controlling cellular senescence and aging-related disorders. RXFP3 has been functionally associated with the senescence process in several studies. Recently Anckaerts et al. [122] demonstrated that interventions that induced premature brain aging and senescence (without excessive cell loss) in the context of AD resulted in significant diminutions in both RXFP3 and GIT2 expression in the retrosplenial cortex. Senescent cellular programs, especially in the aging context, are often induced by the overburdening of cells with oxidative stress. Several studies have linked this deleterious process to the significant alteration of RXFP3 expression levels [24,123] as well as the ROS regulating factor PRDX6 [24,124]. PRDX6 has subsequently been shown to be a crucial integrator of aging-associated cellular senescence programs [59]. 

2.7. Proteostasis/Fibrosis 

Maintaining cellular protein homeostasis, or proteostasis, requires the well-coordinated control of protein synthesis, folding, conformational integrity, and ultimately degradation. Proteostasis activities coordinate these diverse processes across the lifespan of all organisms [125]. The proteolytic regulatory network ensures that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of aging-associated proteinopathies, such as Alzheimer’s, Parkinson’s, and Huntington’s disease [126–130]. It is now clear that the capacity of cells to maintain proteostasis undergoes a decline during aging, rendering the organism susceptible to these pathologies. One of the most common pathological sequelae of altered proteostasis is the dysfunction of basement complexes (an extracellular matrix network of glycoproteins and proteoglycans) that can cause fibrosis in multiple tissues across the lifespan [41]. Given our previously demonstrated evidence regarding the potential anti-aging activity of RXFP3 [24], it is not surprising that components of the RXFP3/RLN3 system have been shown to have antifibrotic activity. For example, Hossain et al. [131] showed that RLN3, albeit acting via the RXFP1 receptor, could decrease collagen expression in a murine cardiomyopathy model. It has also been shown that RLN3 treatment of cardiac fibroblasts inhibited ROSand inflammasome-mediated collagen synthesis under high glucose conditions [132]. In addition to this, in the context of cultured cardiac fibroblasts, exposure of these cells to hyperglycemic conditions (that predispose to fibrosis) causes an elevation in mRNA levels of RXFP3 [133]. Based on this data, it is clear that RLN3/RXFP3 signaling could represent a novel therapeutic avenue for diabetic cardiomyopathy [133]. 

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