Inter-organ communication is critical machinery to regulate metabolism and aging

Abstract

Recent discoveries have highlighted the significance of inter-organ communication (IOC) in maintaining metabolic homeostasis and counteracting aging. In this review, we delve into IOCs mediated by hormonal signaling, circulating metabolites, cytokines, miRNAs, organelle signaling, and neuronal networks and examine their roles in regulating metabolism and aging. We further discuss recent findings identifying the hypothalamus as a high-order control center for aging and longevity. Dysregulation of distinct IOCs is linked to metabolic derangements and age-related pathologies, implicating IOC as a potential target for therapeutic intervention to promote healthy aging. We particularly emphasize the importance of IOCs between the hypothalamus and peripheral organs and pave the way for a better understanding of this critical machinery in metabolism and aging.

Inter-organ communication (IOC) provides new insights into metabolism and aging

A comprehensive understanding of metabolic processes has long been considered foundational in uncovering the mechanisms of aging. Over the past 30 years, several evolutionarily conserved signaling pathways and factors have been identified as key to connecting metabolism to aging and longevity control, including insulin/insulin-like growth factor 1 (IGF-1) signaling [1,2], mechanistic target of rapamycin (mTOR) signaling [3,4], and the sirtuin family of nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacetylases/deacylases [5,6]. Whereas we still have not gained a fully articulated picture of how exactly aging and lifespan are regulated, cutting-edge genetic engineering and extensive omics analysis, rather than simply focusing on individual signals or organs, now enable us to examine how organs crosstalk with each other, how age-related changes in one organ affect others, and which organs need to be targeted to counteract aging. Over the past decade, the concept of inter-organ communication (IOC) has been recognized increasingly as a critical component in maintaining robust metabolic networks and healthy lifespan [7,8].

Over time, the delicate balance of IOC is disrupted, leading to the deterioration of physiological homeostasis at both the tissue and organismal levels [9,10]. Indeed, recent studies have revealed that IOC dysfunction underlies age-associated physiological decline, inducing various age-associated metabolic derangements and limiting healthspan and lifespan [11–15]. Therefore, understanding how IOC shifts and collapses over time will shed new light on the mechanisms underlying age-related metabolic changes and organ dysfunction. Interestingly, “Inter-organ Communication in Aging” was highlighted as a new area of research in the September 2022 gathering of the National Advisory Council on Aging (NACA) (https://www.nia.nih.gov/approved-concepts#Interorgan). Furthermore, this concept has received funding since May 2024 through Cooperative Agreement Awards (U01) granted by the National Institute on Aging (NIA). These efforts emphasize the increasingly appreciated significance of IOC in deciphering the mechanisms of aging and longevity control.

In this review article, we discuss how IOC regulates metabolism and aging via hormonal signaling, circulating metabolites, cytokines, miRNA, organelle signaling, and neuronal networks. Additionally, we delve into how the hypothalamus, as a high-order control center of aging, regulates metabolism and aging via IOC. These recent developments have set the stage for a new research direction focusing on these fascinating IOCs.

Circulating hormones from adipose tissue, skeletal muscle, and bone

Over the past few decades, there have been extensive researches on classical hormonal regulation in various endocrine organs, such as the pituitary gland, adrenal glands, pancreas, thyroid gland, testes, and ovaries [16]. Recent studies have suggested that the majority of organs and tissues can be reclassified as endocrine organs, as they communicate with one another through a diverse array of molecular signals [17–20]. A recent review article nicely summarized major circulatory proteins and their axis of secretion [21]. Even organs traditionally categorized as “non-endocrine organs” send humoral signals to others, such as adipose tissue, skeletal muscle, and bone.

Adipose tissue

Since the discovery of leptin and adiponectin as adipokines (see Glossary), many other factors secreted from adipose tissue have been identified and implicated in the control of systemic metabolism [22]. For example, transforming growth factor-β2 (TGF-β2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice [23]. Among those newly identified adipokines, the extracellular version of nicotinamide phosphoribosyltransferase (eNAMPT) plays a unique and essential role in the regulation of aging and longevity. The majority of eNAMPT secreted from adipose tissue into plasma is encapsulated into extracellular vesicles (EVs) and remotely enhances NAD⁺ biosynthesis in the hypothalamus, hippocampus, nucleus accumbens, pancreas, and retina and counteracts aging [24–27]. Recently, it has been demonstrated that stimulation of eNAMPT secretion from white adipose tissue (WAT) by activating a specific neuronal subpopulation in the dorsomedial hypothalamus (DMH) significantly delays aging and extends lifespan in mice [11]. We further discuss the importance of EVs and this newly identified neuronal population in later sections. Brown adipose tissue (BAT) can also secrete numerous humoral factors, called batokines, which exert endocrine actions, in addition to autocrine and paracrine actions. However, to date, no study has identified a batokine specific to BAT. Therefore, batokines are classified as factors that are preferentially secreted by BAT compared to WAT and, in some cases, compared to other tissues or organs [28,29].

Skeletal muscle

In addition to directly consuming excess energy, muscle contraction also influences metabolism. Although the molecular mechanisms underlying the effects of exercise on metabolism remain an area of intensive investigation, muscle-secreted factors, known as myokines, have been identified and studied extensively. Interleukin 6 (IL-6) and myostatin are well-studied myokines that regulate skeletal muscle growth through autocrine and paracrine mechanisms. IL-6 from skeletal muscle regulates glucose disposal, lipolysis, oxidative metabolism, and energy expenditure in multiple tissues. Myostatin is involved in the regulation of insulin sensitivity, glucose utilization, and bone formation [30]. Other myokines, including FGF21 [31] and irisin [32], stimulate white adipocytes to induce uncoupling protein 1 (UCP1) expression, thus contributing to WAT browning and promoting thermogenesis. Moreover, irisin and a newly identified myokine, cathepsin B, have been shown to stimulate neurogenesis and exert neuroprotective effects in the hippocampus via induction of brain-derived neurotrophic factor (BDNF) [33,34]. More myokines that affect vascularization [35], bone formation [36], and cardioprotection [37,38] have been characterized. These beneficial effects of myokines may provide a reasonable explanation for the effects of exercise on the whole-body metabolism.

Bone

Bone has traditionally been viewed for its structural role in the human body. Recent research has further shed light on the multifaceted role of bone, including its new, important role as a complex endocrine organ that regulates whole-body metabolism [19]. Osteocalcin is one of the most critical factors produced in bone tissues. Circulating osteocalcin increases insulin secretion and sensitivity [39], lowers blood glucose levels [40], and decreases visceral adipose tissue [41]. While bone marrow mesenchymal stem cells (BMSCs) play a critical role in regulating hematopoiesis within the bone marrow microenvironment, they also have the ability to secrete active molecules that can impact energy metabolism throughout the body [19]. Specifically, a BMSC-derived exosomal microRNA, miR-29b-3p modulates age-related insulin resistance through SIRT1 signaling [42].

Other humoral factors for IOCs

Many studies have highlighted EVs as an essential mediator of intercellular and inter-organ communication that plays a crucial role in various physiological processes, primarily through the encapsulation of proteins, nucleic acids, and other signaling molecules. Recently, the effect of purified plasma EVs on mouse lifespan has been reproduced [12]. Skeletal muscle-secreted EVs, which are induced by exercise, remodel metabolism towards beneficial cardiovascular outcomes [43]. Furthermore, a growing body of evidence suggests that EVs also play a role in mitigating many detrimental consequences associated with aging, including cellular senescence, metabolic dysfunction, cardiovascular disease, cancer, and neurodegeneration [44] (Figure 1). At this moment, it remains unclear what humoral factors, metabolites, miRNAs are encapsulated into EVs and what kinds of EVs contribute to the regulation of metabolism and aging. To understand those details, further investigation will be required. Therefore, in this section, we will discuss metabolites and cytokines that can function without being encapsulated into EVs, and then focus on senescence-associated secretory phenotype (SASP). Additionally, newly identified miRNA-mediated and organelle signaling will be discussed.

Figure 1. Humoral components for inter-organ communication (IOC) in metabolism and aging.

The five humoral components for IOCs in metabolism and aging, discussed in this review, are hormones, cytokines, microRNAs (miRNAs), metabolites, and organelle (mitochondrial) signaling. The extracellular vesicles (EVs) deliver some of those humoral factors to mediate IOCs, as indicated by dotted arrows. Early in life, these factors serve as beneficial signaling molecules and promote organ health. As an organism ages, those beneficial factors decrease, and inflammatory cytokines, such as the ones from the senescence-associated secretory phenotype (SASP), increase throughout the body. The green box indicates changes in those beneficial factors known to counteract aging and extend lifespan in model organisms. The purple box shows genetic manipulations or treatments that accelerate aging and shorten lifespan in model organisms. Abbreviation: MUFAs, mono-unsaturated fatty acids. PF4, platelet factor 4. upd3, cytokine unpaired 3. IL-6, interleukin 6. eNAMPT, extracellular nicotinamide phosphoribosyltransferase. This figure was created using BioRender (www.biorender.com).

Metabolites

Circulating metabolites play a pivotal role in representing the metabolic status of various tissues and organs [45,46]. Dysregulated metabolite profiles have been implicated in age-related metabolic disorders, reflecting metabolic flux and cellular homeostasis perturbations [47–49]. Furthermore, restriction or supplementation of different metabolites can change the activity of these metabolic pathways in ways that improve healthspan and extend lifespan in various organisms [50]. For example, supplementation of alpha-ketoglutarate (α-KG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan, compress morbidity, and decrease the levels of systemic inflammatory cytokines in aged mice [51]. In recent years, lipid metabolites, also known as lipokines, have been recognized as crucial signaling molecules that actively contribute to various metabolic processes. By genetic manipulation, the accumulation of mono-unsaturated fatty acids (MUFAs) extends lifespan in worms, and dietary MUFAs are sufficient to extend their lifespan [52]. In contrast, signature metabolic reprogramming that occurs during aging can predict the onset of age-related diseases and lifespan before symptoms become evident. Metabolic reprogramming during aging causes reductions in overall fitness, an increase in susceptibility to age-related dysfunctions, a decrease in stress response capacity, and an increase in frailty. In a recent study, untargeted metabolomic profiling of plasma metabolites from healthy individuals, comprising twin pairs aged 6 months to 82 years, identified 52 metabolites predictive of age [53]. Another interesting study showed that centenarians have a distinct gut microbiome enriched in microorganisms that can synthesize unique secondary bile acids, including various isoforms of lithocholic acid [54]. These emerging data demonstrate that understanding the role of circulating metabolites in mediating IOC provides valuable insights into the pathogenesis of metabolic dysfunction during aging and offers potential targets for therapeutic intervention (Figure 1).

Cytokines

A recent study revealed that, like mammalian interleukins and leptin, Drosophila cytokine unpaired 1 (upd1) regulates intestinal metabolism, spermatogenesis, and food intake through bidirectional testis-midgut interactions under physiological conditions [55]. Another study revealed that systemic administration of exogenous platelet-derived chemokine platelet factor 4 (PF4), also known as CXCL4, attenuates age-related neuroinflammation in the hippocampus, induces molecular changes in synaptic plasticity, and improves cognitive function in aged mice [56]. In contrast, alterations in cytokine levels can also contribute to physiological deterioration or accelerate metabolic dysfunction and aging. For example, acute pancreatitis often leads to multiorgan damage, especially in the lungs and intestines, mainly due to a cytokine-mediated inflammatory response [57]. Additionally, the “cytokine storm” induced by COVID-19 is characterized by excessive production of pro-inflammatory cytokines in the blood, which leads to acute respiratory dysfunction and, eventually, widespread tissue damage, multi-organ failure, and death [58]. A recent study also revealed that the age-dependent induction of cytokine unpaired 3 (upd3), a homolog of mammalian IL-6, in Drosophila oenocytes (hepatocyte-like cells) is the primary mechanism causing cardiac aging [59]. Chronic inflammation mediated by pro-inflammatory cytokines constitutes a critical component of age-associated pathophysiologies called inflammaging, which largely share the same molecular mechanisms with metabolic inflammation [60].

Senescence-associated secretory phenotype (SASP)

The SASP has been suggested to contribute to inflammaging. Selective elimination of senescent cells (senolytics) or blocking of the SASP (senostatics or senomorphics) have been extensively studied as potential pharmaceutical interventions for age-related diseases [61]. A recent study demonstrated that Luteolin, a polyphenolic extract from Salvia haenkei, shows anti-senescence effects. Daily oral administration of this extract extends the lifespan and healthspan of naturally aged mice [62]. However, studies have also revealed the role of senescent cells in non-harmful physiological processes [63]. Indeed, the elimination of senescent cells that express high levels of p16 disrupts blood-tissue barriers, with subsequent liver and perivascular tissue fibrosis and health deterioration [64], underscoring the critical role of these cells in maintaining homeostasis and physiology. Additionally, the newly developed senescent-cell separation technique demonstrated that senescence is a more complex array of states than previously anticipated [65]. Suppressing the SASP without eliminating senescent cells is a viable therapeutic alternative to address senescence-related metabolic phenotypes and aging. Senostatics or senomorphics can alleviate the SASP of senescent cells directly or indirectly by suppressing multiple pathways, including NF-κB, JAK-STAT signaling, and mTOR, which are involved in the activation and maintenance of SASP [66]. Developing age-related therapies that focus on eliminating senescent cells is a promising approach, although it is expected to be more intricate than initially envisioned.

microRNAs (miRNAs)

Among various components in EVs, miRNAs have been the most extensively studied. miRNAs, classified as noncoding RNAs (ncRNAs), may alter IOC through their critical role in epigenetic reprogramming, a putative hallmark of aging, via post-transcriptional gene silencing [9,67] (Figure 1). Adipose tissue-derived EVs and their cargo miRNAs can be transferred to the brain in a membrane protein-dependent manner, preventing cognitive impairment in obese mice with insulin resistance [68]. Worm miRNAs undergo age-dependent inter-tissue trafficking mediated by EVs, while miRNAs are controlled in a tissue-specific manner to modulate gene expression during aging [69]. A recent study provided a map of the organism-wide expression of ncRNAs with aging in mice. This study identified a set of broadly dysregulated miRNAs that may function as systemic regulators of aging via plasma factors, such as EVs [70]. Interestingly, miRNAs produced and released by hypothalamic stem cells contribute to the speed of aging [71], and miRNAs encapsulated within young EVs ameliorate age-related dysfunction by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism [12]. Given their tightly regulated secretion, signaling properties, and significance in physiological processes and pathological conditions, a novel nomenclature ‘RNAkine’ has been proposed to designate extracellular noncoding RNA, including miRNA, circRNAs, and lncRNAs [72], elegantly conceptualizing the role of extracellular ncRNAs in IOCs.

Organelle signaling

Another exciting and novel biological observation is that cellular organelles send signals between tissues. Recent studies have uncovered mechanisms by which mitochondrial stress in one tissue can affect remote tissues, ultimately promoting organismal health [73,74]. In Caenorhabditis elegans (C. elegans), mitochondria incur age-related damage from reactive oxygen species, harmful metabolic byproducts, and other factors. The mitochondrial stress occurs in neuronal cells, and it triggers the intestinal mitochondrial unfolded protein response (UPR^MT), which restores proper protein folding and removes damaged proteins. Interestingly, germline mitochondria integrate inter-tissue mitochondrial stress signaling via neurons and modulate lipid metabolism to activate UPR^MT in the periphery, promoting organismal health and lifespan [73]. The specific molecule that may originate in neuronal mitochondria and act as a messenger for non-autonomous UPR^MT signaling needs to be identified. However, these data suggest that examining the regulatory mechanisms that underlie lifespan extension in cell-nonautonomous germline-to-intestine processes could provide important insight into how IOC is regulated during aging (Figure 1). Additionally, large EVs, such as microvesicles, apoptotic bodies, migrasomes, and exophers, can be loaded with intact functional or damaged mitochondria, providing a new way of mitochondrial transport for IOCs [75]. In the near future, a newly developed biochemical secretome profiling methodology will enable the direct labeling and identification of secreted proteins in various model organisms at a cell type-specific resolution and provide opportunities to discover novel IOC molecules and associated mechanisms (Box 1).

Box 1: Tools for Dissecting IOC.

A biotin-labeling technique for identifying potential inter-organ signals has been recently developed. Enzyme-catalyzed proximity labeling with BioID and TurboID, which are engineered biotinylation enzymes, is an effective method for investigating IOC. Recent studies have shed light on the molecular identity and cellular source of circulating factors, while elucidating the dynamic regulation of intercellular communication and IOC through TurboID [99–101]. Cell type-specific labeling can be accomplished by restricting the expression of TurboID to specific cells expressing Cre recombinase. Subsequently, biotinylated and secreted plasma proteins can be purified directly from blood plasma using streptavidin beads and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) [102]. The dynamic regulation of intercellular and inter-organ crosstalk by physical activity has also been illuminated by mapping an organism-wide 21-cell-type, 10-tissue secretome in mice using an adeno-associated virus expressing a cre-inducible, endoplasmic reticulum-restricted TurboID [103]. However, viral-mediated approaches for the systemic temporal and spatial analysis of mammalian secretomes in vivo have limitations. The BirA*G3 mouse strain enables Cre-dependent promiscuous biotinylation of protein trafficking through the endoplasmic reticulum [104]. BirA*G3 is a precursor of TurboID generated in the directed evolution of E. coli BirA, which has a higher affinity for biotin and can catalyze biotinylation before adding exogenous biotin [99]. The BirA*G3 mouse model exhibited improved labeling efficiency and tissue-specific expression compared with viral transduction methods. Although not all proteins in the blood are critical for IOC, this method will contribute to a more comprehensive understanding of the interplay between secreted proteins involved in metabolism and aging.

Integration of IOCs through the hypothalamus as a high-order control center for metabolism and aging

Somatosensory input regulates metabolism through the hypothalamus

In addition to humoral factors that control metabolism and aging, neuronal networks are another essential facet of IOCs. Neuronal networks enable bidirectional communication between the peripheral organs and the brain, especially the hypothalamus (Figure 2), which coordinates various neural responses to maintain metabolic homeostasis. It receives and integrates information through hormones and cytokines secreted from peripheral organs and sends neuronal signals back to those organs. Indeed, recent studies have demonstrated that the hypothalamus receives somatosensory input from peripheral organs to fine-tune metabolic homeostasis [76,77]. Somatosensory neurons in the dorsal root ganglia (DRG) and vagal sensory neurons in the jugular and nodose ganglia innervate organs and detect changes in their microenvironments. Information is then relayed to the brain, forming an ascending pathway. Peripheral signals transmitted via vagal afferents regulate behavior and energy homeostasis [78,79]. Interestingly, a specific group of neurons belonging to the DRG, typically associated with transmitting pain, touch, and proprioceptive sensations, has been shown to regulate metabolically active organs, such as bone and WAT. The ablation of somatosensory neurons that project to WAT alters its function, leading to changes in body weight and glucose homeostasis [80].

Figure 2. Neuronal and humoral integration of inter-organ communications (IOCs) in metabolism and aging.

Both secreted humoral factors and the nerve signals passing through the spinal cord convey the metabolic status from peripheral organs to the brain, especially to the hypothalamus, which integrates IOCs to regulate whole-body metabolic homeostasis through the descending sympathetic nerves. Sensory nerve fibers from dorsal root ganglia (DRG) innervate skeletal muscle, adipose tissue, and bone. Distinct afferent sensory neurons have been identified to control appetite and metabolism through different IOCs. Peripheral organs also communicate with each other through a variety of humoral factors. These multi-layered feedback loops maintain healthy metabolism and regulate the aging process in mammals. This figure was created using BioRender (www.biorender.com).

Additionally, the nervous system tightly regulates bone metabolism through the hypothalamus-derived descending interoceptive pathway [77]. Prostaglandin E2, secreted by osteoblasts, activates EP4 in sensory nerves in the ascending pathway that project to the ventromedial hypothalamic nucleus (VMH). This stimulation then downregulates descending sympathetic tone from the VMH, promoting the differentiation of BMSCs into osteoblasts and inducing bone formation, thereby maintaining skeletal homeostasis [81,82]. Moreover, hypothalamus-derived autonomic nervous stimulation is regulated by humoral factors such as leptin [83]. The mechanism by which these endocrine and sensory feedback signals are integrated into the brain, as well as the potential interplay between these signals, remains poorly understood. However, these findings suggest that this integration is likely critical for generating appropriate behavioral responses and hormonal regulation via hypothalamus-derived autonomic nervous signaling to maintain metabolic homeostasis, potentially regulating aging (Figure 2).

The hypothalamus functions as a high-order control center of aging and longevity

Decline in metabolic homeostasis and plasticity is a common characteristic of aging. In 2013, two independent groups reached the same conclusion regarding the importance of the hypothalamus in mammalian aging and longevity. The mammalian NAD⁺-dependent protein deacetylase SIRT1 in the hypothalamus, particularly in the DMH and lateral hypothalamic nuclei (LH), plays a critical role in delaying aging and extending the lifespan of mice [84]. Another group demonstrated that inhibiting nuclear factor-κB (NF-κB) in neurons of the mediobasal hypothalamus (MBH) extends the lifespan of mice, whereas activating NF-κB in MBH neurons shortens their lifespan [85]. Since these groundbreaking findings, hypothalamic dysfunction has been increasingly acknowledged as a significant cause of aging phenotypes at the systemic level [86,87]. For example, mice lacking hypothalamic mTORC2 signaling display reduced activity levels, an elevated set point for adiposity, increased susceptibility to diet-induced obesity, heightened frailty with age, and shorter overall survival [86]. Prdm13, a downstream target of SIRT1 signaling in the dorsomedial hypothalamus (DMH), regulates lipolysis in WAT and sleep-wake patterns, both of which are dysregulated during aging, and mediates the effect of caloric restriction in improving sleep in aged mice [88,89]. DMH-specific Prdm13-knockout mice recapitulate age-associated sleep alterations such as sleep fragmentation with increased adiposity and decreased physical activity, resulting in a shortened lifespan. In contrast, overexpression of Prdm13 in the DMH can ameliorate increased sleep attempts during sleep deprivation in old mice [89].

The hypothalamus is also essential for the regulation of hormone production. For example, hypothalamic secretion of gonadotropin-releasing hormone (GnRH) is impaired during aging, resulting in decreased pituitary secretion of luteinizing hormone [90] and loss of hypothalamic neural stem/progenitor cells (hNSCs) [71]. While the exact mechanism by which GnRH neurons and hNSCs in the MBH regulates aging and lifespan remains unknown, several supportive studies have demonstrated the importance of specific hypothalamic regions in aging and longevity control [71,85,91,92]. Inflammation in the MBH has been causally linked to the pathogenesis of aging phenotypes and metabolic dysfunction [93]. Menin signaling in the ventromedial hypothalamus has recently been shown to reduce inflammatory conditions and counteract systemic aging and cognitive deficits [87]. Additionally, whole hypothalamic single-cell RNA sequencing analysis revealed a clear age-associated induction of inflammatory signaling in microglia and macrophages [94], suggesting that chronic inflammation within the hypothalamus causes detrimental effects on metabolism and induces aging.

Over the past decade, increasing lines of evidence have demonstrated that maintaining a youthful sympathetic nervous system (SNS) plays an essential role in counteracting aging through the IOCs between the hypothalamus and peripheral tissues (Figure 2). Brain-specific SIRT1-overexpressing (BRASTO) mice significantly delay aging and lifespan extension. BRASTO mice also maintain the youthful structure and function of the mitochondria in skeletal muscle during aging due to enhanced SNS [84]. Indeed, hypothalamic SIRT1 induces activation of the sympathetic nervous system, protecting the structure of neuromuscular junctions in skeletal muscles from age-related deterioration [95]. A subset of neurons in the LH expressing solute carrier family 12 member 8 (Slc12a8), which encodes a specific transporter for nicotinamide mononucleotide, also maintains the structure and function of fast-twitching skeletal muscles during aging through β2 adrenergic receptor-mediated sympathetic nervous stimulation. Restoring Slc12a8 expression in the LH can ameliorate age-associated sarcopenia and frailty-like symptoms in aged mice [96].

Most recently, it has been demonstrated that the IOC between the hypothalamus and WAT plays a crucial role in mammalian aging and longevity control. A newly identified neuronal subpopulation in the DMH, marked by protein phosphatase 1 regulatory subunit 17 (Ppp1r17) expression (DMH^Ppp1r17 neurons), counteracts aging and determines lifespan through the IOC between the hypothalamus and WAT via SNS. An age-associated decline in DMH^Ppp1r17 neuronal activity leads to physiological functional decline, including a significant reduction in physical activity, lipolysis, and eNAMPT secretion from WAT. Importantly, activation of DMH^Ppp1r17 neurons by genetic and chemogenetic manipulations in aged mice ameliorates age-associated physiological decline, delaying aging and extending lifespan [11]. Given that eNAMPT-containing EVs promote NAD⁺ biosynthesis specifically in the DMH [97], it is conceivable that DMH^Ppp1r17 neurons and WAT comprise a key feedback loop for aging and longevity control through the combination of neuronal and humoral IOCs. These findings provide critical insights into the importance of IOC in mammalian aging and longevity control. It will be of great importance to understand how the function of this key IOC is disrupted during aging. In addition to the IOC between the hypothalamus and WAT, it is likely that IOCs between the hypothalamus and other peripheral tissues, including skeletal muscle, also cooperate to maintain metabolic resilience and regulate aging and longevity in mammals. These recent discoveries have opened a new avenue to explore the precise mechanisms by which IOCs regulate metabolism and aging, and further investigations are required to elucidate such underlying mechanisms.

Concluding remarks and future perspectives

IOCs represent dynamic and multifaceted physiological processes that are now clearly gaining more attention in metabolic and aging research. As enthusiasm for the mechanistic details of IOC grows, there is an urgent need to develop novel biological tools to identify systems that deliver effector molecules and analyze the interactions between different effector molecules. By unraveling the intricate signaling mechanisms that govern tissue crosstalk, we will gain new insights into the pathophysiology of age-related metabolic derangements and identify novel therapeutic targets to promote healthy aging and longevity. For instance, newly identified signaling molecules mediating IOCs between the hypothalamus and peripheral organs could be used to maintain the strength of targeted IOCs and treat or prevent age-related dysfunctions. We are only beginning to understand how distinct IOCs regulate diverse physiological processes that maintain metabolic resilience and thereby counteract aging. Several outstanding questions remain to be answered to better understand the mechanisms by which IOCs regulate metabolism and aging (see Outstanding Questions).

Outstanding Questions.

Is the IOC a critical determinant for lifespan? If so, is there any specific subset of hypothalamic neurons that controls aging and determines lifespan?

What triggers the deterioration of IOCs in the regulation of metabolism and aging? Where and how does the decline in IOCs start?

How do each IOC, such as the hypothalamus-WAT and the hypothalamus-skeletal muscle, interact with each other in mammalian aging and longevity control?

How do sex differences in IOCs impact the regulation of metabolism and aging?

The hypothalamus functions as a key central hub for IOCs. Additionally, numerous approaches for extending lifespan in animal models, such as specific dietary regimens and metabolic and genetic manipulations, involve the hypothalamus. Despite extensive research in this area over several decades, the complexity of each individual hypothalamic nucleus and the lack of good molecular markers for each neuronal subpopulation still create serious technical challenges in analyzing and manipulating hypothalamic neuronal functions [98]. Our challenge to understand the exact mechanisms by which IOCs between the hypothalamus and peripheral organs regulate metabolism and aging has just begun.

Highlights.

Adipose tissues, skeletal muscle, and bone, traditionally categorized as non-endocrine organs, send humoral signals to others to maintain metabolic homeostasis.

Humoral factors, such as hormones, cytokines, microRNAs, metabolites, and mitochondrial signaling, contribute to metabolic health and aging regulation through inter-organ communication (IOC).

Neuronal integration of IOC by the hypothalamus is a critical contributor to metabolism and aging.