The Insulin–IGF-1 Signalling Axis in Aging: Metabolic Hormones as Targets for Longevity

The insulin and insulin-like growth factor-1 (IGF-1) signalling (IIS) axis is one of the most evolutionarily conserved pathways in the biology of aging. From nematodes to mammals, attenuation of IIS signalling has been repeatedly shown to extend lifespan, reduce age-related disease burden, and promote metabolic resilience. Yet despite decades of research, how this pathway governs the rate of aging in humans and how it can be safely modulated remains incompletely understood.Insulin and IGF-1 act through overlapping receptor tyrosine kinase cascades, converging on key effectors including PI3K, AKT, mTORC1, and FOXO transcription factors — molecular hubs that integrate nutrient sensing with autophagy, DNA repair, proteostasis, and oxidative stress resistance. Dysregulation of this axis underpins many hallmarks of aging and is mechanistically linked to type 2 diabetes, sarcopenia, neurodegeneration, and cardiovascular disease. Its deep interconnection with mTOR, AMPK, sirtuins, and the growth hormone axis further creates a tissue-specific regulatory landscape rich with therapeutic opportunity.This Research Topic welcomes contributions spanning molecular, cellular, physiological, and clinical dimensions. The scope below reflects the breadth and depth of the field, and authors are encouraged to engage with these themes in an integrative and mechanistically rigorous way.Healthspan versus lifespan — Decoupling survival from function. A central priority of this collection is to move beyond survival curves as the primary readout of IIS modulation. Strong IIS inhibition can extend lifespan while leaving functional aging trajectories intact or even worsened, and late-life IGF-1 deficiency in mice does not reliably extend lifespan. Studies employing multi-dimensional functional metrics — including motility, cognitive performance, immune competence, and tissue integrity — are strongly encouraged alongside or in place of mortality-based endpoints.Sex as a mechanistic variable — Sex differences in IIS signalling are not a secondary consideration but a central organising theme of this collection. Divergent hormonal environments, body composition, and metabolic phenotypes between males and females produce fundamentally different IIS trajectories across the lifespan. Contributions that examine sex as a primary biological variable, including studies of sex-specific FOXO activity, IGF-1 receptor expression, and differential responses to dietary or pharmacological interventions, are particularly welcome.Tissue-specific and cell-non-autonomous IIS coordination — IIS does not operate uniformly across tissues. Inter-tissue communication and cell-non-autonomous regulation — whereby IIS activity in one tissue influences aging trajectories in distal organs — represent an important and underexplored dimension of the field. We welcome work on brain, muscle, liver, and vascular IIS signalling, as well as studies addressing how systemic IIS coordinates organ-level aging responses.The gut microbiome as an IIS modulator — Microbial metabolites, including short-chain fatty acids and bile acid derivatives, directly regulate insulin sensitivity and downstream IIS activity. Dietary restriction, one of the most robust IIS-modulating interventions, also substantially reshapes the gut microbiome. Contributions exploring the microbiome-IIS interface, including the mechanisms by which microbial communities influence metabolic aging, are an important part of this collection.Circadian–IIS crosstalk — The circadian clock and the IIS axis are reciprocally regulated, with disruption of circadian rhythmicity accelerating insulin resistance and metabolic aging. This emerging area of research is explicitly within scope, including studies on clock-controlled IIS gene expression, time-restricted feeding, and chronobiological modulation of longevity pathways.Inflammaging and immunosenescence as IIS outputs — Chronic low-grade inflammation and the progressive decline of immune function are discrete and measurable outputs of IIS dysregulation. Inflammaging and immunosenescence should be treated as primary endpoints rather than incidental observations, and contributions addressing the mechanistic links between IIS, NF-κB signalling, senescent cell burden, and immune aging are strongly encouraged.Natural human IIS loss-of-function cohorts — Human populations with naturally occurring IIS loss-of-function mutations — including individuals with Laron syndrome and IGF-1 receptor haploinsufficiency — offer the most direct evidence available for the IIS-longevity axis in our species, including demonstrated protection from cancer and type 2 diabetes. Studies drawing on these cohorts, or integrating their findings into translational frameworks, address a notable gap in the current literature and are a priority for this collection.Pharmacological and dietary modulation — We welcome studies on established and emerging interventions including metformin, rapamycin, IGF-1 receptor modulators, caloric restriction, and time-restricted feeding, with particular interest in work that addresses long-term safety, tissue specificity, and functional rather than purely survival outcomes.Multi-omics and computational approaches — Contributions integrating multi-omic datasets — including single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, proteomics, metabolomics, and epigenomics — to map the IIS interactome are strongly encouraged. The application of machine learning and AI-driven approaches to IIS network analysis and biomarker discovery represents a rapidly growing frontier that this collection explicitly welcomes.We invite Original Research, Review, Mini Review, Perspective, Clinical Trial, Systematic Review, and Meta-Analysis articles, particularly those bridging basic science and clinical application. Topic editors: Janaina Lombello Santos Donadio, Andrey Santos Source: https://www.frontiersin.org/research-topics/82260/the-insulin-igf-1-signalling-axis-in-aging-metabolic-hormones-as-targets-for-longevity