Beyond GLP‐1s: The blueprint for systemic therapeutics that will reshape aging and medicine

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide (Ozempic, Rybelsus and Wegovy), dulaglutide (Trulicity) and tirzepatide (Mounjaro, Zepbound), have gained attention for weight management. However, viewing these drugs solely through the lens of obesity treatment overlooks their broader potential. The effects of these drugs extend far beyond obesity—research emerging over the last year or so suggests GLP-1 drugs could play a critical role in treating cardiovascular disease, kidney dysfunction, neurodegeneration and possibly even aging itself.1, 2 However, as recent research also demonstrates, there is potential for complications in the form of accelerated aging phenotypes, from macular degeneration to sarcopenia3, 4—thereby highlighting the need for deeper mechanistic insights into how these drugs work. Key questions remain: Why do these drugs have such wide-ranging effects—and can their success be replicated? And, can this replication be achieved in a second-generation form where benefits are realized without any biological costs? The broad system-level effects of GLP-1 drugs were, in fact, anticipated by the Blueprint Theory of Aging (BPT) back in 2023.5 The BPT proposes that much of the aging process is driven by pathological pathways, or patho-pathways, that is the out-of-context activation of biological pathways in the wrong place and/or at the wrong time (and their resulting maladaptive downstream cascade of effects). BPT identifies GLP-1 signalling as one such key ‘patho-pathway’—a biological mechanism that drives widespread disease progression. It predicted that modulating this pathway could have far-reaching implications for disease treatment and age-related decline as early activation of this patho-pathway accelerates aging. Aditionally, BPT provides tools to unpack complications due to network trade-offs. BPT also proposes that drug discovery and disease intervention would be far more effective if focused on other such key patho-pathways—the biological nodes that amplify and drive cascading degeneration and decline. By providing a framework for identifying and mapping these patho-pathways, which are shared across seemingly distinct diseases, BPT could pave the way for a new era of broad-spectrum drug discovery and drug classification. Modern medicine recognizes that age-related diseases are both multifactorial and interconnected, that is, somehow ‘linked’—organ systems interact, and dysfunction in one affects others. Yet conditions like cardiovascular disease, diabetes, kidney disease and neurodegeneration are still treated in isolation. This is despite their frequent co-occurrence, whether as comorbidities (secondary conditions) or as multimorbidity (multiple conditions with no single primary and typically unresolved causes for their co-occurrence). This fragmented approach often overlooks underlying shared mechanisms, contributing not just to suboptimal therapeutic impact (where drugs are inappropriately discarded because they are developed in the ‘wrong’ indication from the start), but to widespread failure. When research focuses narrowly on individual diseases, it tends to rely on well-worn, disease-specific mechanisms and often misses broader drivers that are more likely to underscore the disease—reflected in the 90% clinical drug development failure rate and billions lost on narrowly targeted treatments.6 Nevertheless, this ‘single-drug-single-disease’ approach persists due to an incomplete understanding of the nature of these links between different diseases. Are diseases connected by genetic programmes, cumulative damage, or by cascading effects of both? And how do environmental factors (e.g., injury and infection) shape individual disease progression? No alternative classification system has emerged to replace the traditional Medical Textbook approach, which categorizes diseases as distinct entities, emphasising their individuality rather than their interconnected nature. BPT introduces the concept of pathological pathways or ‘patho-pathways’—the biological mechanism (i.e., the overarching pathophysiological process) that links and drives multiple diseases. BPT argues that complex disease, and aging itself, result from biological pathways being inappropriately triggered due to network constraints. At a high level, patho-pathways are molecular pathways activated out of context (i.e. dysactivated)—at the wrong time or place. These pathways may reflect dysactivated genetic programmes, or they may arise from molecular and cellular networks activated out of context, operating beyond the scale of genes. Molecular pathways regulate cellular functions, maintaining tissue integrity, organ and system performance. When triggered out of context by environmental factors (e.g., infection, injury and molecular damage) or intrinsic factors (e.g., other patho-pathways), they become pathological, driving destructive cellular processes such as hypertrophy, hyperplasia, dysplasia and atrophy. These changes underlie age-related traits (e.g., wrinkles and sarcopenia) and major diseases (e.g., cancer, arthritis and cardiovascular disease). Patho-pathways emerge because biological pathways operate within densely interconnected networks, making it impossible to optimize all functions simultaneously. Their existence reflects these inherent system trade-offs (Figure 1A). BPT's key insight is that many diseases share the same core patho-pathways—like critical nodes in an electrical grid, where failure amplifies damage across multiple systems. This means that a drug designed for targeting these patho-pathways could be highly effective across multiple disease indications and for aging itself. The success of GLP-1 agonists across multiple diseases and potentially aging is proof of this concept. Existence of conserved patho-pathways also provides an explanation for the origin of multimorbidity (i.e., multiple conditions with no single primary). Put simply, multimorbidity arises because these conserved patho-pathways drive multiple diseases simultaneously (Figure 2). The concept of trade-offs from network constraint identified in the BPT also helps explain the unwanted side effects of GLP-1s in certain contexts. It also hints at how identifying the next generation drugs can be achieved, where trade-off costs are mitigated. In particular, this is by identifying and targeting key patho-pathways that are not ‘programmed’, that is, arising outside the level of gene regulation (cf., necrosis patho-pathway, where necrosis underlying degeneration across organs and biology is an un-programmed process; Figure 2 and Table 1). Summary: Systemic inflammation triggers reduction of GLP-1 secretion from gut L-cells, driving a patho-pathway linked to reduced satiety and increased food intake. This contributes to systemic inflammation via secondary patho-pathways (which due to a positive feedback loop worsens the GLP-1 patho-pathway) and elevates blood levels of free fatty acids (FFA) and glucose, fuelling multiple diseases. Obesity is a prime example of how this chain of events unfolds, with three stages identified5: (i) Early stage: Increased food intake leads to fat accumulation, causing adipocyte expansion to its limit, resulting in hypoxia and triggering pro-inflammatory patho-pathways (e.g., TNFα increase). These in turn trigger patho-pathways of insulin resistance in adipocytes, leading to FFA release into the circulation from the adipose tissue (Stage 1). (ii) Mid-stage: FFA are taken up by organs like the liver and muscle, which are ill-equipped for fat storage, leading to lipotoxicity and conditions like metabolic dysfunction-associated steatotic liver disease (MASLD; formerly non-alcoholic fatty liver disease (NAFLD) (Kanwal et al., 2024)). This is via lipotoxicity induced patho-pathways of local insulin resistance and inflammation, creating a feedback loop that drives systemic insulin resistance and inflammation that is characteristic of metabolic syndrome (Stage 2). (iii) Late stage: Insulin resistance in the liver and muscle triggers patho-pathways of dysactive gluconeogenesis and reduced glucose catabolism, increasing blood glucose. This contributes to pancreatic insulin resistance, which in turn causes patho-pathways of reduced glucose uptake at muscle, culminating in type 2 diabetes (Stage 3). Further secondary patho-pathways: Lipotoxicity, high glucose, and inflammation cause tissue damage through an exaggerated wound healing response (e.g., fibrosis), which destroys organ microarchitecture (e.g., MASLD progresses to liver fibrosis and cirrhosis). Elevated glucose, FFA, and inflammation (that affect mRNA integrity) also trigger patho-pathways of vascular calcification, explaining the calcium paradox. While high blood calcium is not critical to vascular calcification, it does worsen the condition. Vitamin D (vit D) retention in the adipose tissue triggers dysactivity of parathyroid hormone (PTH) and together with inflammation, this induces patho-pathways of calcium retention by the kidney and enhanced bone resorption via driving patho-pathways of osteoclast dysactivity in the bone. Together, these changes increase blood calcium levels that worsen ectopic calcification progression. Finally, worsening systemic inflammation can trigger neurodegeneration via microglial dysactivity. For example, systemic inflammation is increasingly linked to Alzheimer's disease, as immune signals enter the brain through various pathways (e.g., brain barriers and vagal nerve). This leads to neuroinflammation, exacerbating amyloid beta and tau pathologies, which drive cognitive decline. Similarly, Parkinson's disease is linked to neuroinflammation worsened by systemic inflammation. Summary: Stress, from disrupted physiology, trauma or acute disease, triggers a necrosis patho-pathway within cells that ultimately leads to irreversible cell death. Necrosis serves as a key upstream mechanism, positioned at the interface between exposure to stressors and the pathways through which they induce deleterious physiological changes, ultimately contributing to frailty. It is also a mechanism that is universally conserved across tissue and organ types. In necrosis, three stages of disease syndrome can be distinguished7: (i) Factors initiating cell stress: Necrosis is a multi-factorial process, initiated by a multitude of diverse stressors. These stressors can have exogenous or endogenous origins and include inflammation, mechanical stress, metabolic by-products like free radicals and associated reactive oxygen/nitrogen species (ROS/RNS), ischemia (characterized by both hypoxia and nutrient deprivation), thermal stress, ionizing radiation, pollutants, and pathogens, among others. (ii) Triggering of an intracellular necrosis patho-pathway: Triggers of stress activate a cascades of change within cells, principally driven by disrupted calcium ion (Ca2+) homeostasis. Uncontrolled increases in intracellular calcium ([Ca2+]i) activate Ca2+-dependent signaling pathways in a heightened and destructive manner. This includes mitochondrial dysactivity, DNA damage, phospholipase dysactivity, calpain dysactivity, loss of integrity and spillage of lysosomal contents, such as hydrogen peroxide and calpain protease, into the cell that in turn go on to digest the cell from the inside out, producing the characteristic ‘necrotic’ appearance. This necrosis patho-pathway can be activated to varying degrees. At high levels, it directly induces cell death via necrosis. While insufficient to cause uncontrolled cell death, low-grade necrosis-associated cellular damage also has other harmful consequences. Notably, the damage can be picked up by various programmed cell death pathways, leading to the simultaneous occurrence of multiple forms of programmed cell death and widespread tissue structural loss through this. Terms like ‘PANoptosis’—referring to the concurrent activation of pyroptosis, apoptosis, and necroptosis—have been introduced to describe this phenomenon. Finally, low-grade necrosis-associated cellular damage may simply result in disrupted cell states inducing, for example, DNA damage that is linked to carcinogenesis. (iii) Patho-pathways associated with cascades of necrosis and a dysactive wound healing response: Following cell necrosis, the release of hazardous intracellular contents in an unregulated manner alongside damage-associated signals go on to trigger cascades of further necrotic cell death alongside a dysactive wound healing response. The latter includes patho-pathways of inflammation, cellular senescence and dysactivity in fibroblasts, resulting in excessive extracellular matrix (ECM) production (e.g., collagen), which contributes to fibrosis and disrupts tissue microarchitecture and function. These changes that are characteristic of aging can lead to chronic diseases, exemplified by the progression from acute kidney injury to chronic kidney disease for instance. Intervening during stage (ii) could significantly mitigate pathological changes following stress.7 The utility of the BPT is in its predictive and explanatory capacity. BPT predicts the systemic benefits of GLP-1 agonists, arguing that drugs targeting core biological pathways would have broad therapeutic effects treating multiple diseases simultaneously. A preprint from 2023 explored semaglutide's impact on inflammation, insulin sensitivity and other pathways, proposing that it could have effects on aging itself in regard to inducers of accelerated aging5 (Figure 2A). This prediction has been validated by the recent surge in research, not only on semaglutide's cardiometabolic benefits but also on its effects when combined with other drugs—such as those preserving lean muscle mass and countering sarcopenia. BPT also makes several additional, yet-to-be-tested predictions regarding GLP-1 drugs (Table 2). BPT can also explain complex conditions previously considered idiopathic (i.e., of unknown etiology) (Figure 1B), such as osteoporosis, where hormonal shifts pathologically hyper-activate bone-remodeling cells, or the calcium paradox, where bone loss contributes to vascular calcification despite normal blood calcium levels.5 The BPT framework paves the way for a new therapeutic classification system, shifting from a focus on individual diseases to targeting key patho-pathways. Rather than categorising drugs by single indications, this approach envisions grouping them based on their effects on core systemic disease mechanisms. For example, while GLP-1 agonists like semaglutide are known for weight loss, much of their benefit demonstrated over the last year—across cardiovascular, renal and CNS health, potentially even for neurodegenerative conditions like Alzheimer's and Parkinson's1, 2—occurs independently of weight reduction. A patho-pathway-based system could transform how we develop and deploy drugs, capturing their full therapeutic potential. By shifting the focus of drug discovery from treating symptoms to targeting underlying biological networks, BPT provides a blueprint for the next generation of medicine, where diseases—and aging itself—can be tackled at their root cause. Beyond GLP-1, BPT has identified other critical patho-pathways that could support a second-generation class of therapeutics with broad system-level effects. One especially promising target is the necrosis-driven degeneration pathway (Figure 2B), which may give rise to an entirely new therapeutic category aimed at halting age-related decline and disease progression.7 Necrosis represents a central node within the network of degeneration: once triggered, it unleashes damaging cascades. Unlike beneficial programmed cell death, which follows tightly regulated genetic programs, necrosis is unregulated, pathological and initiated by cellular damage. Various intrinsic and/or extrinsic stressors—including oxidative stress, metabolic stress, ischemia and lipotoxicity—can converge to induce necrosis, even within the same tissue. At the molecular level, these stressors disrupt calcium ion (Ca2+) homeostasis due to their effects on membrane integrity. Calcium ions are key intracellular messengers, but excessive intracellular calcium ([Ca2+]i) activates multiple futile and destructive Ca2+-dependent pathways—constituting the necrosis patho-pathway—which leads to cellular damage. This includes the activation of phospholipases, proteases, mitochondrial dysfunction and DNA damage. At the tissue level, necrotic cells release harmful intracellular contents, including DAMPs and proteases, in an uncontrolled manner. This promotes further necrosis, chronic inflammation, senescent cell accumulation and fibrosis.7 Targeting the necrosis patho-pathway could thus prevent damaging cascades at molecular, cellular and tissue levels that underpin degeneration in multiple tissues and diseases, including kidney and liver disease, cardiovascular disease and neurodegeneration.7 A key advantage over GLP-1s is the greater resolution of the underlying mechanism and more predictable trade off costs, if any. Since necrosis is not governed by genetic regulation, its suppression is unlikely to carry the compensatory costs often seen with targeting genetically regulated processes.7 GLP-1 receptor agonists like semaglutide are more than just weight-loss drugs—they are a harbinger of a fundamental shift in medicine. The systems-level thinking of BPT highlights the power of targeting shared biological pathways rather than isolated disease symptoms. By focusing on key patho-pathways, we can address interconnected diseases and age-related decline more effectively. As research continues to unravel complex physiological interactions through the BPT, drug classes with broad systemic effects will be key to tackling major diseases and potentially extending healthspan, marking the beginning of a new era in drug discovery. All authors contributed equally to this work. This work did not receive any funding from public, commercial or not-for-profit organizations. Figures were created partially in BioRender. Kern, C.(2025) and partially using images under license from iStock.com. C.K. is CEO of LinkGevity. B.D. and J.A. are part of LinkGevity and formerly held senior leadership positions, director and vice president, respectively, at GlaxoSmithKline (GSK). J.S. has sat on SABs/advisory boards for Lilly, Agenus, Celltrion, Enhanced, Glyphic, Greenmantle, vTv Therapeutics, APIM, Onconox, Medannex, IO Labs, Clinical Ink, Zephyr AI, Benevolent AI, Biozen, Pear Bio, Sable Bio and Linkgevity. He has consulted with Lansdowne partners and Vitruvian. Since 2024 he has been a board member for Graviton Bioscience BV, Etira Therapeutics and Portage, and previously chaired the board of BB Biotech Healthcare Trust PLC. A.J. is Chair of The Court of the London School of Hygiene & Tropical Medicine and sits on the boards and advisory boards of several private and public companies, including Genomics England and LinkGevity, and was formerly committee member of the Science Board to the US Food & Drug Administration. She is a trustee of the British Heart Foundation and Cancer Research Horizons at Cancer Research UK. N.R. D. Nageshwar Reddy is Chairman of the Asian Institute of Gastroenterology and AIG Hospitals (India), was formerly president of the World Endoscopy Organization, and is on the editorial board of a number of journals and media outlets. N.G. is CTO at LinkGevity. T.W. is CEO of Collider Health and trustee of the British Society for Research on Aging. R.F. advises several longevity-focused funds and companies, including LinkGevity, and co-leads the UK BLAST network on aging science and formerly chaired the British Society for Research on Ageing, the International Association of Biomedical Gerontology, and the American Aging Association.