Targeting Aging Pathways with GLP-1 Analogs: From Metabolic Disorders to Healthspan Extension

During the August convening of the Aging Research and Drug Discovery conference in Copenhagen, representatives from Novo Nordisk and Eli Lilly captivated attendees by positing that glucagon-like peptide-1 receptor agonists (GLP-1RAs)—widely recognized for their efficacy in managing obesity and type 2 diabetes—may represent the inaugural class of longevity therapeutics. In addition to their exceptional performance in these metabolic conditions, accumulating evidence over recent years has demonstrated their capacity to mitigate associated comorbidities. This includes reductions in cardiovascular events such as myocardial infarction, cerebrovascular incidents, heart failure, and peripheral arterial disease, as well as improvements in renal and hepatic function, knee osteoarthritis, and obstructive sleep apnea. The succession of regulatory approvals and pivotal clinical investigations has fueled discussions in scientific literature regarding these agents as multifaceted interventions potentially warranting widespread prophylactic use. While comprehensive delineation of their therapeutic scope will necessitate rigorous longitudinal studies, preliminary indications of efficacy against various age-associated chronic pathologies are evident, particularly in individuals with underlying metabolic dysregulation. For the broader population, however, empirical data remain insufficient. Nonetheless, the convergence between leading GLP-1RA developers and the longevity research domain underscores a paradigm shift toward pharmacological agents that exert pleiotropic effects on diverse pathophysiological mechanisms, paving the way for preventive strategies that identify vulnerabilities early and deploy sustained interventions to avert disease onset.

Therapeutics aimed at extending healthspan present distinctive opportunities and obstacles relative to conventional biopharmaceuticals. Given that chronological aging constitutes the predominant risk factor for late-onset disorders—including cardiovascular disease, stroke, malignancy, Alzheimer’s disease, and osteoarthritis—interventions targeting core aging processes could theoretically confer protection against a spectrum of conditions simultaneously. Aging per se is not formally classified as a pathological entity; at a macroscopic level, it manifests as progressive multisystem deterioration resulting from an imbalance between accumulative insults and intrinsic reparative mechanisms. These insults encompass environmental exposures such as ultraviolet radiation and modifiable behaviors including dietary patterns, physical activity, sleep quality, psychosocial stressors, environmental toxins, interpersonal relationships, and access to medical services. Over decades, investigations into the quantification, modulation, and underlying biology of aging have advanced the field toward molecularly precise pharmacological interventions.

Pivotal experiments in the 1990s established aging as a genetically tractable phenomenon by demonstrating that organismal lifespan is modulated by specific loci and amenable to genetic perturbation. Ensuing inquiries elucidated evolutionarily conserved molecular cascades implicated in aging, culminating in the delineation of nine hallmarks of aging in 2013 (ref. 1), subsequently refined to encompass 12 and later 14 attributes (ref. 2). These encompass perturbations at genomic, epigenomic, proteomic, mitochondrial, cellular, extracellular, and organismal scales, characterized by interdependent networks, overlapping signaling pathways, and variable measurability. Concurrently, high-throughput omics profiling coupled with computational algorithms has yielded predictive models and biological clocks that estimate chronological deviations, tissue-specific aging trajectories, and prognostic indicators, alongside facilitating the identification of therapeutic targets and biomarkers suitable for validation as surrogate endpoints in clinical contexts.

The 2006 revelation by Shinya Yamanaka that a discrete set of transcription factors can induce somatic cell reversion to a pluripotent state underscored the malleability of cellular senescence and the feasibility of rejuvenation. This paradigm has been leveraged in anti-aging paradigms via partial reprogramming protocols, which induce age reversal without full dedifferentiation, as exemplified by recent applications in counteracting mesenchymal stem cell lineage drift (ref. 3).

The lexicon surrounding “longevity” encompasses multiple connotations, potentially engendering ambiguity; however, the Longevity Biotechnology Association has articulated clarifying criteria (ref. 4). Accordingly, a longevity therapeutic modulates at least one aging pathway, exhibits potential to ameliorate or forestall multiple age-associated pathologies, and thereby augments healthspan—defined as the duration of functional well-being. Although such agents are anticipated to prolong lifespan indirectly through disease mitigation, empirical assessments indicate that societal priorities emphasize enhanced vitality over mere chronological extension. Prioritizing healthspan is pragmatically advantageous, as trials predicated on lifespan endpoints demand prohibitive scale, duration, and expenditure absent robust surrogates.

To date, no gerotherapeutic has achieved regulatory endorsement, though certain extant pharmaceuticals might qualify upon rigorous evaluation (ref. 5). The United States Food and Drug Administration does not acknowledge aging as an approvable indication, lacking a dedicated pathway for geroprotective modalities. Consequently, contemporary anti-aging trials are constrained to discrete age-related indications. Human evaluations of candidates such as anti-inflammatory compounds, sirtuin agonists, senolytic agents, nicotinamide adenine dinucleotide precursors, metformin, and rapamycin have yet to substantiate deceleration of aging or delayed multimorbidity onset. The termination of GlaxoSmithKline’s substantial investment in sirtuin activation, following acquisition from Sirtris Pharmaceuticals, marked a significant impediment. In contrast, GLP-1RAs demonstrate superior metabolic potency and are supported by extensive human datasets.

The Copenhagen symposium was not the inaugural intersection of GLP-1RAs and geroscience, nor the initial foray of pharmaceutical entities into longevity; nevertheless, the presentations by prominent figures Lotte Bjerre Knudsen of Novo Nordisk and Andrew Adams of Eli Lilly, addressing the geroprotective attributes of these compounds to an aging-focused audience, were perceived as a watershed moment. Their discourses highlighted evolving preventive paradigms and the multisystemic advantages of GLP-1RAs, spanning pancreatic, gastrointestinal, cardiovascular, vascular, cerebral, renal, and hepatic domains, alongside reductions in all-cause mortality in select cohorts.

Among individuals with obesity or type 2 diabetes, randomized trials and observational data affirm that GLP-1RAs attenuate age-related comorbidities in high-risk subsets. Enhancements in cardiovascular endpoints and overall survival have been documented in diabetic populations (ref. 6) and in non-diabetic obese cohorts (refs. 7,8). Notably, approximately one-third of cardiovascular gains in the latter were independent of adiposity reduction (ref. 9), implicating alternative mechanisms like anti-inflammatory pathways with potential applicability beyond metabolic syndromes. Critically, these benefits predominantly manifest in elevated-risk groups, constraining extrapolation; discerning effects in lower-risk demographics necessitates amplified trial power, and diminishing returns may erode therapeutic viability.

The extent to which GLP-1RAs satisfy longevity criteria—encompassing prophylaxis or management of diverse aging pathologies—awaits elucidation. Published investigations in euglycemic, non-obese populations are absent, and such inquiries may be deferred. Nonetheless, evaluations in non-metabolic indications are commencing. The anti-inflammatory and immunomodulatory profiles of GLP-1RAs intimate expansive utility, including in cardiovascular, neuroinflammatory, and autoimmune disorders. Weight-independent antifibrotic actions have contributed to efficacy in metabolic dysfunction-associated steatohepatitis (ref. 10). The ongoing phase 3 EVOKE and EVOKE+ trials (ref. 11) assess semaglutide in prodromal Alzheimer’s disease, building on favorable dementia outcomes in diabetic cohorts (ref. 12), wherein diabetes elevates risk. These studies, which omitted phase 2, incorporate substantial non-diabetic participants; affirmative findings would bolster assertions of pan-geroprotective efficacy.

Optimizing GLP-1RA utility for longevity entails systematic interrogation of parameters including indications, molecular analogs, delivery modalities, regimens, combinatorial profiles, biomarkers, and adverse event mitigation strategies. Exploratory gene therapy initiatives seeking meal-responsive GLP-1 secretion are also underway. Contemporary discontinuation rates for GLP-1RAs are elevated, attributable to tolerability issues and economic barriers. Compliance challenges similarly afflict preventive regimens like statins, which lack perceptible symptomatic relief. Gerotherapeutic success hinges on sustained safety and efficacy across decades, accessibility, protracted duration of action, and personalized implementation.

Advancing GLP-1RA applications to geroscience-relevant domains relies on data analytics to interrogate trial datasets and interpret voluminous, temporally resolved real-world evidence from heterogeneous patient cohorts. Such methodologies can illuminate mechanistic underpinnings, refine experimental frameworks for prioritized hypotheses, and facilitate individualized therapeutic optimization.

Beyond GLP-1RAs, burgeoning engagement in longevity by entities like Novo Nordisk and Eli Lilly encompasses diverse modalities. Attenuating inflammaging—persistent low-grade inflammation underpinning age-associated pathologies—via inhibition of inflammasome components such as NLRP3 holds promise for healthspan extension. The cGAS-STING axis represents another inflammaging target. Alternatively, apelin mimetics, exercise-induced signaling factors, promote anti-aging effects and myogenesis in preclinical models, addressing sarcopenia in geriatric frailty. Further candidates include myostatin and activin type II receptor antagonists for muscle atrophy, NR3C1 modulation for metabolic homeostasis, interleukin-11 blockade for fibrosis, PHD1/2 inhibition for anemia and epithelial integrity, and orexin receptor agonists for sleep disturbances.

In the United States, average life expectancy stands at 79.3 years, trailing Hong Kong by six years and Canada by three, ranking 63rd globally. Annual expenditures on age-related chronic conditions exceed trillions of dollars. Interventions targeting etiological substrates to postpone or preclude these afflictions would revolutionize healthcare economics and quality of life.

Two decades have elapsed since the inaugural GLP-1RA approval for type 2 diabetes. Subsequent indications have incrementally expanded for populations with diabetes or elevated body mass index, encompassing weight management, cardiovascular protection, sleep apnea, chronic kidney disease, and metabolic dysfunction-associated steatohepatitis. The proposed TAME trial of metformin (ref. 13) advocates a streamlined composite endpoint assessing time to incident cardiovascular events, malignancy, or dementia, enabling detection of concordant signals in modest cohorts. Amid accelerating AI-driven discovery, regulatory innovation in trial methodologies attuned to healthspan paradigms could expedite gerotherapeutic validation, optimize resource allocation, and stimulate industrial investment. Legislative proposals, such as the THRIVE Act spearheaded by a former FDA commissioner instrumental in statin and metformin approvals, seek to establish a framework for healthspan-oriented products.

As articulated by geroscience investigator Alex Zhavoronkov, aging and life are inextricably linked. While immortality remains unattainable, substantial advancements are feasible in prolonging healthful and fulfilling existence.