Editorial: Nutrition as a pharmacological approach to metabolic disorders and ageing

Modifying lifestyle and dietary habits is widely recognized as a powerful strategy for counteracFng diseases associated with metabolic dysfuncFon (e.g., obesity, ageing) and represents the first line of intervenFon (Baskin and Karp, 2025). In the classical biochemical view, food-derived molecules are regarded primarily as substrates for energy producFon. However, growing evidence indicates that specific nutrients acFvely modulate metabolic health, influencing both disease development and prevenFon (Ruocco et al., 2021). These bioacFve components (i.e., amino acids, short-chain fa`y acids, polyphenols) regulate signalling pathways, interact directly with proteins, and shape the gut microbiota (Ryan and Seeley, 2013;MenicheO et al., 2025). Consistently, more than 139,000 dietary compounds have been idenFfied with potenFal biological acFvity, and approximately 2,000 are already employed for pharmacological purposes (MenicheO et al., 2025).In other words, owing to their mechanisms of acFon, nutrients may be closer to drugs than to the simple energy substrates tradiFonally defined in nutriFonal biochemistry. Together, these insights emphasize that the qualitaFve composiFon of the diet, beyond caloric content, plays a crucial role in determining whole-body metabolism, longevity, and health span (Fig. 1).Ageing and obesity are associated with several chronic diseases, including cardiovascular disorders, type 2 diabetes (T2D), leaky gut, metabolic dysfuncFon-associated steatoFc liver disease (MASLD), and cancer. They also share hallmark features such as systemic inflammaFon, reduced mitochondrial acFvity, excess reacFve oxygen species (ROS) producFon, and impaired metabolic flexibility across organs and Fssues (BraFc and Larsson, 2013;Muoio, 2014). These common features suggest that both condiFons arise from overlapping cellular and molecular pathways regulaFng metabolic health. Moreover, long-term obesity has been associated with the expression of molecular ageing signatures during young adulthood in both females and males, reinforcing the view that obesity may consFtute a state of accelerated biological ageing (Correa-Burrows et al., 2025).Metabolic homeostasis depends on a highly integrated network of signalling pathways, and perturbaFons in any component of this system can propagate across Fssues, ulFmately leading to mulF-organ dysfuncFon (Sung et al., 2023). In this context, the chronic consumpFon of a Western diet rich in processed foods, sugars, and unhealthy fats promotes chronic inflammaFon in mulFple organs (Clemente-Suárez et al., 2023), driving adipose Fssue expansion and dysfuncFon, factor that The Lancet Commission idenFfied as key determinants of the clinical manifestaFons of obesity (Rubino et al., 2025). In turn, the resulFng metabolic disturbances impair nutrient uFlizaFon (i.e., fa`y acids, amino acids, and glucose) and contribute to the development of obesity-related diseases (Sung et al., 2023) (Fig. 1).Challenging the noFon that "a calorie is just a calorie," this Research Topic examines how nutrient quality shapes metabolic health and contributes to the prevenFon or miFgaFon of metabolic diseases. Despite increasing recogniFon of the therapeuFc potenFal of nutrients, mechanisFc understanding remains incomplete and is currently the subject of extensive research.The bibliometric analysis included in this Research Topic confirms the rapid expansion of studies in this area. Notably, citaFon burst analysis in the field of vitamin D reveals a shij from an early emphasis on correlaFon-based studies (e.g., associaFons between vitamin D levels and obesity or the effects of dietary calcium supplementaFon) toward invesFgaFons exploring causal relaFonships between obesity and vitamin D deficiency, as well as the prevenFve or therapeuFc effects of vitamin D supplementaFon in metabolic diseases (Song et al. 2024).SubstanFal inter-and intra-individual variability in nutrient metabolism, shaped by sex, age, geneFcs, and physiological state, is criFcal for understanding metabolic responses to nutriFonal intervenFons. Such variability provides key insights into the molecular mechanisms through which dietary restricFon (DR) may influence lifespan (Mihaylova et al., 2023). In this context, Ruocco et al.discuss DR, long considered a universal "magic bullet" for longevity. Human studies, including the CALERIE trial, show that moderate DR improves cardiometabolic health and modulates pathways related to proteostasis, DNA repair, mitochondrial funcFon, and inflammaFon, while revealing links between cellular senescence and metabolic health (Kitzman et al., 2016;Aversa et al., 2024).However, DR responses vary markedly, geneFc background can outweigh the intervenFon itself, and sex-specific factors criFcally shape lifespan outcomes (Di Francesco et al., 2024) (Ruocco et al. 2024).Together, these findings underscore the necessity of personalized nutriFonal intervenFons that account for biological variability to effecFvely promote health span (Fig. 1).Building on previous evidence demonstraFng the prevenFve and therapeuFc effects of essenFal amino acids (EAA) in obesity and insulin resistance (Ruocco et al., 2020) (Ruocco et al., 2022).Ageing, as well as obesity, is accompanied by metabolic alteraFons that drive cellular senescence. Consequently, targeFng senescence has emerged as a promising strategy to counteract these processes and improve metabolic health (Childs et al., 2015;Zumerle et al., 2024). Accordingly, He et al. report that ageing induces senescence in tongue mucosa and disrupts amino acid, and carbohydrate metabolism. Carnosine levels decline with age in both mice and humans, suggesFng its potenFal as a biomarker of ageing, whereas carnosine supplementaFon, a`enuates oxidaFve stress-induced senescence and lowers p21 and β-galactosidase expression (He et al. 2025).Increasing evidence indicates that cellular senescence is a significant risk factor for atherosclerosis, a condiFon closely linked to both ageing and obesity. Tao et al. show that sodium nitrate supplementaFon reverses atheroscleroFc lesions in apolipoprotein E knockout mice fed HFD, a classical preclinical model of atherosclerosis, while reducing vascular inflammaFon and prevenFng senescence. These effects are mediated through modulaFon of the miR-34a-FGF21 axis, highlighFng how nutrient-derived intervenFons can exert anF-senescent and vasculo-protecFve acFons (Tao et al. 2025).Together, these findings reinforce the concept that specific nutrient composiFons can act as metabolic modulators by restoring mitochondrial funcFon, enhancing anFoxidant defences, reducing senescence, and lowering inflammaFon across organs and Fssues, thereby prevenFng or reversing metabolic disturbances associated with obesity and ageing (Fig. 1).Obesity and ageing are also major associated with cancer development, a condiFon characterized by mitochondrial dysfuncFon and metabolic reprogramming that drive tumour cells toward aerobic glycolysis (i.e., Warburg effect) and amino acid addicFon (Ragni et al., 2022a).Branched chain amino acids (BCAAs) can fuel tumour growth, raising concerns about their supplementaFon in nutrient-based anF-cancer strategies. In this Research Topic, Zhou et al. highlight that many tumours undergo BCAA metabolic rewiring, with some cancers overexpressing key catabolic enzymes and others exhibiFng elevated BCAA levels that promote mechanisFc target of rapamycin acFvaFon. Notably, BCAA supplementaFon improves survival in hepatocellular carcinoma paFents, whereas colorectal cancers display inhibiFon of BCAA catabolism (Zhou et al. 2025).Conversely, EAA-enriched diets can impair tumour growth in mice by sFmulaFng BCAA catabolism, restoring metabolic flexibility, and promoFng apoptosis selecFvely in cancer cells (Ragni et al., 2022b). These findings underscore the context-dependent nature of amino acid metabolism, which varies according to tumour type and reflects the inherent complexity of amino acid metabolic pathways.Accordingly, Akinlalu et al. comprehensively review the cancer-specific and ojen exclusive metabolic roles of individual amino acids, proposing tailored supplementaFon or withdrawal strategies, as well as targeFng amino acid transporters. They further argue that mapping amino acid metabolic heterogeneity across cancer types may yield diagnosFc biomarkers and guide precision nutriFon-based therapies (Akinlalu et al. 2025). This is confirmed by Liu et al., who report in a nested case-control study that higher serum taurine correlates with reduced overall cancer risk, elevated Sadenosylmethionine (SAM) with increased gastrointesFnal cancer incidence, and cysteine with cancer risk in women. However, Bayesian Kernel Machine Regression revealed that the combined mixture of taurine, SAM, and cysteine was negaFvely associated with cancer risk, indicaFng a complex, non-linear interacFon among these metabolites (Liu et al. 2024).NutriFonal strategies may also support the management of cancer-associated condiFons such as cachexia, a disorder characterized by muscle wasFng, inflammaFon, and metabolic dysfuncFon. Faiad et al. highlight that early, individualized nutriFonal intervenFons, parFcularly high protein intake and anabolic amino acids (e.g., BCAAs), can help a`enuate muscle loss and inflammaFon, especially when combined with supplements such as arginine, omega-3 fa`y acids, glutamine, and β-hydroxy-β-methylbutyrate. However, clinical evidence supporFng the use of carniFne, omega-3 fa`y acids, or anFoxidants such as resveratrol, curcumin, and EGCG when administered individually remains limited and inconclusive (Faiad et al. 2025).Building on the concepts summarized in this Research Topic, it is increasingly clear that treaFng obesity and ageing as whole condiFons, rather than as clusters of individual complicaFons, may offer a more effecFve strategy for improving health span (Garmany et al., 2021;Rubino et al., 2025). Within this framework, nutrient-based intervenFons, by targeFng mitochondrial funcFon, anFoxidant and anF-inflammatory pathways, and cellular senescence, represent powerful therapeuFc tools, either as alternaFves or complements to pharmacological treatments, which, despite their efficacy, are ojen limited by adverse side effects. This is parFcularly relevant given the rapid rise of increFn-based drugs, such as GLP-1R agonist (i.e., semagluFde), GLP-1R/GIPR dual agonists (i.e., FrzepaFde), or next-generaFon triple agonists (GLP-1R/GIPR/GlucagonR), which exhibit unprecedented clinical efficacy in metabolic disease management. Notably, evidence that FrzepaFde induces a thermogenic-like amino acid signature in brown adipose Fssue (i.e., increase of energy expenditure), similar to that observed with nutrient-based intervenFons such as EAA feeding, highlights a mechanisFc convergence between drugs and nutrient modulaFon of metabolism (Samms et al., 2022;Ruocco et al., 2023). Yet, increFn-based therapies pose nutriFonal challenges, including lean mass loss, underscoring the need for tailored dietary strategies encompassing adequate protein intake, amino acid support and resistance training (Ben-Porat et al., 2025). Altogether, these insights emphasize the importance of integraFng personalized nutriFonal approaches with pharmacological treatments to opFmize metabolic health and promote longevity.Figure 1. Nutri-on as a pharmacological approach: From organ damage to health by restoring metabolic flexibility. The figure illustrates nutrients as metabolic modulators that directly influence metabolic flexibility (i.e., the ability to switch efficiently between fuel sources in response to changing metabolic demands) with sex-specific differences. Diets high in sugars, unhealthy fats, and ultra-processed foods (e.g., a Western-style diet) promote mitochondrial dysfuncFon, increased reacFve oxygen species (ROS) producFon, cellular senescence (e.g., the senescence-associated secretory phenotype, SASP), and chronic inflammaFon. These processes drive metabolic inflexibility across mulFple organs and Fssues (adipose Fssue, liver, heart, and skeletal muscle), ulFmately contribuFng to organ damage and metabolic diseases (e.g., obesity, ageing, and associated disorders). By contrast, targeted nutrient-based intervenFons, including essenFal amino acids (EAAs), curcumin, polyphenols, and other bioacFve food-derived compounds, can improve mitochondrial funcFon, lower ROS levels, limit senescence, and a`enuate chronic inflammaFon. CollecFvely, these effects support metabolic flexibility at the Fssue/organ level and improve wholebody metabolic health, reinforcing the concept that appropriately designed nutriFonal strategies can funcFon as pharmacological-like tools to prevent or reverse metabolic dysfuncFon.