Omega-3 fatty acids as modulators of advanced glycation end products in aging: mechanistic pathways and clinical implications - a narrative review

Aging is characterised by the progressive accumulation of advanced glycation end products (AGEs), formed through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs contribute to tissue damage through irreversible protein cross-linking and receptor-mediated inflammatory signalling via the receptor for AGEs (RAGE). Elderly individuals are disproportionately affected due to cumulative oxidative stress, chronic low-grade inflammation (inflammaging), impaired renal and enzymatic clearance, and prolonged exposure to dietary AGEs. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may modulate these pathways through anti-inflammatory, antioxidant, and metabolic mechanisms.

To synthesise available preclinical, in vitro, and clinical evidence on the mechanistic and therapeutic relationships between omega-3 PUFA supplementation and AGE formation, accumulation, and signalling, and to evaluate the effects of omega-3 supplementation on key age-related clinical outcomes in elderly populations, including cardiometabolic health, cognitive function, mental health, functional capacity, and quality of life.

A narrative review was conducted using searches of PubMed, Scopus, and Web of Science. Eligible study designs included in vitro experiments, animal models, randomised controlled trials (RCTs), observational studies, and systematic reviews published in English. Evidence was synthesised thematically across mechanistic and clinical domains, with priority given to studies addressing AGE-related pathways and clinically relevant endpoints.

Preclinical evidence demonstrates that omega-3 PUFAs attenuate oxidative stress and inflammatory signalling, partly through RAGE axis regulation and PPARγ activation. Clinical studies report reductions in circulating AGEs, RAGE, and pentosidine following supplementation, alongside upregulation of protective scavenger receptors such as AGER1. Omega-3 supplementation has also been associated with improvements in inflammatory markers, cardiometabolic risk, cognitive function, and physical capacity in older adults. However, RCT evidence assessing tissue-level AGE accumulation using non-invasive measures such as skin autofluorescence remains limited in elderly populations.

Omega-3 PUFAs demonstrate therapeutic potential in modulating AGE-related mechanisms and improving age-associated outcomes. Well-designed RCTs targeting tissue AGE accumulation and long-term endpoints in elderly cohorts are warranted.