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Epidemiological evidence from observational studies suggests that dietary polyphenols (PPs) – phytochemicals found in a variety of plant-based foods – can reduce the risk of developing type 2 diabetes mellitus (T2DM). Clinical trials have also indicated that PPs may help manage the two key features of T2DM, hyperglycemia and dyslipidemia. Since the incidence of T2DM is dramatically increasing worldwide, identifying food-based approaches that can reduce the risk of developing it and help manage its main risk factors in early-stage disease has clinical and socioeconomic relevance. After a brief overview of current epidemiological data on the incidence of T2DM in individuals consuming PP-rich diets, we review the evidence from clinical trials investigating PP-enriched foods and/or PP-based nutraceutical compounds, report their main results, and highlight the knowledge gaps that should be bridged to enhance our understanding of the role of PPs in T2DM development and management.

Telomere shortening accompanies mammalian aging in vivo, and the burden of senescent cells with short telomeres and a senescence-associated secretory phenotype (SASP) increases with aging. The release into the cytoplasm and the extracellular vesicle-mediated intercellular exchange of telomeric TTAGGG repeats could exert an anti-inflammatory activity by preventing the activation of the misplaced nucleic acid-sensing pathway. Many pharmacological and genetic strategies have been developed to prevent telomere shortening or to achieve telomere elongation. Recently, it was demonstrated that telomere elongation can be obtained – without genetic manipulation – by culturing mice embryonic stem cells into appropriate media. Based on this observation, we hypothesize that environmental factors could affect the initial length of telomeres by modulating the activity of telomerase during the early stages of pregnancy. Therefore, organisms with longer telomeres could exploit the anti-inflammatory activity of telomeric sequences over an extended time span, eventually delaying the development and progression of age-related diseases.

Metformin is the first-choice therapy to lower glycaemia and manage type 2 diabetes. Continuously emerging epidemiological data and experimental models are showing additional protective effects of metformin against a number of age-related diseases (ARDs), e.g., cardiovascular diseases and cancer. This evidence has prompted the design of a specific trial, i.e., the Targeting Aging with Metformin (TAME) trial, to test metformin as an anti-ageing molecule. However, a unifying or prevailing mechanism of action of metformin is still debated. Here, we summarize the epidemiological data linking metformin to ARD prevention. Then, we dissect the deeply studied mechanisms of action explaining its antihyperglycemic effect and the putative mechanisms supporting its anti-ageing properties, focusing on studies using clinically pertinent doses. We hypothesize that the molecular observations obtained in different models with metformin could be indirectly mediated by its effect on gut flora. Novel evidence suggests that metformin reshapes the human microbiota, promoting the growth of beneficial bacterial species and counteracting the expansion of detrimental bacterial species. In turn, this action would influence the balance between pro- and anti-inflammatory circulating factors, thereby promoting glycaemic control and healthy ageing. This framework may reconcile diverse observations, providing information for designing further studies to elucidate the complex interplay between metformin and the metabiome harboured in mammalian body compartments, thereby paving the way for innovative, bacterial-based therapeutics to manage type 2 diabetes and foster a longer healthspan.