Tackling the pillars of ageing to fight COVID-19
Authors: Francesco Prattichizzo, Jacopo Sabbatinelli, Paola de Candia, Fabiola Olivieri, Antonio Ceriello
Journal: The Lancet Healthy Longevity (2021)

Patients with type 2 diabetes show an increased rate of mortality in relation to COVID-19 when compared with individuals without type 2 diabetes. A chronic status of low-grade inflammation (ie, inflamm-ageing) and an accelerated ageing of the immune system have been proposed among the potential mechanisms explaining the higher susceptibility to worst outcomes of patients with type 2 diabetes and other age-related diseases.1Bonafè M Prattichizzo F Giuliani A Storci G Sabbatinelli J Olivieri F Inflamm-aging: why older men are the most susceptible to SARS-CoV-2 complicated outcomes.Cytokine Growth Factor Rev. 2020; 53: 33-37Crossref PubMed Scopus (116) Google Scholar In their article, Bramante and colleagues report the results of an elegant retrospective cohort study showing that the use of home metformin in female patients affected by obesity or type 2 diabetes was associated with statistically significantly reduced in-hospital mortality for COVID-19.2Bramante CT Ingraham NE Murray TA et al.Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.Lancet Healthy Longev. 2021; 2: e34-e41Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar From a gerontological perspective, the results from the study by Bramante and colleagues are not surprising. Epidemiological data have suggested that metformin might foster health span and lifespan when compared with both type 2 diabetes patients on other therapies and age-matched patients without diabetes, protecting against a large range of age-related endpoints, including all-cause mortality.3Campbell JM Bellman SM Stephenson MD Lisy K Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.Ageing Res Rev. 2017; 40: 31-44Crossref PubMed Scopus (250) Google Scholar In spite of their observational nature, the solidity of the results has finally prompted the design of the Targeting Aging with Metformin trial, specifically aimed at testing whether metformin can reduce the rate of ageing by measuring a number of surrogate endpoints in a large cohort of heterogenous subjects.4American Federation for Aging ResearchThe TAME trial. Targeting the biology of aging. Ushering a new era of interventions.https://www.afar.org/tame-trialDate: 2021Date accessed: March 3, 2021Google Scholar Mechanistically, years of research have indicated that metformin might interfere with most hallmarks of ageing, such as genomic instability, epigenetic alterations, nutrient-sensing pathways, mitochondrial dysfunction, cellular senescence, stem cell dysfunction, loss of proteostasis, microbiota shifts, and development of inflamm-ageing, although, which (if any) of the proposed effects might represent the key putative anti-ageing mechanism of metformin remains unknown.5Prattichizzo F Giuliani A Mensà E et al.Pleiotropic effects of metformin: shaping the microbiome to manage type 2 diabetes and postpone ageing.Ageing Res Rev. 2018; 48: 87-98Crossref PubMed Scopus (69) Google Scholar However, the drug favourable effects also on mortality rates in patients with sepsis6Liang H Ding X Li L Wang T Kan Q Wang L Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies.Crit Care. 2019; 23: 50Crossref PubMed Scopus (52) Google Scholar might support a metformin immune-modulating action that could restrain inflamm-ageing. Consistently, metformin users show lower levels of circulating cytokines, including IL-6, a prototypical marker of inflamm-ageing, and a predictor of poor prognosis in patients with COVID-19.1Bonafè M Prattichizzo F Giuliani A Storci G Sabbatinelli J Olivieri F Inflamm-aging: why older men are the most susceptible to SARS-CoV-2 complicated outcomes.Cytokine Growth Factor Rev. 2020; 53: 33-37Crossref PubMed Scopus (116) Google Scholar, 5Prattichizzo F Giuliani A Mensà E et al.Pleiotropic effects of metformin: shaping the microbiome to manage type 2 diabetes and postpone ageing.Ageing Res Rev. 2018; 48: 87-98Crossref PubMed Scopus (69) Google Scholar Broadly, given the key role of age and age-related diseases in determining COVID-19 outcomes,1Bonafè M Prattichizzo F Giuliani A Storci G Sabbatinelli J Olivieri F Inflamm-aging: why older men are the most susceptible to SARS-CoV-2 complicated outcomes.Cytokine Growth Factor Rev. 2020; 53: 33-37Crossref PubMed Scopus (116) Google Scholar it is conceivable that a candidate ageing-modifying drug with interlaced reverberations on the function of the immune system, such as metformin, might favourably affect COVID-19-related mortality. Overall, additional studies are needed to substantiate the metformin protective role against COVID-19 and explore the potential underpinnings. The assessment of a range of inflammatory mediators in large cohorts of patients treated with metformin before and during SARS-CoV-2 infection might help understand whether and how this drug affects the complex interplay among ageing, inflamm-ageing, and COVID-19. More importantly, Bramante and colleagues' data should boost a research effort in studying the pillars of ageing and identifying the interventions able to promote healthy longevity. This approach might not only prevent or delay common age-related diseases, but also limit the deleterious consequences of communicable infectious diseases, such as the ongoing pandemic. AC discloses the following conflicts of interest: advisory board membership of Eli Lilly; consultancy with Roche Diagnostics, Eli Lilly, and Theras; lectures with Berlin Chemie, Eli Lilly, Novo Nordisk, and Roche Diagnostics; and a research grant with Mitsubishi. FP reports lecture fees from Berlin Chemie, outside the submitted work. All other authors declare no competing interests. This work has been supported by the Italian Ministry of Health—Ricerca Corrente to IRCCS MultiMedica. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysisMetformin was significantly associated with reduced mortality in women with obesity or type 2 diabetes who were admitted to hospital for COVID-19. Prospective studies are needed to understand mechanism and causality. If findings are reproducible, metformin could be widely distributed for prevention of COVID-19 mortality, because it is safe and inexpensive. Full-Text PDF Open Access