Calorie restriction has been presented as a method of increasing longevity and reducing the effects of ageing on cells. Yet, restricting calories has proven a difficult lifestyle for people to adhere to. Simon Sedej, Associate Professor at the Medical University of Graz, is undertaking an exciting study programme looking at how compounds that mimic the effects of calorie restriction could protect the heart from disease and might even expand lifespan in mice.
As medical advancements have improved, and more people are living longer, we are also living with more age-related diseases, including cancers, dementia, diabetes and cardiovascular disease. As well as devastating implications for individual lives, these diseases have crippling consequences for health and social care systems as more people are living with debilitating conditions and reliant on caregiving.
Many attempts have been made to extend our lifespan and to understand the biological mechanisms that cause functional decline over time as scientists seek insights into how we might intervene in the ageing process. Biomarkers of ageing including dysfunction of mitochondria, the main energy source for the cell, and increased amounts of toxic compounds known as reactive oxygen species, have been identified but much remains unknown. Whilst the biological root of cellular ageing has yet to be pinned down, it is likely to be complex and involve several key mechanisms.
Despite a long search for the biological fountain of eternal youth, we have made little progress in slowing the ageing process. A significant amount of attention has been placed on calorie restriction, limiting the energy intake from drinks and foodstuffs. In fact, this is almost the only approach that has been shown to significantly improve lifespan in a number of species, including primates, although the effects on humans are not fully elucidated. It is thought that calorie restriction might increase longevity by improving mitochondrial function, reducing reactive oxygen species production or improving several cellular processes. However, despite some evidence of its beneficial effects in other species, following a calorie restrictive diet is difficult, if not impossible, for people to adopt into their lifestyle in the long term, essentially ruling it out as a public health strategy. Researchers, led by Professors Simon Sedej (Medical University of Graz) and Frank Madeo (University of Graz), have switched the focus to compounds that could mimic the effect of caloric reduction without the need for unfeasible changes to lifestyle.
Lifestyle and diet are very much in the spotlight as health researchers look to prevent age-related diseases. Much of this focus has been on the Mediterranean diet, which is easy to adhere to and has been heralded for reducing rates of a number of conditions from dementia to diabetes. Although the exact reasons why this diet could be beneficial are not established, it is known to contain higher levels of polyamines, including spermidine. Spermidine has been shown to increase lifespan in yeast and worms and reduces memory decline in flies. Levels of spermidine decrease with age in humans, suggesting that it could be a key target for boosting youthful cell function and tissue health. Spermidine is found in highest concentrations in whole grains, green peas, soy beans, some types of mushrooms and legumes and in aged, blue-veined cheeses.
Together with PhD candidate Mahmoud Abdellatif and BioTechMed Graz collaborators Professors Frank Madeo and Tobias Eisenberg from the University of Graz, Professor Sedej recently undertook an elegant set of studies to look at how an altered diet supplemented with spermidine might protect against heart disease and turn back the clock on functional decline in the heart. They showed that mice given water supplemented with spermidine in early life lived around 15% longer than mice who had been given normal water. Spermidine supplementation also had beneficial effects when given to aged mice, increasing their chances of survival by 10%. Mice given spermidine had better heart function, with reversal of age-related enlargement of the heart muscle, a condition known as hypertrophy.
Professor Sedej – who leads a consortium called Metabolic Therapy for Managing Diastolic Heart Failure (MINOTAUR) – went on to investigate the effects of spermidine in a rat model of congestive heart failure caused by high blood pressure, or hypertension. Hypertension – an increase in blood pressure in arteries – is a risk factor for cardiovascular disease and is linked to lifestyle factors including diet, lack of exercise and smoking. Rats in the study were sensitive to salt and had developed hypertension by being fed a salty diet. However, rats on a spermidine-supplemented diet showed lowered blood pressure, reduced cardiac hypertrophy and a delay in the progression of heart failure compared with their litter mates.
In a complementary study in collaboration with Professor Stefan Kiechl from the Medical University in Innsbruck, data from people taking part in a prospective cohort study showed that high levels of spermidine in the diet, assessed by in-depth food questionnaires, correlated with healthier blood pressure and lower risk of cardiovascular disease. People who report high levels of spermidine in their diet had a 40% risk reduction for fatal heart attack and lowered association with coronary artery disease and stroke compared with people who have a low dietary intake of spermidine. The same effects were not seen with putrescine, another polyamine, suggesting that there is something special about spermidine that is leading to these cardioprotective effects.
The heart is heavily affected by age, undergoing functional decline and even remodelling in older adulthood. Cardiovascular diseases carry an enormous socioeconomic burden and are the leading cause of death worldwide. Signs of ageing in the heart are plentiful and can be seen in breaking down of blood vessels and change in the size of heart cells. Fat deposits develop on blood vessels to and from the heart, making it more difficult for the heart to operate correctly, increasing the likelihood of conditions such as heart failure and angina, as well as vascular dementia. Tackling the effects of ageing in the heart would almost certainly decrease the incidence of age-related disease and increase lifespan.
The results from spermidine studies, carried out in Sedej’s and Madeo’s labs and published in Nature Medicine, are intriguing – so how might spermidine be working to improve our heart health and increase longevity in the animal models? Spermidine was not extending lifespan in these mice by inducing a calorie restrictive state: both groups were of similar weight and body composition. However, spermidine was mimicking significant effects on cells seen in calorie restriction experiments, including reversing mitochondrial decline and improving phosphorylation of titin, which is known to reduce stiffness of the heart. Professor Sedej and colleagues also showed that spermidine enhanced the function of autophagy, a normal process that cells use to clear away unwanted cellular debris, such as degraded proteins. Autophagy, which means ‘self-eating’ in Greek, is a crucial physiological function that declines with age and is improved by calorie restriction. Graz researchers in collaboration with Professor Junichu Sadoshima showed that spermidine increased autophagic flux – a term that refers to how much autophagy activity is taking place. In a further mechanistic study, Sedej and colleagues showed that the cardioprotective effects of spermidine were not seen in mice who lacked a key autophagy protein, suggesting that the compound was working on the heart by boosting autophagy.
Looking to the future
Professor Sedej’s evidence that spermidine could have profound effects on heart health and may even lengthen life is extremely encouraging and deserves much attention at a time when the need to reduce the increasing burden of age-related disease is pressing. The idea that we could increase lifespan by making adjustments to our diets without the need to reduce calorie intake or take expensive medications is tantalising. Clinical trials will be the next step to building evidence that spermidine could improve heart ageing in humans but until then, it probably wouldn’t do any harm to start eating a few more green peas.
Power our research.
- Eisenberg, T. and Abdellatif M. et al., Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016; 22(12):1428-1438.
- Eisenberg, T. and Abdellatif M. et al., Dietary spermidine for lowering high blood pressure. Autophagy. 2017; 13(4):767-769.
- Madeo, F. and Eisenberg T. et al., Spermidine in health and disease. Science. 2018; 26;359(6374).
- Abdellatif M. and Sedej S. et al., Autophagy in cardiovascular aging. Circ Res. 2018 (in press).
This collaborative project aims (1) to explore the cardioprotective effects of a potent natural autophagy-inducer spermidine on structural and functional myocardial remodelling during ageing using relevant animal models, and to (2) elucidate whether these cardioprotective effects induced by a dietary compound supplementation depend on autophagy and/or other mechanisms.
Austrian Science Fund (FWF)
- Prof Dr Frank Madeo and Ass. Prof Dr Tobias Eisenberg:, Institute of Molecular Biosciences, NAWI Graz, BioTechMed, University of Graz, Graz, Austria
- Prof Dr Guido Kroemer: French Institute of Health and Medical Research (INSERM-Paris 6), Paris, France
- Prof Dr Christian Mühlfeld: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
- Prof Dr Wolfgang A. Linke: Physiology and Biophysics Unit University of Münster, Münster, Germany
- Prof Dr Jörn Dengjel: The University of Fribourg, Department of Biology, Fribourg, Switzerland
- Prof Dr Adelino Leite-Moreira: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
- Ass. Prof Dr Jorge Alegre-Cebollada: National Institute of Cardiovascular Research, Madrid, Spain
Dr Sedej studied Biology and earned his PhD in Biomedicine in 2004 at the University of Ljubljana in Slovenia. Currently, he is an Associate Professor of Physiology at the Department of Cardiology of the Medical University of Graz, Austria. His research focuses on the mechanisms underlying age-related cardiometabolic decline and its effects on functional and structural myocardial remodelling. He is the coordinator of the MINOTAUR (Metabolic Therapy for Managing Diastolic Heart Failure) Consortium, a project funded by the European Research Area Network on Cardiovascular Diseases (ERA-CVD) and Austrian Science Fund FWF
Simon Sedej, PhD, Associate Professor
Division of Cardiology
Experimental Cardiology Group (ECG)
Medical University of Graz
T: +43 316 385 72742