| Fasting and its effect on ageing and longevity |
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As a result of higher life expectancy and the associated increase in the elderly population, chronic diseases such as cardiovascular disease, cancer, diabetes and neurodegeneration are becoming increasingly common in society (1)(2). By the associated socio-economic effects chamfering regimes like a nourishing conversion with calorie restriction or intermittent chamfering are used around these to contain. These interventions have been shown in tests to positively influence the health of all model organisms, including rodent models and non-human primates, and to have an effect on prolonging life (2). This is due to anabolic and catabolic reactions, which determine development, but also maturation and ageing, and are controlled by nutrient intake, physical activity and elimination of the body's own waste products (3). Aging is mainly characterized by the accumulation of different molecular damages, which are characterized by defective enzymes, malfunctioning organelles, protein aggregates or mutations in the THEN (4). To promote healthy aging, it is necessary to attenuate or delay cellular and molecular changes that promote the aging process and at the same time promote age-associated pathologies. These include telomere wear, genomic instability, protease loss, epigenetic changes, deregulated nutrient sensing, cellular senescence, mitochondrial dysfunction, stem cell depletion, altered intercellular communication and chronic inflammation. For this reason, measures that extend the life span of model organisms often show pleiotropic effects. These include an improvement in mitochondrial metabolic function and respiration, anti-inflammatory properties, and an improved protease (2).
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| Autophagy as efficient cell purification against aging |
Autophagy is a cell-based recycling program and thus a promising approach to a causal treatment of aging and related diseases. It involves the degradation and recycling of misfolded or defective proteins, as well as cell-intrinsic macromolecules and whole organelles. Autophagy directs the lysosomal degradation of organelles and macromolecules by storing the material to be degraded in autophagosomes, thereby detoxifying and recycling the potentially harmful material that accumulates during aging. Autophagy also maintains homeostasis in the organelles, thus contributing to the attenuation of age-related processes and to the protection of the cell lungs by avoiding proteotoxic stress (2)(4). For this reason, autophagy plays a role in the activation of these cell purification processes and certain diseases and could also have neuroprotective effects and prevent certain cancers. In several organisms, an age-related reduction in autophagy and proteolytic activity has already been observed, accompanied by an accumulation of damaged proteins. These could impair cell function and lead to cell death, so autophagy, through its beneficial effects on cellular health, appears to be an integral mediator of life prolongation (2)(4). As far as nutrition is concerned, caloric restriction (CR) and the polyamine spermidine as a caloric restriction mimetic (CRM) are potent triggers of autophagy and exert life-prolonging effects via this cell-protective pathway (5).
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| Calorie restriction (CR) in relation to longevity and anti-aging |
In the experimental science of longevity and anti-aging, CR is one of the best researched methods with a proven extension of life span and reduction of a variety of age-related risk factors and disease patterns, including type 2 diabetes, obesity, neurodegeneration and cancer in a wide range of organisms, including humans and primates (5). CR is a permanent reduction in caloric intake without malnutrition, but despite its potentially beneficial effects, its implementation is not without risk. The reason for this is the difficulty in finding the right intensity of CR that avoids harmful effects and malnutrition, which is why CR is only recommended in a limited way to people who are already ill and elderly people (2). Correct execution of CR results in an increase in metabolic flexibility, as well as a reduction in white adipose tissue. This particularly affects visceral fat, which is particularly harmful for healthy aging due to its diabetogenic and inflammation-promoting activity. CR achieves the most diverse effects regarding anti-aging by autophagy induction in human tissue, which not only promotes efficient quality control of organelles, but also improves immunological function, supports optimal stem cell activity and inhibits malignant transformation. Autophagy improves several aspects of age-related diseases, including neurodegeneration, arteriosclerosis, type 2 diabetes and liver steatosis (3). To induce autophagy, CR is one of the most effective strategies, since the activation of multiple relevant signaling pathways prolongs both health span and life span (4). Since very few people are able to permanently reconcile strict nutritional programs such as intermittent fasting or calorie restriction with their own lifestyle, supplementation with CRM is a promising option (2).
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| Spermidine as a calorie restriction mimetic (CRM) |
CRM is the term used to describe substances that are able to imitate the positive effects of calorie restriction or fasting in a pharmacological way, without taking over their potentially negative effects. CRMs induce cell-protective autophagy, in which different CRMs target different molecules, through mechanisms involving the deacetylation of cytosolic and nuclear proteins. They inhibit the synthesis of acetyl-CoA, which is necessary for the enzymatically catalyzed acetylation reaction, directly inhibit acetyltransferases or activate deacetylases, especially sirtuins (2). Spermidine is not only considered a natural trigger of autophagy, but also an anti-aging agent. Its beneficial properties, which it shares with CR, quantify this substance as CRM. Spermidine is a polyamine and an ubiquitously occurring polycation that contributes to the maintenance of cell homeostasis and is associated with important cell functions. Polyamines have the property to bind polyamines and stabilize DNA and RNA, have antioxidant activities, are necessary for the regulation of translation and modulate enzyme functions. Therefore, they are essential for cell proliferation and growth, tissue regeneration, learning and memory functions, and apoptosis. In spermidine, many effects in terms of anti-aging are based on the ability to induce cytoprotective autophagy (5). For the availability of spermidine in the body, besides cellular biosynthesis, production by intestinal microorganisms and oral uptake via food are relevant (2). A large number of foods contain spermidine, including fungi, whole grains, corn, wheat germs, ripened cheese and legumes such as soya (5). The oral uptake of spermidine in the small intestine results in rapid distribution of the polyamine without being broken down. The average intake from food is about 7-25 mg per day, although in humans the body's own spermidine content in the tissues decreases with increasing age (6).
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| Absorption of spermidine and longevity |
The direct relationship between spermidine intake and increased survival has already been investigated in various animal models. It has been shown that 30% CR and spermidine supplementation leads to a similar adaptation of processes critical for cell homeostasis during aging and starvation and also effectively induces autophagy. In this context, researchers analyzed the potential links between dietary spermidine levels and human mortality in 2018 in a prospective population-based study. The study revealed an inverse relationship between overall population mortality and dietary spermidine intake and supports the association between a spermidine-rich diet and higher human survival rates (7).
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| Cardioprotective effects of spermidine |
In studies, spermidine administration has been shown to significantly improve characteristics associated with cardiac aging, including diastolic dysfunction, left ventricular (LV) hypertrophy and LV stiffness. Spermidine appeared to directly affect the heart by leaving parameters such as lipid profile, insulin sensitivity and blood pressure unaffected. In this context, in transcriptome and proteome analyses, the heart of spermidine-fed and aged mice showed a rejuvenated molecular pattern in terms of contractile maintenance, mitochondrial function, and the ability to suppress inflammation. The beneficial effects of spermidine in mice were autophagy dependent, similar to other model organisms before. Thus, spermidine from the diet increased the rate at which proteins and cell material are processed in the autophagosome and the elimination of damaged mitochondria of cariomyocytes (8). In one study, scientists used a model for hypertension-induced cardiac remodelling to investigate whether spermidine has a similar protective effect in a disease model and fed salt-sensitive Dahl rats a high-salt diet. It was shown that spermidine-fed rats developed hypertension at a late stage and showed weaker cardiac hypertension and improved diastolic function. It is believed that the cardioprotective and antihypertensive effects of spermidine may be mediated by improved cardiac autophagy and mitophagy, as well as by generally increased bioavailability of arginine (9).
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| Autophagy and CRM and their effects on cancer cells |
Studies prove the connection between short-term fasting or autophagy-inducing CRMs such as spermidine and the improvement of the antitumoral effectiveness of chemotherapy. Furthermore, some data suggest that long-term success of conventional chemo and radiotherapy is largely determined by its ability to restore immune surveillance in the fight against cancer. In particular, chemotherapies with anthracyclines or oxaliplatin lead to a stimulation of immunogenic cell death (ICD) and therefore transform dying tumor cells into a therapeutic vaccine that induces a strong or cytotoxic T-lymphocyte-mediated immune response against the remaining tumor cells. Chemotherapeutic agents that stimulate ICDs also have the special ability to stimulate autophagy. In normal cells, autophagy forms a barrier against promalignant transformation, which is why many oncosuppressor proteins promote autophagy and several oncoproteins suppress it. In contrast, however, autophagy in neoplastic cells can facilitate adaptation to internal and external cell stress and thus promote tumor progression. Therefore, autophagy can either counteract or facilitate malignant progression, depending on the context of oncogenesis (11). Although initial research results in transgenic and knock-out mice suggest that the amplification of polyamine synthesis may promote cancer development, current research in aged mice does not indicate an increased risk of cancer as a result of spermidine feeding. On the contrary, some cancers such as colorectal cancer occurred even less frequently (7). In experiments on mice, the combination of spermidine, CRM and the chemotherapeutic agent mitoxantrone was able to achieve a significantly higher anti-cancer activity than the administration of the individual active ingredients. These results suggest that pharmacologically induced autophagy may improve the efficacy of cancer therapies by enhancing the T-cell-mediated immune response (11).
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| Spermidine and memory functions |
| The aging society also brings with it an increased number of cases of Alzheimer's dementia, making the development of effective strategies in this field of ever increasing importance (1). An age-related decline in cognitive abilities can be prevented by a healthy lifestyle, including CR and the CRMimetic spermidine. In this context, a randomized, placebo-controlled, double-blind Phase IIa pilot study in 2018 investigated the effects of three-month spermidine supplementation on the cognitive performance of older persons with subjective cognitive decline (SCD). As a well-characterized behavioral marker for age- and disease-related memory loss, mnemnomic discriminatory ability is used to describe the inability to distinguish between similar objects stored in memory. The administration of 1.2 mg spermidine resulted in a moderate increase in memory performance and an improvement in mnemonic discrimination after three months of intervention. Potential reasons could be the restoration of autophagy with the associated elimination of pathogenic protein aggregates and protection of brain function. These study results suggest that spermidine supplementation may delay memory loss in elderly people with SCD (a recognized high-risk population) while providing excellent tolerability (12)(13). |
