For several decades, life expectancy has been increasing in most parts of the world, while the “healthspan,” i.e., the period during which a person can live in good health, has not increased to the same extent. This means that more and more elderly people are suffering from age-associated diseases, particularly cognitive decline. “This poses a significant psychological, social, and socioeconomic burden on our societies,” emphasizes Professor Sigrist from the Department of Biology, Chemistry, Pharmacy at Freie Universität Berlin. Caloric restriction and intermittent fasting have been shown to extend the lifespan and healthspan of model organisms and improve human health. “Fasting could, therefore, very likely be a preventive and protective measure to reduce age-related diseases.” However, fasting is difficult to integrate into daily life and hard for many people to sustain. Subsequently, more and more researchers are studying substances that can mimic the positive effects of fasting on the body (“fasting mimetics”). This includes the polyamine spermidine, a nitrogen compound in human cells so named because it was first found and described in male seminal fluid.

Recent research led by Sigrist at Freie Universität Berlin has shown that spermidine possesses fasting mimetic properties. Spermidine levels decrease with age, and dietary spermidine supplementation has been shown to slow down aging processes in model organisms. The Sigrist lab demonstrated that the administration of spermidine directly activates a molecular process called hypusination, which boosts mitochondrial activity in the brain – thereby protecting cognitive function in aging model organisms. However, it remained unclear to what extent spermidine and hypusination are actually involved in the effects of fasting in humans.

The Sigrist lab participated in a study conducted by a research consortium of over twenty universities from around the world, led by Sebastian Hofer and Frank Madeo at the University of Graz. The researchers systematically investigated the molecular mechanisms and effects of fasting and the potential role of spermidine, including data obtained from humans. Sigrist’s team examined the extent to which fasting effects in the fruit fly Drosophila were dependent on spermidine-mediated hypusination. “As expected, fasting processes improved fitness, healthspan, and lifespan,” says Sigrist. “The key finding of the study is that this fasting-induced increase in vitality was strictly dependent on an increase in the body’s own spermidine concentration.” Pharmacological and genetic interventions in model organisms demonstrated that the positive effects of fasting were abolished when the spermidine increase was prevented.

The research consortium also found that chronic inflammation, such as arthritis, and heart function in aging model organisms could be positively influenced by fasting. However, this was only observed when the body’s natural upregulation of spermidine was not experimentally impaired. On a molecular level, it was shown that the spermidine-induced molecular process of hypusination is crucial for the protective effects of fasting. Additionally, the induction of autophagy – a cellular cleaning process that removes age-associated cellular debris – was also shown to be essential. According to the researchers, these findings represent a significant contribution to the development of scientific strategies that can harness the effects of fasting to slow down physical decline during aging.