Can ageing be slowed down?

Although we cannot expect to be able to stop the human ageing process completely, the molecular mechanisms underlying ageing show that ageing is regulated by certain cellular processes. By influencing these processes, it may be possible to slow down the ageing process and improve our health as we age.

Eat less and live longer: The effect of diet on ageing

In most animals, exercise and diet are the main influences on the rate of ageing. In some animals, reducing food intake ('dietary restriction') leads to a healthier and often longer life [Fontana et al. 2010]. However, it seems that it is not so much the amount of food we eat that influences the ageing process in the body, but rather what we eat. The individual nutrients in food have a direct effect on an animal's health and ageing process [Simpson et al. 2017]. For example, Linda Partridge's department has found that fruit flies fed a diet high in protein and amino acids die earlier than flies fed a balanced diet [Piper et al. 2017]. Studies have also shown that a reduced intake of certain amino acids has a positive effect on health, also in humans [Juricic et al. 2020, Fontana et al. 2016]. These findings suggest that avoiding a high-protein diet may prolong life(span) and improve health in old age. However, most diets that are beneficial in model organisms are difficult to maintain in humans, so further research on this topic is needed.

Dieting causes epigenetic changes during ageing

In mice, dietary restrictions can lead to changes in lipid metabolism, thus increasing the animals' lifespans

Naturally, fruit flies feed on ripe fruits.

Genome-based diets maximise growth, fecundity, and lifespan

A new developed diet for fruit flies increases growth and fecundity without shortening life-span

Mice become healthier through a change in diet if they start early in life and are fed this way into old age.

Health in old age is a lifelong affair

Reduced food intake in old mice can no longer improve health

Young gut bacteria

The food we eat, and the amount of food we eat, has a direct effect on our health and the ageing process. But the bacteria in our gut that help us digest food also seem to have a direct effect on our health and the ageing process. Dario R. Valenzano, a former research group leader at our institute, is investigating the influence of gut bacteria on the ageing process. His research group studies ageing in the killifish and has shown that old fish stay active longer and live up to 40% longer if they are given the gut bacteria of young fish [Smith, et al. 2017]. The composition of the microorganisms in the fish’s intestine, the so-called intestinal flora, therefore appears to have a direct influence on the ageing process. Among other things, the microorganisms influence food intake, metabolism and immune defence. The composition of the bacterial community in the intestine changes with age [O'Toole & Jeffery 2015]. The diversity of bacteria that maintain a healthy intestine in youth decreases, and a greater proportion of pathogens are found among the remaining bacteria. Interestingly, the intestinal flora of the killifish is very similar to that of humans, so the results may be relevant to human ageing.

Gut bacteria affect ageing

The life expectancy of older fish is extended if their gut is colonized with the microorganisms of younger fish.

The cell's recycling programme: autophagy and the TOR signalling pathway

The amount of nutrients we take in with food affects the availability of nutrients in cells. When nutrients in the cells become scarce because a small amount of food has been ingested, our cells activate a recycling mechanism called autophagy. The term ‘autophagy’ comes from Latin and means ‘self-consumption’. This is because the process of autophagy breaks down components within our cells in order to recycle and reuse the individual building blocks.

It is now known not only that the process of autophagy decreases with age, but also that activation of autophagy has positive effects on the health and lifespan of an organism [He et al. 2013]. The activation of autophagy is directly dependent on the availability of nutrients and the energy status of the cell. Therefore, its regulation is linked to a network of molecular signalling pathways. The so-called "IIT network" is activated when only a small amount of amino acids is present in the cell and is found in a variety of organisms, from fruit flies to humans [Fontana et al. 2010]. The network controls development, cell division, growth, reproduction and the response to stress. Similar to a very precise sensor, the IIT network measures nutrient status in the body and adjusts metabolic processes accordingly, based on the need and availability of food [Partridge et al. 2011]. Reduced food intake, as in so-called dietary restriction, apparently stops the activity of the network.

It is now known not only that the process of autophagy decreases with age, but also that the activation of autophagy has positive effects on the health and lifespan of an organism [He et al. 2013]. Activation of autophagy is directly dependent on the availability of nutrients and the energy status of the cell. Its regulation is therefore linked to a network of molecular signalling pathways. The so-called ‘IIT network’ is activated when only a small amount of amino acids is present in the cell and is found in a wide range of organisms, from fruit flies to humans [Fontana et al. 2010]. The network controls development, cell division, growth, reproduction and the response to stress. Like a very precise sensor, the IIT network measures the nutrient status in the body and adjusts metabolic processes accordingly, based on the need and availability of food [Partridge et al. 2011]. Reduced food intake, as in so-called ‘dietary restriction’, appears to stop the activity of the network.

One of the signalling pathways of the IIT network is the TOR signalling pathway. TOR links signals such as energy, nutrient and stress status to basic cellular activities. It is fair to say that TOR is the master regulator of cellular metabolism [Dobrenel et al. 2016]. When the TOR signalling pathway is active, cellular functions responsible for cell growth and division are increasingly activated. Deactivation of the TOR signalling pathway activates the process of autophagy, which is beneficial for health. The precise regulation of TOR is therefore an extremely interesting research topic in ageing research.

The roundworm Caenorhabditis elegans is an important model organism in ageing research. The worm in the image is labelled with GFP::RNP-6.

Longer life due to faulty RNA processing

If introns remain in certain RNAs, worms live longer

Immune fluorescence microscopy shows that the key UPS regulator, GRASP55, localizes primarily at the Golgi apparatus in non-stressed cells (left panel), whereas it readily relocalizes to secretory vesicles in response to stimuli that cause mTORC1 inhibition (middle panel). mTORC1 regulates GRASP55 directly at the Golgi, where both proteins colocalize in non-stressed cells (right panel, Image taken with the electron microscope).

How do our cells react to starvation or stress?

Internal sensor coordinates the cellular stress response to alter the composition of extracellular proteins

Mitochondria: More than just production sites for energy

Most of a cell's energy is produced by small components inside our cells called mitochondria. Although mitochondria are best known for their role in energy production, they are actually involved in over 1000 metabolic pathways in a cell, making their proper function essential for the health of an organism.

Mitochondria are of particular interest in ageing research because they generate reactive oxygen species (ROS) during energy production. ROS can damage all molecules in a cell and have long been thought to cause ageing. However, recent evidence shows that both high and low levels of ROS are unhealthy. This means that the radicals produced by mitochondria, in just the right amount, are best for our health and the ageing process [Sies & Jones 2020].

Since mitochondria provide energy for the cell, their activity and functionality directly affect the energy status of a cell. The amount of energy produced by the mitochondria is measured via a specific signalling pathway and influences the rest of the cell’s behaviour. For example, when energy levels are height, the TOR signalling pathway is activated, which is responsible for cell growth and division. When energy levels in the cell are low, the TOR signalling pathway is inhibited and autophagy is switched on instead [Papadopoli et al. 2019].

Since our energy comes primarily from the conversion of nutrients, it is not surprising that reduced food intake also reduces the amount of energy available to the cell. As a result, the process of autophagy is turned on more. On the other hand, the function of mitochondria partly explains why exercise can be so beneficial for health and ageing. For example, exercise releases slightly higher levels of ROS, which have been shown to have a positive effect on health. In addition, the body expends a lot of energy during exercise, which in turn activates autophagy [Brunetta et al. 2020, Watson & Baar 2014].

Mitochondria form large networks in the cell.

Oxygen deficiency rewires mitochondria

Researchers slow the growth of pancreatic tumour cells

Cartoon representation of the POLRMT-Inhibitor complex.

New drug inhibits the growth of cancer cells

Blocking gene expression in mitochondria in mice stops cancer cells from growing

The image shows cells under the microscope that glow fluorescently.

Mitochondria produce antioxidants to protect our cells from dying

Coenzyme Q distribution within the cell is regulated by mitochondria

Isn't there a pill? - Drugs that might stop ageing

There is currently no known drug or treatment that has been proven to extend the lifespan of humans. However, in laboratory animals such as worms, flies and mice, it is already possible to extend lifespan and improve health through various interventions. Dietary restriction can extend healthy lifespan in several animal species [Fontana et al. 2010].

Although reduced food intake also improves certain aspects of human health, it is difficult for humans to adhere to such a diet. Therefore, several compounds are being investigated to target the mechanisms that mediate the health benefits of food restriction. People who are unable to extend their lives even with an optimal diet may still benefit from such compaounds.

For example, the drug rapamycin is one of the most promising anti-ageing agents to date [Selvarani et al. 2021]. Rapamycin is named after ‘Rapa Nui’, the indigenous name for the Easter Islands, where it was discovered as a bacterial metabolic product in a soil sample. Originally, these bacteria released rapamycin into the soil to stop the growth of competing fungi and absorb as many nutrients as possible. Rapamycin was first prescribed as an immunosuppressive drug after kidney transplants [Morath et al. 2007]. Interestingly, rapamycin has a very positive effect on health in old age and life expectancy in general. Rapamycin achieves this effect by switching off the TOR signalling pathway, thereby activating the process of autophagy. For example, when fruit flies are treated with rapamycin, their life expectancy increases significantly [Bjedov et al. 2010]. Linda Partridge's department was able to increase the lifespan of fruit flies by almost 50% when they were given rapamycin and two other substances [Castillo-Quan et al. 2019].

Another potential anti-ageing drug that has been studied is metformin. Metformin is used to treat diabetes and, among other things, inhibits the formation of new glucose in the liver [Soukas et al. 2019]. Mice fed metformin live longer, and metformin is a safe drug with no serious side effects. This is why it has been chosen for the first clinical trial of an anti-ageing drug in humans, the TAME trial, which is being planned in the USA with three thousand participants.

Several so-called senolytics, which specifically induce cell death in senescent cells, i.e. cells that no longer divide [Xu et al. 2018], are also being investigated for their effect on ageing. One such substance is tanespimycin, which has shown an anti-ageing activity in the model organism Caenorhabditis elegans, a nematode often used in basic research. Tanespimycin reduces the number of senescent cells and thus also the number of molecules secreted by them that cause chronic infection [Fuentealba et al. 2019]. It remains to be shown whether tanespimycin can be used as an anti-ageing drug in humans. Its use is associated with serious side effects.

Several so-called ‘senolytics’, which specifically induce cell death in senescent cells, i.e. cells that no longer divide [Xu et al. 2018], are also being investigated for their effect on ageing. One such substance is tanespimycin, which has shown anti-ageing activity in the model organism Caenorhabditis elegans, a nematode often used in basic research. Tanespimycin reduces the number of senescent cells and thus the number of molecules secreted by them that cause chronic infection [Fuentealba et al. 2019]. It remains to be shown whether tanespimycin can be used as an anti-ageing drug in humans. Its use is associated with serious side effects.

So there are already some promising drugs that could slow down our ageing process in the future. Whether they are suitable for use in humans and whether they deliver what they promise as anti-ageing agents still needs to be researched in more detail.