Society is getting older and older. By 2050, one in three people in Germany and more than two billion people worldwide will be over 60 years old. With demographic aging, age-related diseases are also increasing. In order to be able to counteract these better and earlier in the future, research is needed - and consequently older laboratory animals.
In the past, it was thought that signs of aging were mainly due to degenerative processes. In the meantime, however, it has been shown that many chronic diseases in old age are partly caused by so-called senescent cells. These "senescent cells", sometimes also called "zombie cells", can no longer proliferate and usually no longer fulfill their original function. Instead, they often create an inflammatory environment, for example by secreting inflammatory or other factors that damage the surrounding tissue.
The more senescent cells accumulate, the more difficult it is for an aging immune system to break them down. This situation can promote the development of diseases such as dementia, atherosclerosis, diabetes or osteoporosis. To better understand senescent cells and develop therapeutic options, researchers need laboratory animals that develop such cells - and are therefore older than usual.
However, the standard EU housing conditions established in laboratory animal science are not designed for aging animals. In nature, rats often live together in groups of 100 or more, are socially networked, very capable of learning, and play well into adulthood. As a laboratory animal in a standard animal model, a rat often shares a cage with three other rats, limiting social relationships and interaction with the environment.
For example, the meta-analysis "Conventional laboratory housing increases morbidity and mortality in research rodents" makes clear that this standardized long-term housing, largely shielded from stimuli and activity opportunities, is an independent stressor for rodents. Rodents that age under standard housing conditions have been shown to have a higher risk of disease and are more likely to die.
Dietrich Polenz from the Experimental Surgery Department of the Surgical Clinic, wants to know how experimental rats can age more species-appropriate in a sensory and socially enriched environment. "Unfortunately, transplantation medicine has not yet been able to do without animal experiments for many questions," says the veterinary engineer. For example, laboratory animals are needed to investigate how the development of healthy, reproductive cells into senescent cells can be prevented or treated, for example to "rejuvenate" donor organs or to protect recipients of transplants from older donors as effectively as possible from the negative effects of senescent cells. The researchers also want to understand what effects, side effects and interactions arise during treatment with so-called senolytics, drugs that lead to the elimination of senescent cells.
"Since we cannot yet do without animal experiments, the animals should at least be kept and allowed to age under conditions that are favorable for them," Polenz says. "That means improving husbandry conditions so the animals can interact socially and also keep them physically fit."
The research project, "Habitat and Behavior Enrichment in Long-Term Aging Studies in Small Animal Models," is funded by Charité 3R and actively supported and monitored by the responsible animal welfare officer. It directly serves the aspect of refinement at Charité. The aim of the study is to test and document cost-effective and easily implementable solutions such as sensory stimuli, exercise and exploration opportunities for the experimental animals and to investigate their impact on physiological parameters such as stress hormones, senescence and metabolism.
Currently, the veterinary engineer is working with 56 female, genetically largely identical rats that will reach their target age of 22 months in the fall of 2023. Half of the animals will age in standard housing by then, while the other group will live in enriched housing. In this so-called "enriched housing model," the animals in the second group come three times a week to the play cage with climbing facilities, water bath, burrow, tunnels, little house and a running wheel, where they play with up to 14 rats. Throughout the week, they are also given hemp litter, straw or hay to alternate in the cage, as well as cucumbers, carrots, nuts and sunflower seeds to sniff and eat. "The idea is to use manageable resources to establish a husbandry model that stimulates the animals on various sensory levels, encourages them to engage in physical activity such as climbing, foraging and social interaction, and thus comes much closer to meeting their needs than current standard animal husbandry," says the researcher.
Until the animals have reached their target age, their hair samples are examined for hormones such as corticoids and estrogens. In addition, so-called senescence markers are determined from the blood, which allow a statement to be made about the inflammatory processes. When the animals are euthanized at 22 months, Polenz distributes the tissues not needed for his surgical research to collaborating research groups in different disciplines.
In advance of the study, he had written to many different disciplines and institutes for cooperation. Demand for the older experimental animals was high from the start. "The more groups share the animals' organs and tissues for their research purposes, the fewer laboratory animals are needed overall," says the veterinary engineer. Thus, in addition to refinement, the study also contributes to the reduction of needed laboratory animals.
The study has also promoted the idea of a long-term "organ share point" at Charité. "Our work will help to achieve better research conditions in the long term with few resources," says the researcher, who has worked in laboratory animal science for nearly 25 years. "In this way, we are doing our part to improve animal husbandry standards step by step for the benefit of animals and scientists, and to minimize suffering and stress in the keeping of laboratory animals."
(Text: Beate Wagner)
Scudellari, M.: To stay young, kill zombie cells. Nature, 2017.
Freund, A., et al.: Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med, 2010.
Herranz, N. and J. Gil: Mechanisms and functions of cellular senescence. J Clin Invest, 2018.
Lee, B.C. and K.R. Yu: Impact of mesenchymal stem cell senescence on inflammaging. BMB Rep, 2020.
Cait, J., et al.: Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis. BMC Biol, 2022.
Charité 3R Forschungsförderung Refinement
Chirurgische Klinik Campus Charité Mitte und Campus Virchow-Klinikum
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