Genes that control the day-night rhythm are completely different with increasing age than in earlier phases of life. This biological function appears to be directly at the centre of many ageing processes, as a study published in the journal Aging Cell by the University Medical Centre Halle shows. The analysis examined the gene activity of mice of different ages using artificial intelligence. This could lead to new therapeutic concepts to counteract age-related processes.

Halle/Germany, December 10th, 2024 How we age depends on external environmental influences, lifestyle and parental genetic information (genes) and how these are expressed: All processes in the body are controlled by genes and their products. For this purpose, the genetic information is first translated and duplicated before, for example, functional proteins can be formed. Analysing the deviations in the quantity of these gene products provides insights into changes within the body.

‘Particularly in ageing research, where countless cellular processes are involved, the analysis of gene product quantities can help to uncover decisive factors of ageing and the associated disease processes,’ explains Prof Dr Andreas Simm, head of the Research Training Group 2155 at the University Medical Centre Halle, which researches key mechanisms of ageing. In a recent study, his research team looked for previously unknown or underestimated biological processes that play a role in ageing.

Extraordinarily large database analysed with artificial intelligence

Often, only male mice are examined in such studies and then very young animals are compared with animals that are as old as possible in order to obtain large differences in gene regulation. ‘These differences may not always have to do with the progressive ageing process, as growth processes in early phases of life and disease processes such as inflammation at later stages are relatively independent of the actual mechanisms of ageing. The sex or breeding line of the animals should also distort the results of the study,’ explains Dr Patrick Winterhalter, first author of the study.

In order to obtain the most meaningful and generally applicable results possible, the research team therefore analysed the gene activity of male and female mice at five points in time spread over the entire lifespan of the animals. They also included seven different organs from each of two breeding lines. ‘The extraordinary number of biological replicates in our study allowed us to analyse an enormous depth of data with the aim of detecting even the most elusive changes.’ In total, the research group used artificial intelligence to analyse almost 12,000 gene products and created a network with more than 600 genes whose activity changed depending on age.

New aging node discovered in the genetic network

Particularly striking: gene products that control the day-night rhythm (circadian rhythm) are significantly altered in old age. These normally regulate cell functions in line with time-of-day events such as food intake and sleep and help the various tissues and organ systems to fulfil their different tasks. ‘We were able to show that the connection between the circadian rhythm and ageing is much more pronounced than previously assumed. As it is a feedback mechanism that adapts on a daily basis, it may be possible to intervene at this level of the ageing process – perhaps through simple things like daily routines and regulated, higher quality sleep.’

The gene products of the circadian rhythm formed the central hub to which many other age-associated changes are linked, such as those of the immune system, the extracellular matrix (e.g. collagen) or the energy metabolism. Genes that regulate the balance and quality control of the protein balance, known as protein homeostasis, were also part of the central hub.

‘When protein homeostasis is disrupted, this is considered one of the most important cellular hallmarks of ageing. We were able to show for the first time that the genes responsible for this are very closely linked to those of the circadian rhythm and that gene products of both processes form a common centre in the ageing network. This connection appears to be of a fundamental nature and could serve as a biological marker for the ageing process,’ summarises Winterhalter. ‘If we learn to restore the day-night rhythm in old age, this would be a promising therapeutic approach to increase health and possibly also lifespan.’

Originalpublication:

Winterhalter PR, Georgevici AI, Gharpure NJ, Szabó G, Simm A. The circadian rhythm: A key variable in aging? Aging Cell. 2024 Jul 30:e14268. (https://doi.org/10.1111/acel.14268)

Further Information:

(https://www.umh.de/einrichtungen/kliniken-und-departments/herzchirurgie/forschung)
Forschungslabor der Universitätsklinik und Poliklinik für Herzchirurgie an der Universitätsmedizin Halle

ImageSource: Universitätsmedizin Halle,
Prof. Simm (right) and Dr Winterhalter in the laboratory: In order to obtain particularly meaningful results, an unusually large number of biological replicates were analysed in the study.