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Lenhard Rudolph prepares four biomarkers for clinical application

Lenhard Rudolph’s biomarker quartet is extremely promising in terms of progressing medical and clinical treatment in ageing societies. The quartet - EF-1 alpha, Chi3L3, CRAMP and OP 18 – is made up of four proteins that can potentially be used as biomarkers. Specific concentrations of these molecules in human blood provide information on the biological age and renewal capacity of the tissue and organs of patients. The biomarker quartet also enables predictions to be made concerning age-related and chronic human (and animal) diseases.

Cells secrete the four proteins in response to dysfunctional telomeres or other DNA damage. They are easy to detect in blood and other body fluids, as well as in tissue and organ samples.

The discoverer of the biomarker quartet, the well-known stem cell researcher Lenhard Rudolph from Ulm, is not yet able to say whether EF-1 alpha, Chi3L3, CRAMP and OP 18 are suitable as prognostic markers. He is nevertheless convinced that the combination of several parameters allows better prognoses to be made than with those that rely on a single parameter and he does not want to exclude the possibility that the combination of his markers with other mechanistic markers for other causes of biological ageing has an even greater prognostic value than the four biomarkers on their own.

Important for clinicians who need to make decisions

Prof. Lenhard Rudolph has identified four new biomarkers. © Pytlik

Effective prognostic biomarkers would be extremely helpful for clinicians, as they would enable better planning of the medical treatment of elderly patients. If prognostic biomarkers were available, doctors would be able to tell from blood samples whether an elderly patient is likely to benefit from surgical interventions, or if the operative risk is too high or the patient's regeneration capacity too low. If the latter two were the case, the elderly patient would be put on a conservative treatment plan and spared surgery (or transplantation) that is likely to be unsuccessful. "This is what I am aiming to achieve with the new biomarkers," said Rudolph who is well aware of the clinical importance of being able to diagnose many age-associated and chronic diseases at an early stage.

Up to now, it has not been possible to efficiently determine the length of telomeres; time-consuming and complicated methods and the lack of material (biopsies) made this rather difficult. In addition, the length of telomeres only provides limited information about cell function and regenerative ability. 

The winner of the Leibniz award has not yet made up his mind whether to pursue the further development of his markers into clinical markers on his own or whether he will leave it to specialist assay developers, either by setting up a start-up company or working in cooperation with companies. Rudolph has already made contact with potential partners, but has not yet made a final decision. What he does know is that the development of test methods is unlikely to improve his scientific reputation and branching into industry does not seem to be an attractive option either.

The loss of protective telomere ends and its consequences

Shortened telomeres (red) induce chromosomal damage and increase cancer risk. © Lenhard Rudolph

The discovery of the four biomarkers EF-1 alpha, Chi3L3, CRAMP and OP 18 is essentially based on the knowledge that dysfunctional telomeres and DNA damage are associated with ageing and age-related diseases.

Telomeres are regions of repetitive DNA at the end of chromosomes that become shorter over time. Each cell division in humans leads to the loss of around 50 to 100 basepairs of the repetitive, non-coding DNA sequences. The successive shortening of the telomere ends has far-reaching consequences as the telomeres protect the chromosome ends from deterioration or fusion with other chromosomes. Continued cell divisions lead to the deterioration of the three-dimensional structure of the chromosome end, leading to dysfunctions, i.e. something similar to DNA breaks, to which the cell responds by halting the cell division process and triggering apoptosis and attempts to repair the damage. Rudolph points out that these processes are often inter-linked. 

Many correlations, few simple conclusions

However, Rudolph also points out that there is often more than just one correlation, especially in the case of diseases that lead to the early ageing of tissue. Such diseases are caused by mutations in genes (telomerase or telomere-binding proteins) that are important for the maintenance of the protective caps at the chromosome ends. Mutations of such crucial genes lead to shortened or structurally altered telomeres, which in turn can lead to telomere dysfunction and early organ failure. This association has been shown for lung fibrosis, liver cirrhosis and bone marrow failure. Experiments with animals (mice and fish) with a modified telomerase enzyme have led to similar results. However, Rudolph is careful to point out that simple conclusions must not be drawn. It is not yet known whether people age normally due to shortened telomeres alone or in combination with mutated telomere genes.

Younger people have fewer marker proteins, older people have more

Lenhard Rudolph discovered "his" marker proteins in cell culture. He determined which proteins were exclusively present in the supernatant of bone marrow cells of mice (in whom the enzyme telomerase was silenced) and only possessed shortened telomeres (and were hence missing in the medium with cells with functional telomeres). The proteome measurement was later confirmed in blood, something that is important for clinical practice. Rudolph and his team also found elevated concentrations of "his" marker proteins in the kidneys, liver, lungs, brain, spleen and heart of mice with shortened telomeres, but not in mice with long telomeres. These findings were confirmed in human fibroblasts with radiation-damaged DNA.

Rudolph's group of researchers carried out further experiments and discovered that concentrations of these particular proteins increase with age and that young people have smaller concentrations. Subsequent analyses showed that the blood of elderly people who are ill - patients in geriatric hospitals - contained larger quantities of the markers than relatively healthy elderly people.

Lenhard Rudolph and his team have not investigated the function of the four proteins, but have simply used them as markers for ageing and disease.

EF-1 alpha is elongation factor 1 alpha, a protein that controls translational protein synthesis. Chi3L3 is chitinase-3-like protein 3. Chitinase enzymes are mainly known from the insect world, but their enzymatic activity can also be measured in humans. After discovering chitinase activity in mice, Rudolph then went on to look for and find the same enzyme in humans. OP18 is also known as stathmine, a small protein that controls the stability and motility of cellular microtubules and mitosis. CRAMP (cathelicin-related anti-microbial protein) is a protein that was originally found in activated macrophages and is associated with innate immunity. Chitinase is also a component of innate immunity.

These biomarkers are capable of more

In the meantime, there is increasing evidence that the accumulation of DNA damage and telomere dysfunction is a suitable prognostic marker for assessing the risk of age-related diseases, including vascular diseases, diabetes mellitus, dementia and stroke. The new biomarkers can be detected in blood, but also in saliva or cerebrospinal fluid. Rudolph hints that this might also be of importance for the prediction of neurodegenerative disease risk. He is looking forward to disclose more information, but is unable to so before the results are published in early 2012.

Jiang H., Schiffer E. et al.: Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease, PNAS, 12. August 2008, 105, No. 32, 11299-11304.

Song Z., Von Figura G. et al.: Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood, Aging Cell, 9: 607-615 (doi:10.1111/j.1474-9726.2010.00583.x)

Jiang H., Rudolph KL, Telomere shorteing and ageing, Z Gerontol. Geriatry 2007, 40: 314-234

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