By Alexandra Grba
Werner syndrome, a rare autosomal recessive disorder, is characterised by an acceleration in ageing. It results from mutation in the WRN gene, and affects an estimated 1 in every 200,000 people. The disorder is more common in Japan and Sardinia due to what is known as the founder effect: a small ‘founding’ population in these areas meant that the WRN gene mutation, when present, was passed within a limited gene pool, creating a higher rate of occurrence (Cancer.Net, 2020). Symptoms of the syndrome start appearing in early adulthood, with wrinkles, greying hair and hair loss indicating premature ageing. Once in their 30s, sufferers could develop cataracts, type 2 diabetes, skin ulcers, osteoporosis, cancer and atherosclerosis (Cancer.Net, 2020). This acceleration in ageing leads to a poorer quality of life and a lower life expectancy, with the average age of death for sufferers being around 54. Research into Werner syndrome is promising, however it has not yet been fully characterised, and an effective ‘cure’ is yet to be found.
It is thought that epigenetic alterations are associated with Werner syndrome, whereby the physical properties of the DNA are changed, rather than the chemistry of the nucleotide sequence. DNA and associated histones can accumulate chemical marks, such as methyl groups, that can activate or inhibit gene expression. Steve Horvath, professor of human genetics and biostatistics at the University of California, Los Angeles, has used methylation marks to create an ‘epigenetic clock’ that predicts a cellular ‘epigenetic age’, which is correlated with the biological age of a cell. Accelerated epigenetic ageing refers to an individual’s DNA methylation-predicted age being older than their biological age (Mendelson, 2018). Recent studies of blood cells show that accelerated epigenetic ageing is associated with Werner Syndrome, and several hypotheses stand to explain how this may occur (Maierhofer et al., 2017).
The epigenetic ageing effects are thought to be a result of loss of function in the WRN gene, which encodes a 1432 residue protein involved in DNA repair, replication, recombination, transcription, and telomere maintenance (Maierhofer et al., 2017). The WRN protein has a 3′ → 5′ exonuclease domain in its N-terminal region, an ATP-dependent 3′ → 5′ helicase in its central region and a nuclear localisation signal in its C-terminal region (Oshima, Sidorova & Monnat, 2017). It has a central domain, the RecQ helicase conserved region (RQC), that is critical for DNA binding and initiating unwinding of the molecule. Helicases bind and remodel nucleic acid, functioning to separate double stranded DNA in replication, DNA repair, and transcription. It can be deduced that the accelerated epigenetic ageing effect in Werner syndrome results from a process requiring DNA helicase, however further research is required to elucidate the mechanism of this process. Another theory postulates that the epigenetic age acceleration is caused by telomere shortening (Maierhofer et al., 2017). Telomeres are repetitive nucleotide sequences found at the ends of chromosomes, protecting them from damage. The length of telomeric sequences decreases with age, and can lead to senescence, apoptosis, or cancer, affecting the lifespan of an individual (Maierhofer et al., 2017). Loss of WRN helicase activity through mutation could lead to telomere attrition, resulting in genomic instability. However, studies have shown that epigenetic age acceleration is not linked to telomere length in blood cells, placing this theory into question.
The lack of concrete evidence associated with Werner syndrome and the epigenetic mechanisms thought to have causal effects means that currently no ‘cure’ exists. Instead, patients must manage the disorder by screening for and treating the associated diseases. New therapies to treat Werner syndrome may help to treat it more directly, and slow its progression. One such potential therapy exploits rapamycin inhibition of the mTOR pathway, a central regulator of metabolism and physiology, known to be involved in ageing and related diseases across a diverse range of species (Oshima, Sidorova & Monnat, 2017). In fact, mTOR signalling was found to be upregulated in cells displaying Werner syndrome, and prolonged treatment with rapamycin resulted in an increase in the cells’ growth rate, reduced DNA damage and an improvement in nuclear morphology (Oshima, Sidorova & Monnat, 2017).
It is unclear as to what extent epigenetic alterations affect the Werner syndrome phenotype. Despite research showing strong associations between epigenetic marks and this disorder, it is yet unknown whether these genomic marks are the direct cause of disease or a mere by-product of it. The arena for discovery in this area is limitless; research into Werner syndrome could allow for an invaluable insight into ageing and the molecular processes behind it, as well as providing a window into the possibilities of reversing the ageing process.
References:
Cancer.Net. (2020) Werner Syndrome. Available from: https://www.cancer.net/cancer-types/werner-syndrome [Accessed 12 November 2020].
Maierhofer, A., Flunkert, J., Oshima, J., Martin, G., Haaf, T. and Horvath, S. (2017) Accelerated epigenetic aging in Werner syndrome. Aging, 9 (4), 1143-1152. Available from: doi: 10.18632/aging.101217
Mendelson, M., (2018) Epigenetic Age Acceleration. Circulation: Genomic and Precision Medicine, 11(3). Available from: doi: 10.1161/CIRCGEN.118.002089
Oshima, J., Sidorova, J. and Monnat, R. (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Research Reviews, 33, 105-114. Available from: doi: 10.1016/j.arr.2016.03.002
Imperial Bioscience Review 