Aging-associated changes in the DNA methylome and characteristics of the epigenetic clock

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Arvo building, auditorium F115, address: Arvo Ylpön katu 34.

Laura Kananen

Doctoral defence of M.Sc. Laura Kananen

Aging-associated changes in the DNA methylome and characteristics of the epigenetic clock

The field of science of the dissertation is Microbiology and Immunology (Molecular Immunology).

The opponent is docent Riikka Lund (University of Turku). Professor Mikko Hurme acts as the custos.

The language of the dissertation defence is Finnish.

Aging-associated changes in the epigenome

During the aging process, the physiological integrity of an organism gradually diminishes. Eventually, disabilities in functioning and diseases evolve. The rate of aging differs between individuals, and thus, in practice, 20-years-old individuals are more similar with each other than 70-years-old individuals are. Older individuals have different risks in morbidity and mortality when compared to each other. Cellular mechanisms contributing the aging process and the rate of aging are still widely unclear.

Distinct functions of different cell types are enabled with the precise activation of cell type specific gene expression patterns, and this is controlled by regulatory systems such as epigenetics and DNA methylation. In DNA methylation, a methyl group may be either added to or removed from a cytosine that is located in the DNA sequence CpG. The interindividual differences between genome-wide DNA methylation profiles increase with age, and genetic and environmental factors contribute to this change. Altered genome-wide DNA methylation profiles have been widely associated with diseases and mortality, and DNA methylation is a well-acknowledged biomarker of aging and disease. In addition to erosion-like changes in DNA methylation levels, more systematic and clocklike-behaving changes occur during aging. In the clocklike-behaving methylation sites, DNA methylation level decreases or increases with almost constant rate with age. These changes have been considered as the base for the epigenetic clock. DNA methylation levels in these clock-CpG sites correlate highly with the chronological age of an individual, and interestingly, the correlation is even better than between telomere length and chronological age.

The PhD thesis by Laura Kananen focused on the aging-associated DNA methylation changes. The analyses in Studies (I-IV) were performed using epidemiological follow-up cohorts, The Young Finns and the Vitality 90+. In Studies I and IV, single CpG sites were analyzed genome-wide. The results from Study I highlighted that clocklike-behaving CpG site methylation may be reliably detected from a cross-sectional sample with an age range of only nine years. The data showed that aging-associated increase or decrease in methylation at CpG sites were related to different cellular functions and are enriched in different ways in single genes. In Study IV, DNA methylation sites that could be used as mortality predictors in the elderly (over 90 years of age), were searched. As a result, the mortality-predicting methylomic signature performed better than the conventional aging biomarkers and was independent from the aging-associated DNA methylation changes.

It has been shown recently that clocklike-behaving CpG sites can be used to estimate calendar age of “a blind sample” of DNA with a high level of accuracy. The difference between chronological age and this epigenetic age estimate is now considered as highly promising biomarker of the aging rate, and many accounts of its significance in human fitness, morbidity, mortality and longevity have been reported elsewhere. In Studies II and III, the epigenetic age estimate was studied in more details. Results in Study II showed that increased epigenetic age of the blood cells was associated with latent cytomegalovirus infection, which is an important immune system modifying factor.

Importantly, longitudinal methylomic data (III) provided evidence that the difference between chronological and epigenetic age is surprisingly stable over several years or even decades in the adulthood, and, when accompanied with previous reports, it may be hypothetized that the main trajectory of the blood DNA methylome aging rate is largely set before adulthood. In other words, this conclusion points that these DNA methylation features that are constructed during the period of growth and development in childhood remain the same, and these features may be relevant to health condition in later life. However, detailed cellular mechanisms inside the epigenetic clock are still unknown and need to be characterized in the future studies.


The dissertation is published in the publication series of Acta Universitatis Tamperensis; 2355, Tampere University Press, Tampere 2018. The dissertation is also published in the e-series Acta Electronica Universitatis Tamperensis; 1861, Tampere University Press 2018.

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