Today I thought I'd point out one of the recent results to emerge from the discovery that DNA methylation patterns correlate well with age. These patterns best correlate not with chronological age, but with biological age, as they reflect the pace at which cell and tissue damage has accumulated. They are thus a potential biomarker capable of distinguishing natural variations in the pace of aging between individuals. The authors of the paper linked below show that, per their chosen forms of DNA methylation assessment of age, stroke patients tend to be biologically older. This all ties together very well: age-related diseases are caused by an accumulation of molecular damage. That damage takes the same form in every individual, and thus the cellular reactions to that damage are much the same. These reactions include alterations in DNA methylation, a part of the epigenetic system of controls that determine whether and how rapidly various proteins are manufactured from their genetic blueprints. Variations in aging between individuals take the form of more or less damage at a given age, and thus these methylation patterns reflect an earlier or later age by level of damage. More damage means a greater risk of biological systems failures, such as chronic age-related disease or incidents like stroke.
The paper below is but one example of a range of initiatives focused on building and trialing accurate biomarkers of biological age. DNA methylation patterns are the best and most advanced of these to date; there has been something of a blossoming in this part of the field as researchers eagerly apply and attempt to validate this class of biomarker. For example, a recent study showed that older age as assessed by a methylation clock correlates with higher mortality. This isn't just about the gloomy matter of being able to quantify exactly where in the downward spiral of degenerative aging any one particular individual might be, however. The real advance in the state of the art that accompanies a reliable biomarker for aging is the ability to quickly and cheaply assess the potential of newly developed rejuvenation therapies. At present the only way to figure out whether something works or not is to, at minimum, run a lifespan study in a large enough number of mice to ensure statistical significance. That is something that tends to cost millions and take years, and such a high level of required investment means that there is far less experimentation and development than might otherwise be the case. But if that can be cut down to a month-long study with a biomarker test at beginning and end? Well, a much larger set of laboratories and projects now become contenders - and, as an added bonus, the proposals that don't in fact work will be quickly winnowed rather than lingering on in a state of uncertainty.
One thing to take away from this particular paper is that there is a still a fair way to go for DNA methylation - or another approach to a biomarker of biological age - to reach desirable levels of accuracy. It is still better than other candidate biomarkers, but at present would only be capable of detecting fairly large effects if used to assess interventions intended to slow or reverse the aging process. That might be good enough for the type of therapies proposed in the SENS vision of rejuvenation biotechnology: large positive effects on molecular damage and aging are the goal, after all. As work on the SENS approach of senescent cell clearance progresses, we'll soon enough be seeing DNA methylation biomarkers used as a matter of course in mouse studies of that rejuvenation treatment, I'd imagine.
Ischemic stroke (IS) is a complex age-related disease with high mortality and long-term disability. Despite current attention to risk factors and preventive treatment, the number of stroke cases has risen in recent decades, likely because the aging population has increased. Stroke pathogenesis involves a number of different disease processes as well as interactions between environmental, vascular, systemic, genetic, and central nervous system factors. Approximately 10% of IS occurs in individuals younger than 50 years, which is called "young stroke". In older patients, stroke remains associated with the traditional risk factors: hypertension, hypercholesterolemia, diabetes mellitus, and obesity.
The epigenetic marker that has been studied most extensively is DNA methylation (DNAm), which is essential for regulation of gene expression. This mechanism consists of the covalent addition of a methyl group to a cytosine nucleotide, primarily in the context of a CpG dinucleotide. This dinucleotide is quite rare in mammalian genomes (~1%) and is clustered in regions known as CpG islands. Methylation of the CpG island is associated with gene silencing. DNAm is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. Given its dynamic nature, epigenetics has been referred to as the interface between the genome and the environment.
Age-related changes in DNA methylation are well documented, and two recent studies used methylation measured from multiple CpGs across the genome to predict chronological age in humans. Hannum et al created an age predictor from whole blood DNA, based on a single cohort of 656 individuals aged 19 to 101 years. Horvath developed a multi-tissue age predictor using DNA methylation data from multiple studies. Both models are based on the Illumina BeadChip. The difference between chronological age and methylation-predicted age, defined as average age acceleration (Δage), can be used to determine whether the DNAm age is consistently higher or lower than expected. These age predictors are influenced by clinical and lifestyle parameters, they are predictive of all-cause mortality, indicating that they are more suggestive of biological age than of chronological age.
Age is one of the main risk factors for stroke. We hypothesized that biological age would be even more closely associated with stroke risk, and that "young stroke" patients may be undergoing accelerated aging, with a higher biological than chronological age. We examined a cohort of 123 individuals, 41 controls and 82 patients with IS, matched by chronological age. We initially used two approaches described in the literature to predict biological age, the Hannum and Horvath methods. The average biological age of controls showed a mean Hannum-predicted age higher than their chronological ages by a mean of 1.1 years; their Horvath-predicted age was lower than their chronological ages by 4.6 years. In patients with IS, we observed a Hannum-predicted age higher than their chronological age by a mean of 3.3 years, statistically significant compared to controls. Their Horvath-predicted age was lower than their chronological ages by 3.2 years. DNAm age had a strong positive correlation with chronological age in control samples (0.93 for both Hannum and Horvath methods, and 0.94 between the Hannum- and Horvath-predicted ages). In IS cases, the correlations were lower (0.83 for the Hannum method, 0.72 for the Horvath method, and 0.82 between the two. Although both age predictors showed high accuracy in our samples, Hannum DNAm age performed better, with fewer differences in chronological age in controls and better correlation in patients with IS than the Horvath method.
The sensitivity analysis evaluating which age predictor performed better in our study determined that the Hannum predictor was superior. This is likely because this method is constructed on the basis of DNA methylation data from whole blood, like our data, while the Horvath method is constructed on a range of different tissues and cell types. In conclusion, we found that IS status was associated with a significant increase in Hannum DNA methylation, likely as a consequence of the accumulation of cardiovascular risk factors, and near signification with Horvath method. Patients with IS were biologically older than controls, a difference that was more obvious in young stroke. This could open up the possibility of useful new biomarker of stroke risk.