Inflammaging – What Epigenetic Associations with Kidney Health Can Tells Us
October 25, 2022
Table of Contents:
Chronic, low-grade inflammation in the absence of infection represents an important and undesirable process that accompanies normal human aging. This phenomenon – inflammaging – may contribute to the development of serious age-related diseases, including kidney disease, and a body of recent research has demonstrated a link between inflammaging and increased mortality and morbidity in older human patients (Ferrucci and Fabbri, 2018 and Franceschi et al., 2018). The underlying factors that drive inflammaging, including genetic susceptibility, obesity, microbiomal alterations, cell senescence, oxidative stress, and immune dysregulation, make a deeper understanding of inflammaging and its clinical management a challenging task. Can epigenetic analyses help towards these aims?
Monitoring Human Disease and Aging Non-invasively with Epigenetics
Monitoring human patients via the detection of blood-based biomarkers (such as epigenetic modifications) has vast potential in the diagnosis, prognosis, and treatment of various systemic diseases. Furthermore, exploring alterations to epigenetic profiles could provide insight into complex disease-associated mechanisms. A large body of research has also connected altered epigenetic profiles to both normal and pathological aging; therefore, further exploration into links between inflammaging and epigenetic alterations detected in patient blood samples may offer a quick and non-invasive means to detect the onset, monitor the progress/severity, aid treatment choices, and understand the basic principles underlying this age-related phenomenon.
A team of researchers led by Pamela R. Matías-García (Technical University of Munich), Melanie Waldenberger (Helmholtz Zentrum München, Munich, Germany), and Nora Franceschini (University of North Carolina, USA) understood that changes to DNA methylation profiles in blood samples could reflect the systemic effects of normal and pathological age-related processes. Indeed, accelerated epigenetic aging (which captures life-long environmental exposures and age-related physiological changes) measured via DNA methylation-based epigenetic clocks correlates with an increased incidence of age-related disease and overall morbidity and mortality (Horvath and Raj, 2018, Dhingra et al., 2018, and Fransquet et al., 2019). Therefore, assessing DNA methylation profiles from patient blood samples may provide us with a deeper appreciation of how inflammaging impacts human disease development.
Linking Kidney Health, Inflammaging, and Epigenetics
In this case, the authors focused on relating DNA methylation profiles to age-related alterations to kidney health, given that chronic kidney disease represents an increasingly prevalent disease with a considerable burden on patients and health systems worldwide (Eckardt et al., 2019, Hill et al., 2016, and Levey et al., 2007). Furthermore, a range of studies has demonstrated that kidney function declines with increasing age and that inflammaging, immune dysregulation (Tecklenborg et al., 2018), and oxidative stress (Kooman et al., 2014) all negatively impact kidney health (Franceschi et al., 2018 and Franceschi et al., 2014). Of note, previous applications of advanced DNA methylation-based aging measures had incorporated biomarkers that correlate with kidney health (Levine et al., 2018 and Lu et al., 2019); however, the relationship between DNA methylation-based predictors and those parameters describing the functional output of the kidneys during aging remained incompletely defined (Dhingra et al., 2018, Shiels et al., 2017, and Jung and Pfeifer, 2015).
Epigenetic Age Acceleration and Kidney Health
In their study, the authors evaluated associations between facets of DNA methylation-based epigenetic age acceleration and mortality predictors (derived from DNA methylation analysis of whole blood samples employing the Illumina Infinium HumanMethylation450K or EPIC array) with a range of aging- and disease-associated kidney health parameters in a sizeable trans-ethnic cohort, which included approximately 10,000 European, African American, and Hispanic/Latino individuals from seven population-based studies. Their approach revealed that accelerated epigenetic aging is broadly associated with worsened kidney health, which includes the development of chronic kidney disease. Specifically, the team discovered associations between all parameters of poor kidney health and epigenetic age acceleration calculated with the DNA methylation-based PhenoAge predictor (Levine et al., 2018), epigenetic mortality risk score (Zhang et al., 2017 and Gao et al., 2019), and extrinsic epigenetic age acceleration calculated with Hannum’s DNA methylation-based age predictor (Quach et al., 2017 and Chen et al., 2016). The commonly employed Hannum (Hannum et al., 2013) and Horvath (Horvath, 2013) “first-generation” epigenetic clocks and GrimAge - a mortality predictor based on mortality-related DNA methylation-estimated traits (Lu et al., 2019) – provided proof of associations only with specific kidney health parameters. The authors note that the overall lack of clear association patterns across kidney health parameters supports the hypothesis that DNA methylation-based predictors reflect different aspects of biological aging.
The strengths of this fascinating inflammaging-related research include the large sample size, the inclusion of multiple independent studies of multi-ethnic patient populations, the comprehensive assessment of aging and lifespan as predicted by DNA methylation, and the assessment of multiple traits that reflect various aspects of kidney health. Further research into the gene expression alterations and functional cellular consequences associated with DNA methylation changes may help to clarify the mechanisms linking inflammaging and epigenetic age acceleration with worsened kidney function. However, noted limitations include their analysis of blood rather than actual kidney tissue (although no kidney-based epigenetic clocks currently exist) and the overall lack of mechanistic or causal explanations for kidney health parameters and blood-derived biomarkers of epigenetic aging.
Conclusions – Can Epigenetics Tell Us More About Inflammaging?
Overall, DNA methylation-based aging/lifespan signatures may represent valuable biomarkers when managing kidney health throughout a lifetime while also helping to further explore the fundamental nature of inflammaging. To this end, future research will have to provide a more in-depth understanding of epigenetic aging in relation to chronic disease in general, the clinical utility of DNA methylation-based predictors or other epigenetic scores, and the causes and outcomes of inflammaging.
For more on the links between epigenetic age acceleration, kidney disease, and inflammaging, see Clinical Epigenetics, June 2021.
About the author
Stuart P. Atkinson, Ph.D.
Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!
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