Psychological and biological resilience modulates stress and its influence on epigenetic aging Original paper

This cohort study suggests that cumulative stress is associated with accelerated epigenetic aging, adrenal sensitivity, and insulin resistance in healthy people. Emotional regulation and self-control appear to modulate these associations. Given the observational nature of this study, further research is required to show causation.

This Study Summary was published on January 31, 2022.

Background

Chronic stress is associated with accelerated biological aging (e.g., reduced telomere length), non-communicable disease (e.g., cardiometabolic diseases, mental disorders), and unhealthy behaviors (e.g., smoking, alcohol). Behavioral and psychological resilience factors, which include culture, environment, and lifestyle habits, may also modify these associations.

Epigenetic “clocks” based on DNA methylation (DNAm) are a popular way to assess biological age, and appear to provide more accurate assessment than previously established biomarkers, like telomere length, but a potential connection with cumulative stress and psychological and biological resilience has yet to be investigated.

There are different kinds of aging. Chronological age is the calendar time that has passed since birth, while biological age is the physiological state of a person, typically evaluated via biomarkers that predict the functional capability of a person’s system, organs, and other functions. Epigenetic age is an estimate of biological age from algorithms based on DNAm states in specific regions, such as CpGs, a cytosine nucleotide followed by a guanine nucleotide.

The relationship between stressors and accelerated aging

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Chronological vs. biological age

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The study

This cross-sectional study included psychological and biological stress and epigenetic data from 444 healthy adults ages 18–50 (45% male).

Cumulative stress, emotional regulation, self-control, and overall health were assessed with various tools that have demonstrated high levels of reliability. Specifically, researchers used the Cumulative Adversity Inventory, Difficulties with Emotion Regulation Scale, Self-Control Survey-Brief, and Cornell Medical Index.

Blood samples were taken for DNAm and epigenetic clock analysis, as well as fasting insulin, glucose, adrenocorticotropic hormone, and cortisol measurements.

The GrimAge epigenetic clock was used to estimate biological age and mortality.

🔍 Digging Deeper: Epigenetic clocks

Advancements in gene expression assessment and biostatistics, along with the completion of the Human Genome Project, has allowed for the identification of “epigenetic clocks” (or DNAm-based biomarkers) that have emerged as the most promising molecular estimators of biological age, compared to other estimators like telomere length and composite biomarkers.[1]

Different estimators include different specific DNAm sites associated with certain aspects of health, ranging from BMI and cognitive function to immune cell telomere length and senescence — when cells stop dividing and secrete (typically) inflammatory compounds, often as a result of aging or stress.[2][3] DNAm age estimates may even be useful for evaluating anti-aging interventions.

GrimAge is a specific epigenetic clock developed using biomarkers of mortality and indicators of health (e.g., plasma protein levels and smoking pack-years) that has been reported to outperform other epigenetic clocks in the prediction of age-related decline and overall mortality.[4][5]

The results

Cumulative stress was associated with accelerated epigenetic aging and stress-related physiologic measures (adrenal sensitivity and insulin resistance).

Emotional regulation moderated the association between stress and aging, in that worse emotional regulation resulted in greater stress-related aging, while self-control moderated the association between stress and insulin resistance, in that better self-control increased insulin sensitivity.

Note

Since this is a cross-sectional study, the causality of these associations cannot be established, and the long-term implications of the results are unclear.

Despite seemingly being the best tool available, estimations made with epigenetic clocks should still be interpreted with caution because their underlying mechanism is not completely understood.

However, the consistency between subjective and objective measures of psychological and biological resilience factors suggest a robust result.

The big picture

An April 2021 systematic review reported that BMI, HIV infection, and being male was associated with acceleration of one or more epigenetic clocks. While chronic disease was also associated with acceleration of epigenetic clocks, stress associated outcomes were not mentioned. [6]

An October 2021 secondary analysis of a 24-month RCT in healthy postmenopausal women covered in a previous Editor’s Pick demonstrated that physical activity and a healthy diet can slightly reduce biological age.[7]

A 2018 meta-analysis reported that lifetime post-traumatic stress disorder (PTSD) severity and childhood trauma were associated with advanced epigenetic age, while PTSD diagnosis and lifetime trauma were not, when measured using the Hannum epigenetic clock (Hannum), but not the Horvath epigenetic clock.[8]

A 2019 longitudinal study of very preterm infants reported an inverse association between telomere length erosion and salivary cortisol reactivity to stress.[9]

A 2019 meta-analysis of twin studies reported a heritability estimate of 60% for self-control.[10] This suggests that self-control is influenced by genetics, while the study summarized here suggests self-control also influences genetics in turn.

A January 2021 cohort study of children that followed participants from birth to 45 years old reported that children with better self-control aged more slowly. Their self-control was independent of social class origin and intelligence and shifted naturally across adult life, suggesting an opportunity for intervention.[11]

An August 2021 longitudinal study reported improvements in self-control following intervention that were associated with reduced epigenetic (GrimAge) age.[9]

Epigenetic clocks appear to be good at predicting biological age, but they are limited to the specific biomarkers and outcomes that drive the estimation. Given that their underlying mechanisms and some of the outcomes they are being used to predict are not completely understood, and a lot of the related data is observational, further research is needed to shed light on their best use.

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This Study Summary was published on January 31, 2022.

References

  1. ^Juulia Jylhävä, Nancy L Pedersen, Sara HäggBiological Age PredictorsEBioMedicine.(2017 Jul)
  2. ^Matthew J RegulskiCellular Senescence: What, Why, and HowWounds.(2017 Jun)
  3. ^Steve Horvath, Kenneth RajDNA methylation-based biomarkers and the epigenetic clock theory of ageingNat Rev Genet.(2018 Jun)
  4. ^Ake T Lu, Austin Quach, James G Wilson, Alex P Reiner, Abraham Aviv, Kenneth Raj, Lifang Hou, Andrea A Baccarelli, Yun Li, James D Stewart, Eric A Whitsel, Themistocles L Assimes, Luigi Ferrucci, Steve HorvathDNA methylation GrimAge strongly predicts lifespan and healthspanAging (Albany NY).(2019 Jan 21)
  5. ^Cathal McCrory, Giovanni Fiorito, Belinda Hernandez, Silvia Polidoro, Aisling M O'Halloran, Ann Hever, Cliona Ni Cheallaigh, Ake T Lu, Steve Horvath, Paolo Vineis, Rose Anne KennyGrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause MortalityJ Gerontol A Biol Sci Med Sci.(2021 Apr 30)
  6. ^Lara Oblak, Jeroen van der Zaag, Albert T Higgins-Chen, Morgan E Levine, Marco P BoksA systematic review of biological, social and environmental factors associated with epigenetic clock accelerationAgeing Res Rev.(2021 Aug)
  7. ^Giovanni Fiorito, Saverio Caini, Domenico Palli, Benedetta Bendinelli, Calogero Saieva, Ilaria Ermini, Virginia Valentini, Melania Assedi, Piera Rizzolo, Daniela Ambrogetti, Laura Ottini, Giovanna MasalaDNA methylation-based biomarkers of aging were slowed down in a two-year diet and physical activity intervention trial: the DAMA studyAging Cell.(2021 Oct)
  8. ^Erika J Wolf, Hannah Maniates, Nicole Nugent, Adam X Maihofer, Don Armstrong, Andrew Ratanatharathorn, Allison E Ashley-Koch, Melanie Garrett, Nathan A Kimbrel, Adriana Lori, Va Mid-Atlantic Mirecc Workgroup, Allison E Aiello, Dewleen G Baker, Jean C Beckham, Marco P Boks, Sandro Galea, Elbert Geuze, Michael A Hauser, Ronald C Kessler, Karestan C Koenen, Mark W Miller, Kerry J Ressler, Victoria Risbrough, Bart P F Rutten, Murray B Stein, Robert J Ursano, Eric Vermetten, Christiaan H Vinkers, Monica Uddin, Alicia K Smith, Caroline M Nievergelt, Mark W LogueTraumatic stress and accelerated DNA methylation age: A meta-analysisPsychoneuroendocrinology.(2018 Jun)
  9. ^Man-Kit Lei, Gene H Brody, Steven R H BeachIntervention effects on self-control decrease speed of biological aging mediated by changes in substance use: A longitudinal study of African American youthFam Process.(2021 Aug 14)
  10. ^Y E Willems, N Boesen, J Li, C Finkenauer, M BartelsThe heritability of self-control: A meta-analysisNeurosci Biobehav Rev.(2019 May)
  11. ^Leah S Richmond-Rakerd, Avshalom Caspi, Antony Ambler, Tracy d'Arbeloff, Marieke de Bruine, Maxwell Elliott, HonaLee Harrington, Sean Hogan, Renate M Houts, David Ireland, Ross Keenan, Annchen R Knodt, Tracy R Melzer, Sena Park, Richie Poulton, Sandhya Ramrakha, Line Jee Hartmann Rasmussen, Elizabeth Sack, Adam T Schmidt, Maria L Sison, Jasmin Wertz, Ahmad R Hariri, Terrie E MoffittChildhood self-control forecasts the pace of midlife aging and preparedness for old ageProc Natl Acad Sci U S A.(2021 Jan 19)