Telomeres and the Science of Stress – a Blog from Our Co-Founder, Dr. Jue Lin at UCSF

Being stressed out seems to have become the normal condition of our modern lives. Work, school, parenting, caregiving, traffic, finances, the 24-hour news cycle, loneliness, loss of community, family pressures, health concerns—the list is long. In fact according to the National Institute of Mental Health, Americans are one of the most anxious nations in the world, with over 18% of our population suffering from an anxiety disorder in any given 12-month period, with 22.8% of these categorized as severe.

https://www.nimh.nih.gov/health/statistics/prevalence/any-anxiety-disorder-among-adults.shtml

My name is Jue Lin, and I am a Research Biochemist at UCSF and co-founder of Telomere Diagnostics, the company that provides the TeloYears genetic test. In my academic work, I have extensively focused on the effects of stress on telomere length and aging. Over the past decade, our published findings have consistently shown that stress is inversely correlated to telomere length. In other words, greater stress is associated with shorter telomeres.

Before I go into my research, I would like to briefly review what I describe as “stress.” Recognize first that not all stress is bad. Throughout the course of vertebrate evolution, the stress response has been one of our most successful evolutionary mechanisms. It has allowed us to evade predators, cope with resource shortages, and move quickly to grab that tasty nugget of protein that is scurrying by. The behavioral changes that stressful conditions induce are made possible by the release of stress hormones from the hippothalamic-pituitary-adrenal (HPA) axis. Cortisol is the most important stress hormone in humans. When stress hormones increase from baseline levels, they enable us to heighten our energy expenditure, concentrate our mental focus, and achieve a hyper-alert sensory state to maximize our chance of success in dealing with the emergency at hand. When the threat is over, stress hormone levels quickly return to normal and homeostasis is restored. There is a trade-off in this beneficial boost. When stress hormone levels are raised, normal organismal growth, maintenance, and reproduction are suspended. But because this short-term cost affords longer term benefits like catching prey, evading predators, or surviving some other life-or-death threat, the HPA-driven stress response confers a high degree of survival advantage. In our daily lives, it’s easy to see how we all benefit from some degree of stress beyond our evolution as vertebrates. Stress can motivate us to complete projects on time, respond quickly when a car cuts you off in traffic, or face and overcome our challenges and fears.

However problems arise when acute stress becomes chronic. When we are exposed to repeated or enduring threats, the HPA axis is continually stimulated to raise levels of cortisol without returning to baseline levels. The long-term exposure to cortisol from chronic stress can wreak widespread havoc in many of our bodies’ systems – it encourages higher blood sugar, weakens the immune system by blocking T-cell signaling by interleukins, increases the output of proinflammatory cytokines, and can negatively impact memory by overwhelming a part of the brain with a high density of cortisol receptors called the hippocampus. Some studies indicate that when our HPA axis is in a protracted high state of alert, the delicate balance of cortisol production and inhibition becomes dysfunctional.

In addition to these changes in the larger physiological systems in the body, chronic stress also takes a toll on our bodies at the level of DNA, specifically on the structures at the ends of our DNA called telomeres. Telomeres are the protective caps on the ends of our chromosomes that protect our genetic information from getting scrambled during division. However, every time a cell replicates, a bit of the telomere is used up due to a phenomenon we scientists call the “end replication problem.” This happens again and again over the natural lifetime of a cell until the telomere reaches a critically short length such that there is not enough telomere left for the cell to reproduce. When telomere length reaches this limit and cell division stops, the cell becomes senescent. Senescent cells are cells that, in addition to no longer being able to divide to replace old worn out tissue, undergo changes that result in further damage to the organism. Whereas young cells secrete proteins that maintain healthy, functioning tissue, senescent cells begin to secrete inflammatory cytokines and proteins that promote tumor progression. This phenomenon at a microscopic level has been described as the causal nexus that, in combination with other factors, leads to macroscopic effects of tissue breakdown manifested in the phenotypical effect of aging. In addition to time, other lifestyle factors have been implicated in the rate of telomeric shortening – such as diet, exercise, sleep and more.

The focus of much of my academic career has been on the association between stress and telomere length. For example, in 2004 I published a controlled study in the peer-reviewed journal Proceedings of the National Academy of Sciences (PNAS) with Elizabeth Blackburn, Elissa Epel and Richard Cawthon titled “Accelerated telomere shortening in response to life stress,” in which we hypothesized that chronic stress impacts health by affecting the rate of cellular aging. In our cohort of pre-menopausal mothers, 39 had chronically ill children, whereas 19 had healthy children. We asked all subjects to complete a ten-question survey to measure their perceived level of stress over the prior month so that both perceived and objective stress levels could be assessed. Telomere length was measured from blood samples (peripheral blood mononuclear cells or PBMCs) using qPCR and activity of telomerase, the enzyme that extends telomeres, was measured by the telomerase repeat amplification protocol. An index of oxidative stress was calculated as the ratio of isoprostanes per milligram of creatinine to vitamin E. We found that the more years of caregiving a mother provided, the shorter her telomere length, the lower her telomerase activity, and the greater her oxidative stress, even after controlling for the mother’s age.

In addition, we found significant correlation between perceived caregiver stress and all three markers of cellular aging across both the control and caregiver group. This finding was intriguing in that it indicated that telomeric shortening was not specific to the extreme and unique stress of caring for an ill child, but it was also observed across the range of normative stress levels, most markedly at the lowest and highest scores for perceived stress.

The difference in telomere length between the high stress and low stress groups was 550 base pairs, the equivalent of 9-17 years of cellular aging. In addition, the high perceived stress group also had depressed telomerase activity and higher oxidative stress than the low perceived stress group. This study suggested that premature cellular senescence might be influenced by chronic or perceived stress. From our findings, we were unable to determine that people who had lower perceived stress because their longer telomeres made them more resilient or vice versa with the higher perceived stress group. However the data related to the telomeric shortening in concert with chronicity of caregiving, did provide us with a compelling rationale that stress from years of caregiving precedes telomeric shortening as it is not reasonable to conclude that telomere length determined their duration as caregivers. In summary, the study showed that in healthy women, psychological stress is associated with indicators of accelerated cellular and organismal aging: oxidative stress, telomere length, and telomerase activity in PBMCs. This was the first study that showed chronic psychological stress is associated with shorter telomere length. Since then, researchers have found associations of short telomere length with many forms of stress, including neighborhood adversity, poverty and social disadvantage, domestic violence, and childhood adverse experience.

Early life stress (ELS) increases risk for many psychological disorders as well as somatic conditions and diseases including cardiovascular disease and type 2 diabetes. Cellular aging, as measured by shortened telomere length, is recently shown to be associated with early life stress. A paper published by Audrey R. Tyrka at Brown University in the journal Biological Psychiatry in 2009 examined the association of childhood maltreatment and leukocyte telomere length in 31 young-middle age adults. The participants were surveyed on the 28-item Childhood Trauma Questionnaire that probed five aspects: physical abuse, sexual abuse, emotional abuse, emotional neglect, and physical neglect. Telomere length was measured by the qPCR based on the Cawthon method. The paper found that participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment after adjusting for age, sex, smoking, body mass index, or other demographic factors. Specifically, both physical neglect and emotional neglect were significantly linked to shorter telomere length. This study showed that detrimental effects of adverse childhood experience on telomere length can extend to adulthood. Another study led by Dr. Janice Kiecolt-Glaser at Ohio State University found that childhood emotional/physical/sexual abuse, childhood adversity (parental death, parental marital conflict, familial mental illness, familial alcohol problems, lack of close relationship with adult) is associated with shorter telomeres in elderly, emphasizing the life-long impact of ELS on telomere length. This study included 132 healthy older adults (mean age = 69.70, SD=10.14), 58 of them are dementia family caregivers and 74 are non-caregivers. The association of multiple childhood adversities and shorter telomeres persisted after controlling for age, caregiving status, gender, body mass index, exercise, and sleep and is equivalent to 7-15 years of cellular aging.

In 2011, Elissa Epel, Elizabeth Blackburn and I again published a study to look at the relationship between telomere length and stress, this time along with Janice Humphreys, PhD, UCSF School of Nursing, in the Journal Biological Research for Nursing. In this study, we investigated the association between telomere length in women with a history of intimate partner violence (IPV). IPV refers to physical or sexual violence or the threat of such violence or psychological/emotional abuse and/or coercive tactics when there has been prior physical and/or sexual violence between persons who are partners or former partners (Saltzman, Fanslow, McMahan, & Shelley, 1999). In North American surveys, between 25% and 30% of women of all ages reported having experienced IPV at some point in their lifetimes. In addition to its prevalence, IPV is a well-documented source of chronic stress and negative health effects for women. As telomeres shorten in response to chronic stress, we hypothesized that women with a history of IPV would have shorter telomeres than control. We recruited 61 formerly abused women and 41 women that had no history of abuse. We then measured the mean telomere length of both groups’ PBMCs using quantitative PCR. As obesity and age can also influence telomere length, we also included these two factors in our analysis. We found that formerly abused women in our sample had significantly shorter mean telomere length than women who had never been abused. We also found that the best predictors of telomere length were being a mother and the length of time spent in an abusive relationship. Our findings suggested that mothering adds significant additional burden to women experiencing IPV and indicates that the longer the duration of IPV, the more damaging the effects.

These three studies are just several in a larger body of published work on the role of stress in premature telomere shortening. Although there is much literature that documents the increased mortality and morbidity of chronically stressed individuals, the exact mechanism of action for this relationship has remained elusive. Increasingly we are coming to understand that stress-mediated changes in telomere length are a compelling model for this mechanism as critically short telomeres lead to cellular senescence in which cells in the body cease normal function and can lead to chronic inflammation and age-related diseases such as heart disease, cancer and diabetes. Research is continuing in an effort to understand the relationship between chronic stress, telomeres, disease, and aging. As these relationships become better understood, researchers are also looking at what practices best mitigate how stress harms our cells and our health.

Please look for my next blog post in the upcoming weeks, when I will review what the published literature says about what measures have been found to be effective at reducing the damaging effects of chronic stress on our DNA.

 

 

Jue Lin, PhD

Dr. Lin is a Research Biochemist in the Department of Biochemistry and Biophysics at UCSF and a co-founder of Telomere Diagnostics. She did her postdoctoral work with Dr. Elizabeth Blackburn, a Nobel Laureate in telomere research, investigating telomerase function and regulation.

Read more about Dr. Lin at www.teloyears.com