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Compr Psychoneuroendocrinol
Compr Psychoneuroendocrinol
Comprehensive Psychoneuroendocrinology
2666-4976
Elsevier

S2666-4976(24)00036-5
10.1016/j.cpnec.2024.100260
100260
Review
Psychoneuroimmunology and the research of Janice Kiecolt-Glaser: It informs self-care and the practice of medicine
Malarkey William B. william.malarkey@osumc.edu
a⁎
a The Ohio State University, Columbus, OH, USA
⁎ 2115 Dodd Hall, 480 Medical Center Dr, Columbus, OH, 43210, USA. william.malarkey@osumc.edu
22 8 2024
11 2024
22 8 2024
20 1002602 4 2024
6 8 2024
16 8 2024
© 2024 Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Dr. Janice Kiecolt-Glaser as an undergraduate obtained a major in psychology and a minor in biological sciences which was an early indication of her budding interest in how the brain talks to a variety of physiologic systems. Early in her research career Jan began to build a research team that eventually consisted of scientists with expertise in a variety of disciplines including virology, immunology, endocrinology, nutrition science, biostatistics, genetics, and the microbiome. Additionally, Jan enlisted the aid of a group of bright energetic pre- and post-doctoral graduate students, obtained numerous NIH grants, and utilized an excellent Clinical Research Center. Over many years Jan directed these teams to help with understanding some of the biologic consequences of common life stressors such as loneliness, academic examinations, marital discord, breast cancer survivorship, and dementia caregiving. In this survey of her accomplishments, I will present some of the highlights of her prolific contributions which have encouraged many to enter the field of psychoneuroimmunology.
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pmcIt is an honor to be asked to provide my thoughts concerning the research career of Janice Kiecolt-Glaser. I have collaborated with her for over 30 years. This opportunity has provided great joy as I observed her brilliance in framing research questions, laboriously spending hundreds of hours writing grant proposals, and then meticulously executing the proposed work which has influenced so many fields of research. The latter point is supported by her work being cited over 75,000 times by the end of 2023.

Dr. Kiecolt-Glaser has been a pioneer in the field of psychoneuroimmunology and has incorporated a systems biology approach to evaluate common human stressors. It is her latter contribution on which I will focus my comments as I am also a clinician and most of her work directly relates to the symptoms and diseases we all experience.

1 Loneliness

In the 1980's Jan began to focus on various stressors and their psycho-social-biologic consequences. Her initial work was with short term stressors like medical school examinations. In one of her first studies blood was drawn from 75 first-year medical students, one month before their final examinations and on the first day of final examinations. Natural killer (NK) cell activity declined significantly over that month. High scorers on stressful life events and loneliness developed significantly lower levels of NK activity [1].

This paper and others to follow initiated her focus on the immune consequences of loneliness and other relationship challenges. Loneliness is presently a common focus of research and community concern as discussed in a recent New England Journal of Medicine article entitled Social Isolation and Loneliness as Medical Issues [2]. In addition loneliness has recently been declared a medical emergency in the UK, and the States of New York and California [3].

Jan's initial work on loneliness was published in the 1980's [1,4,5] and this focus has continued for decades. She has published on the influence of loneliness in producing pain, depression and fatigue [6], cognitive problems in breast cancer survivors [7], dysfunctional appetite regulation [8], and advanced aging via shortened telomeres [9].

2 Marital distress

Another relationship model Jan has extensively studied is marital stress and its biological consequences.

In the 1980's, she began what was to become decades of research evaluating the immune/endocrine consequences associated with marital dysfunction. Jan found that among married subjects, “poorer marital quality was associated with greater depression and a poorer response on three qualitative measures of immune function. Women who had been separated 1 year or less had significantly poorer qualitative and quantitative immune function than their social and demographically matched married counterparts. Among the separated/divorced cohort, shorter separation periods and greater attachment to the (ex)husband were associated with poorer immune function and greater depression. These data were consistent with epidemiologic evidence linking marital disruption with increased morbidity and mortality” [10].

This work was followed by developing a marital interaction paradigm consisting of video recording couples arguing about important life issues and simultaneously acquiring multiple immune, endocrine and behavioral measures. These stressful marital interactions have produced or have been associated with immunologic dysfunction [[11], [12], [13], [14], [15], [16]], altered pituitary and adrenal hormone secretion [12,[17], [18], [19], [20]], disordered appetite regulation [21], cardiac effects [22] as well as effects on wound healing [23], emotion regulation [[24], [25], [26], [27]], pain [27], a “leaky gut” [28] and obesity [29].

3 Caregiving

Jan also intensively investigated marital stress and its biologic consequences in the setting of caring for a spouse with Alzheimer's disease [30]. Her initial investigation evaluated 69 spousal caregivers and matched controls followed for a year. Caregivers experienced a decrease in three measures of cellular immunity, had more days of infectious illness, and more depression [31]. Caregivers were also noted to have impaired immune responses to influenza virus and pneumococcal pneumonia vaccines [32,33].

The impact of caregiving on the proinflammatory cytokine IL-6, which is associated with many age-related conditions, was evaluated in a longitudinal community study of non-caregivers and those caring for a spouse with dementia. This study found that over 6 years caregivers average rate of increase in IL-6 was four times as large as that of non-caregivers. Moreover, the mean annual changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse [34]. These data provided evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response.

Additionally in a subset of this longitudinal caregiving study, the role of childhood adversity was explored. The presence of multiple childhood adversities was related to both heightened IL-6 levels and shorter telomeres, compared with the absence of adversity; this telomere difference could translate into a 7- to 15-year difference in life span [35].

Among these caregivers who experienced bereavement, those who had fewer social ties while caregiving showed marked declines in immune responses over time both before and after bereavement, whereas their socially connected counterparts had shallower declines. In addition, more socially isolated caregivers reported poorer health before and after bereavement compared to their less isolated counterparts, whose self-rated health declined as the loss neared but later recovered to exceed prior levels. These findings suggest that introduction of more social connectedness during a chronic stressor can improve function and slow aging of the immune system [36].

4 Breast cancer survivorship-fatigue and inflammation

The previously discussed findings informed her next major interest which was investigating psychosocial influences on breast cancer survivorship. Fatigue is a common finding in any patient population, but it is particularly bothersome in cancer survivors. Jan and her team reported that women who noted more fatigue had significantly higher norepinephrine and lower heart rate variability (HRV) before and after speech and arithmetic stressors. Based on research that had demonstrated characteristic age-related HRV decrements, these findings suggested a 20-year difference between fatigued and non-fatigued cancer survivors [37].

Fatigue in women with newly diagnosed breast cancer was related to higher cytomegalic antibody titers and herpes virus latency [[38], [39], [40]]. Also in breast cancer survivors, more fatigue was noted in women who were abused or neglected as children. They reported more cancer-related psychological distress, and poorer physical, emotional, functional and breast cancer-specific well-being after treatment [39]. Furthermore, increased relationship quality in breast cancer survivors was related to lower “leaky gut” inflammatory markers as well as other indices of inflammation e.g. IL-6 and CRP [41].

5 Nutrition and obesity

Next, Jan's research portfolio of the biology of stress expanded into considering the role of nutrition in immunologic and cognitive dysfunction. She outlined the reasons for this new direction in an editorial entitled “Psychiatry and Social Nutritional Neuroscience” [42]. She stated that “although the human brain represents only about 2 % of human body mass, it accounts for approximately 20 % of the total resting metabolic rate. As a consequence of the brain's intense energy requirements, metabolic aberrations can have substantial consequences for its function” [42]. The social nutritional neuroscience perspective incorporates key bidirectional influences: e.g. how social processes and behavior impact diet, both of which affect neuro-chemistry and neurobiology [42].

Over the next decade Jan began to evaluate interactions of stress, nutrition, obesity, and the endocrine-immune interface. She first looked at interpersonal stress and it's association with weight gain. She found that women who experience more interpersonal stress had larger hunger increases and post-meal ghrelin, an appetite regulating hormone stimulating food intake. However, this finding only occurred among participants with a non-obese BMI. These data suggest that ghrelin, an important appetite-regulation hormone, and hunger may link loneliness to weight gain [43].

Jan next expanded this social nutrition initiative to evaluate the effect of daily stress on metabolic function in 58 healthy middle-aged women after a high fat meal. The following impressive results were noted: greater numbers of prior day stressors were associated with lower post-meal resting energy expenditure, lower fat oxidation, and higher insulin levels. The cumulative 6-h difference in energy between one prior day stressor and no stressors translated into 435 kJ, a difference that could add almost 11 pounds per year. She argued that these findings illustrate how stress can alter metabolic responses to high fat meals in ways that promote obesity [44].

6 Nutrition and marital distress

Next, Jan evaluated the influence of marital discord and past depression on metabolic responses to a high fat meal. Couples discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors.

Men and women who displayed more hostile behaviors and who also had a mood disorder history had higher insulin, and higher peak triglyceride responses than other participants. Participants with a mood disorder history had a steeper rise in postprandial IL-6 and glucose. Higher levels of hostile behaviors were associated with higher post-meal proinflammatory cytokine, TNF-α and significantly lower post-meal resting energy expenditure [45].

She concluded “people spend about 18 of every 24 h in a postprandial state, and dining with one's partner is a common daily event. Among subjects with a mood disorder history, a significantly lower post-meal resting energy expenditure was found. This difference in energy expenditure between high and low hostile behaviors translated into 128 kcal per day, a difference that could add 7.6 pounds/year. These findings illustrate novel pathways through which chronic marital stress and a mood disorder history synergistically heighten the risk for obesity, metabolic syndrome, and cardiovascular disease” [45].

This interaction of diet and relationships was further explored in middle aged and older normal weight individuals. Upregulation of inflammatory genes was found in those individuals consuming a proinflammatory diet. However, this influence was negated in those individuals reporting greater social engagement [46].

7 Nutrition and breast cancer survivorship

In breast cancer survivors, cognition was also influenced by increased saturated fat intake. In a randomized clinical trial in breast cancer survivors and non-cancer control women, higher levels of “leaky gut” inflammatory markers and saturated-fat intake individually and jointly influenced attention [47].

In another study in breast cancer survivors, Jan evaluated the satiety hormone leptin. Leptin influences inflammation and tumor growth and leptin signaling is often dysregulated among obese breast cancer survivors. She found that obese survivors' leptin was significantly higher at visits when they had higher anxiety and depression symptoms than their own average level of symptoms. In contrast, within-person fluctuations in depression and anxiety were not related to leptin levels among non-obese survivors [48].

8 Nutritional interventions: loneliness, aging, and inflammation

An ongoing interest of her research has been dietary interventions that could modify the inflammatory pathways that were engaged in stressed, depressed and lonely individuals. For example, dietary intakes of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) influence inflammation; high n-6:n-3 ratios enhance proinflammatory cytokine production, and n-3 has anti-inflammatory properties.

Initially, Jan found that Omega-3 supplementation lowered inflammation and anxiety in medical students during exam weeks [49].

In a study of older adults, mean age 66 yrs, she found that higher n-6:n-3 ratios were associated with progressively elevated TNF-alpha and IL-6 levels as depressive symptoms increased. Jan concluded that diets with high n-6:n-3 PUFA ratios may enhance the risk for both depression and inflammatory diseases [50]. In these same older adults it was found that telomere length increased with decreasing n-6:n-3 ratios. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging [51].

In a randomized clinical trial of 138 middle aged and older adults who were sedentary and overweight she gave varying doses of 3-omega and noted an improvement in serum IL-6 and TNF-alpha [50].

Loneliness enhances risk for episodic memory declines over time [52]. Omega-3 supplementation can improve cognitive function for people experiencing mild cognitive difficulties. They therefore performed a clinical trial with varying doses of 3-omega fatty acids and found that this supplementation attenuated loneliness-related verbal episodic memory decline [53].

Additionally, in a study of 633 breast cancer survivors higher serum levels of 3-omega fatty acids were associated with decreased CRP levels and less fatigue [54]. They concluded that the triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions [54].

Further benefits of 3-omega supplementation were noted before and after a Trier Social Stress Test. In this study, supplementation protected the stress induced decline in telomerase and IL-10 levels while reducing overall cortisol and IL-6 levels during the stressor. These findings suggested positive influences of 3-omega supplementation on aging and depression risk [55].

9 Yoga and inflammation

In addition to her studies with 3-omega fatty acids, Jan evaluated the potential benefits of Hatha yoga in decreasing inflammatory and endocrine responses to stress. She initially evaluated 25 novice and 25 expert female practitioners. She reported that novices' serum IL-6 were 41 % higher than those of experts across sessions, and the odds of a novice having detectable CRP were almost 5 times as high as that of an expert [56].

To address the mechanisms underlying hatha yoga's potential stress-reduction benefits, she compared adiponectin and leptin data from well-matched novice and expert yoga practitioners. These adipocytokines have counter-regulatory functions in inflammation; leptin plays a proinflammatory role, while adiponectin has anti-inflammatory properties. Jan noted that experts' average adiponectin levels were 28% higher than novices across the three visits. In addition, experts' average adiponectin to leptin ratio was nearly twice that of novices [57].

Further benefits of yoga practice were evaluated in 200 breast cancer survivors. A randomized controlled 3-month trial was conducted utilizing 90-min twice per week hatha yoga classes or a wait-list control. At 3 months, fatigue, and cognitive complaints were lower in the yoga group, vitality was higher and the proinflammatory cytokines, IL-6, TNF-aplha, and IL-1 beta were lower for yoga participants [58,59].

In this review I have produced a sampling of Dr. Kiecolt-Glaser's prodigious research output. Papers continue to be published, using rich data sets from these clinical trials, by her superb group of trainees, most of whom now hold university positions.

These investigative efforts help inform the practice of medicine. First, they suggest that the initial encounter with an individual in a clinical setting should incorporate some understanding of the life stressors that may be influencing their symptom profile. Pain, fatigue, loneliness, marital discord, appetite dysfunction, depression, caregiving are often present in the life of patients seeking medical care.

As previously discussed, these life stressors often produce neuro-endocrine-immune dysfunction with metabolic consequences and associated signs and symptoms, yet their laboratory report often comes back “normal”. However since the normal range for any laboratory test is population based, it gives no insight into how far an individual may be from their physiologic “sweet spot”.

This dilemma of symptoms without an established disease to explain them leads to millions if not billions of dollars of wasted medical testing each year, some of which may be associated with unnecessary procedures and their associated complications [60].

Hence the tension between the patient and physician when a group of symptoms remains undiagnosed when one or both are not acquainted with the information provided by the studies of Janice Kiecolt-Glaser and others in this field.

Furthermore, as Jan has shown these symptoms can often be improved by non-pharmacologic approaches such as nutritional and meditative interventions that can repair the underlying endocrine-metabolic-immune mechanisms responsible for the presenting complaints.

Finally, stress induced physiologic pathways are also operative after a disease diagnosis such as breast cancer has been made and can be responsible for symptoms that are being ascribed to treatment failure or drug side effects.

One day while awaiting to see patients in the clinic and reflecting on the thoughts just discussed the following came to mind:

When I see these patients today, I know practically nothing about their DNA, their billions of cells and bacteria, their intrauterine beginnings, or their psycho-social-biologic journey.

What is producing their chief complaint?

Can I give it a label?

Is there any way of knowing where their physiologic sweet spot resides?

Is a pharmacologic intervention going to help rather than harm?

If used what dose for this individual?

Thank you, “guidelines”, for comforting me when I unknowingly error!

Furthermore, will the placebo effect of my concern for the patient outweigh my verbal and nonverbal nocebo blunders.

When we finish our time together will we both leave encouraged that we have flattened the aging curve we were on before our time together?

Thanks Janice Kiecolt-Glaser for your many insights into the stress biology of our symptoms and alternative ways they might be managed.

CRediT authorship contribution statement

William B. Malarkey: Writing – original draft.

Declaration of competing interest

None.
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References

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