Significant improvement of stress and aging biomarkers using a novel stress management program with the cognitive restructuring method "Pythagorean Self-Awareness Intervention" in patients with type 2 diabetes mellitus and healthy adults

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Highlights

  • An interventional study to assess psycho-/physiological stress and aging biomarkers.

  • PSAI resulted in a significant increase of LTL in healthy adults.

  • PSAI improved LTL and proteasome levels in subjects with type 2 diabetes.

  • Psycho/ bio-factors improved in both healthy adults and patients with type 2 diabetes.

  • Putative prognostic tools for the assessment of aging pace in clinical practice.

Abstract

Stress accelerates aging by affecting relevant cellular pathways including, among others, leucocyte telomere length (LTL) and proteasome levels. Their impaired function underlies several age-related and non-communicable conditions, such as type 2 diabetes mellitus. The aim of the present study was to investigate, for the first time, the dynamics of stress-related aging factors in the frame of a novel stress-management technique, the Pythagorean Self Awareness Intervention (PSAI), in healthy volunteers and adults with type 2 diabetes. To this end a cohort of 311 healthy volunteers was initially studied and LTL and proteasome levels were analysed in a subgroup of healthy volunteers and adults with type 2 diabetes who were enrolled in the PSAI, with regards to specific physio- and psychometric characteristics of the participants (baseline and post-intervention). We have found a significant improvement of aging biomarkers and of psycho-/bio-factors in all participants. More specifically, post-intervention, both healthy adults and patients with type 2 diabetes demonstrated improved LTL and proteasome levels. Significant improvements were also observed in psychometric, anthropometric and key metabolic features as well as in hair cortisol. In conclusion our results highlighted potential key targets of such interventions and prognostic tools for the assessment of aging pace in clinical practice.

Introduction

Stress is considered as the “health epidemic of the 21th century”, according to the World Health Organisation (WHO). The adult population worldwide is excessively exposed to a vast number of diverse stressors, resulting in poorer wellbeing and overall health status. Acute and chronic stress is characterized by specific and measurable clinical manifestations, indicative of putative disorders in multiple physiological factors of body homeostasis (McEwen, 2008). The analogous responses engage physio-biological and metabolic homeostatic mechanisms that extend from cellular to organismal level and are highly interchangeable.

Numerous studies have shown that chronic stress accelerates the overall rate of aging by affecting relevant biological pathways and cellular functions (de Magalhaes and Passos, 2018). Concomitantly, long term stress and anxiety have been proved to interfere with various immune responses, mediated by stress hormones released by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal medullary (SAM), such as glucocorticoids or catecholamines. These mediators directly interact with immune cells via respective receptors on their surface, modulating their functions and secretory phenotype within a feedback loop of HPA axis (Fali et al., 2018). Antioxidant defence by increased expression of antioxidant enzymes and molecules is another major stress response cellular system; however, excessive stressors can lead to protein modifications and degradation, DNA damage, and eventually to cell aging and death (Rösen et al., 2001; Fukagawa et al., 2000). Collectively, stress induced premature aging, is inevitably reflected in the immune system as well; a condition described as immunosenescence (Bektas et al., 2017).

Telomeres’ dynamics, a major pillar of cellular homeostasis, also characterized as a hallmark of aging (Lopez-Otin et al., 2013), are largely affected by exposure to stressors. Briefly, telomeres are non-coding chromatin fragments consisting of small, repetitive DNA and proteins, located at the ends of the chromosomes that evert a protective role during cell division, by preventing truncation of coding regions. Each replication results in a small reduction of base pairs at the ends of a chromosome and an overall shortening of the chromosome after many duplications. In turn, systematic telomere attrition may possibly threaten genomic integrity and contribute to aging as well as to many age-related diseases (Der et al., 2012; Ellaway et al., 2019). Importantly, shortened leucocyte telomere length (LTL) has been associated with exposure to chronic psychological stress (Epel et al., 2004), depression (Boeck et al., 2018) and represents a risk factor for a range of non-communicable diseases, like diabetes (Baltzis et al., 2018; Wang et al., 2016). As cells’ telomeres status can change in response to various stimuli (Puhlmann et al., 2019; Ornish et al., 2013), it could represent a key target of innovative interventions that may positively influence health span.

Another hallmark of aging, also in a constant interplay with various stressors, is the maintenance of proteostasis (Lopez-Otin et al., 2013). Specifically, the Ubiquitin-Proteasome System (UPS) holds a crucial role in diverse cellular functions, including the regulation of non-functional or aggregated proteins’ degradation (Chondrogianni et al., 2014). The 20S proteasome core is a barrel-like heptametrical rings structure composed of 28 protein subunits. The two outer rings comprise seven different α subunits that control the entry of proteasome’s substrates into the interior rings, consisting of seven β subunits, responsible for the proteolytic activity. In addition, various regulatory complexes bind the proteasome core to control its function (Aiken et al., 2011). Importantly, it has been demonstrated that the accumulation of misfolded or oxidized proteins, advanced glycation end-products (AGEs), lipofuscins, peroxidised lipids, altered N-glycans, and high mobility group Box 1 (HMGB1) protein among others (Berendsen et al., 2014), e.g. "cellular garbage" (Franceschi et al., 2017), is linked to an age-related decline in proteasome content and activities, which in turn, occurs due to the down-regulation of the catalytic subunits of the 20S complex (Chondrogianni et al., 2003). Recent findings also suggest that proteasome activation can delay aging in vivo and also decelerate the onset or progression of aggregation-related pathologies (Mladenovic Djordjevic et al., 2021).

An increasing line of evidence supports the notion that such biomarkers are highly modifiable by interventions towards a healthier lifestyle, like nutritional habits or exercise (Athanasopoulou et al., 2018; Freitas-Simoes et al., 2019; Araujo Carvalho et al., 2019). For instance, a number of lifestyle interventions have been shown to be effective on building resilience against stress and also to favourably impact LTL or telomerase activity (Ornish et al., 2013). Moreover, stress reduction techniques and meditations may reduce cognitive stress and stress arousal and increase benevolent states of mind and hormonal factors, which could, in turn, prevent telomere attrition (Schutte and Malouff, 2014). Under these premises, a novel and multifaceted intervention inspired from the Pythagorean philosophy was developed as a new tool to counteract the multiple aspects of stress. Pythagoras endowed humanity with a timeless philosophy, with a series of daily mental and physical exercises, thereby providing a holistic approach with a positive impact on the daily lives of trainees. Recent studies have shown beneficial effects of Pythagorean Self-Awareness Intervention (PSAI) in patients with severe conditions, as a complementary therapy (Charalampopoulou et al., 2019).

Given these intriguing preliminary findings, the primary aim of this study was to investigate for the first time the dynamics of stress-related aging factors in the frame of this novel and highly promising intervention and decipher regulatory networks between specific metabolic, hormonal, and mental characteristics. To this end, healthy volunteers and adults with type 2 diabetes mellitus (type 2 diabetes) were examined, as type 2 diabetes is largely affected by lifestyle and is associated with impaired cellular homeostasis, resulting to shorter telomeres (Baltzis et al., 2018; Wang et al., 2016) and proteasome dysfunction (Díaz-Ruiz et al., 2015; Queisser et al., 2010).Secondary aim of the study was to assess changes in metabolic, hormonal, anthropometric/body composition parameters and psychometric characteristics.

Section snippets

Research design

Initially, to validate the correlation between relative LTL and age, as a proof-of-concept preliminary study, relative LTL was assessed in a reference sample from NHRF’s Biorepository, consisting of 311 healthy volunteers of an age-range between 18–93 years. Likewise in previous studies Gonos’ group have shown a proteasome decline with age (Athanasopoulou et al., 2018 and references therein). Participants enrolled in the Pythagorean Self-Awareness Intervention (PSAI), were both healthy adults

Results

Firstly, LTL was analysed in a cohort of 311 healthy adult volunteers aged 18–93 years old. As shown in Fig. 2A correlation analysis demonstrated a significant negative relationship between LTL and age. Regarding the two groups enrolled in PSAI, no losses and no harm or unintended effects were noted in the follow-up period.

Discussion

Numerous lines of evidence indicate that senescence is a pivotal underlying mechanism mediating stress response and a carefully orchestrated cellular program. Within this context, telomeres’ dynamics along with proteostasis regulation, share a critical role as activators of the senescence program. Both are highly sensitive to intracellular stressors, such as protein oxidation and aggregation, or DNA-replication stress (de Magalhaes and Passos, 2018). Impaired function of those two significant

Conclusions

PSAI could be considered an inclusive, meta-cognitive process of stress management and self-empowerment that has close resemblance to cognitive-behavioural interventions and, nonetheless, is accompanied by a deeper philosophical reflection. Given the continually accumulative evidence associating cognitive-behavioural methods with stress reduction, improved learning and memory capacity and alleviation of physiological disorders such as systemic inflammation, it is tempting to speculate that the

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

ESG, CD and GC designed the conceptual framework. CD directed the PSAI Intervention and is this Study’s guarantor. NT and AK provided their laboratory’s facilities as the recruitment point for PSAI. DS, FB and MC were in charge of monitoring volunteers’ participation in the PSAI, as well as sample collection and distribution. SA carried out blood sample handling for leucocytes isolation and conducted the subsequent biological experiments. SA and MC conducted the statistical analysis. DS, MC, EA

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