In the past, beside UV-irradiation many stress factors have been investigated and were linked to accelerate telomere shortening in humans. Accordingly telomere shortening was linked to psychological and physiological disease and poor lifestyle.
The telomere length determined in the hematopoietic system. Most of the studies connecting telomere length as biomarker with health or lifestyle status were performed with leukocyte telomere length (LTL). Leukocytes or white blood cells (WBC) are nucleus-containing cells of the blood Each dot on the graph represents the mean telomere signal intensity in one skin sample in keratinocytes (green), dermis (gray) and melanocytes (blue) from the sun exposed skin, and from the rarely exposed skins. Note the high variation within each group due to interpersonal differences and the small size of sample (5 donors only per group), nevertheless there is a tendency for longer telomeres in the non-exposed group in the keratinocytes and melanocytes, and significant difference in
11 protecting the body against pathogenic organisms or foreign cells. They are generated from multipotent mesenchymal stem cells in the medulla ossium ruba mainly found in the episternum and pelvis and further differentiated into the different leukocyte categories. These are B cells, T cells and natural killer (NK) cells and the myeloid cells consisting of monocytes (subdivided in macrophages, mast cells and dendritic cells) and the granulocytes (class-divided in neutrophil, eosinophil and basophil) (Cumano & Godin 2007). The discovery of the hematopoietic stem cells (HSC) and their frequent production of blood cells were made in the mid-twenties century (Till & Mc 1961; Metcalf 1970; Moore & Metcalf 1970). For a continuous production of blood cells, the HSC undergo a massive proliferation including their self-renewal for long-term. On average, 99 % of the HSC cells were found to divide every 57 days (Cheshier et al. 1999). After differentiation 20-45 % are lymphocytes (therefrom 15-25 % B cells and 40-75 % T cells) and 55-80 % are myeloid cells of the blood stream containing leukocyte. While monocytes and granulocytes exhibit a half-life of some hours up to few days, the memory cells of lymphocytes are able to survive for years (Blumenreich 1990). All other lymphocytes in the peripheral blood reveal a half-life of 1-6 weeks but according to the type of labelling, the half-life was found to vary. In particular, morphologically maturated B cells displayed a half-life of 5-6 weeks but residual B cells maintain for several days only (Fulcher &
Basten 1997). Interestingly, human naive matured T-cells have a longer half-life and longer telomeres than memory T cells of the same donor (Weng et al. 1995; De Boer & Perelson 2013) (fig. 6).
With the analysis of telomere length in leukocytes of different aged donors, age-dependent telomere erosion was found in T cells, B cells and granulocytes (Rufer et al. 1999; Chen et al. 2011; Ishikawa et al. 2016). This age-dependent telomere loss was also detected in other tissues like endothelial cells of the vascular system (Chang & Harley 1995), skin cells (Sugimoto et al. 2006), skeletal muscle, subcutaneous fat (Daniali et al. 2013), thyroid and parathyroid tissue (Kammori et al. 2002) and mucosa of large and small intestines (Hiyama et al. 2009). The telomere loss is for most parts linked to
[Image from nuclear cells (PBMCs) can be divided into myeloid cells (plasmacytoids and monocytes, the latter can differentiate into macrophages or dendritic cells) and lymphoid cells (B, T or NK cells). The white blood cells granulocytes derived from myeloid cells are polynuclear leukocytes and thus not represented in the image.
Introduction and Aim
12 the end replication problem but is also suggested to a age-related decrease in telomeric repair capacities of the (stem) cells (Kruk et al. 1995). In the human hematopoietic system lymphocytes and granulocytes showed a 30-time faster telomere decrease in the first years in childhood in comparison to the rest of the human life-span which supported a link between HSC division and loss of telomeric DNA. Furthermore, adults revealed to have longer granulocyte telomeres than lymphocytes telomeres.
(Rufer et al. 1999) While age-dependent telomere loss was calculated as being 33 bp per year in T-cells, B cells only showed a telomere loss of 15 bp/year revealed to be slower in. On that account, B cells showed 15 % longer telomeres (about 1 kb longer) compared with T lymphocytes in adult peripheral blood. (Martens et al. 2002) Like T cells, the subpopulations of B cells show differences in telomere length. Based on the differentiation, naïve matured B cells reveal shorter telomeres than their activated germinal-center (GC)-form. After differentiation of the GC B cell to memory cells, lymphocyte telomeres occurred to be shortened again. (Weng et al. 1997)
The hematopoietic cells reveal telomerase activity. Like other extensively proliferating tissues the HSCs of the hematopoietic system express telomerase activity. In 1995, Counter and co-workers first showed evidence that peripheral, cord blood and bone marrow leukocytes of normal donors expressed low levels of telomerase activity (Counter et al. 1995). An increase in T cell telomerase activity was seen after their stimulation through serially transplanted HSCs. Furthermore, in this study Allsopp and co-workers found, a proliferating dependent HSC telomere shortening in the bone marrow of the donor mice. (Allsopp et al. 2002) The contrary of these two findings, that the telomerase positive HSCs show telomere shortening is not yet fully clear. One may speculate for a too rapid proliferation and too little telomerase activity. In addition, peripheral-blood T cells show almost no detectable telomerase activity, but T cells subpopulations in the thymocytes exhibit high levels. However, activation through chronic inflammation can also increase the telomerase activity in peripheral-blood T cells. (Weng et al. 1998) Furthermore, naïve or memory B cells showed little to no expression of telomerase activity, while GC B cells in the lymph nodes have a 128-fold higher telomerase activity (Weng et al. 1997).
Life style may influence telomere length in human peripheral blood cells. So far, an accelerated telomere shortening of leukocytes was associated with several lifestyle determinants. For example, two studies directly focused on the alcohol consumption and humans LTL revealed and showed shorter LTL after regular alcohol intake ranging from alcohol abuse to minor alcohol consumption (Pavanello et al. 2011; Strandberg et al. 2012). Additionally, a connection between short LTL and cigarette smoking was demonstrated (Muezzinler et al. 2015; Gao et al. 2016; Zhang et al. 2016).
Valdes and colleagues even demonstrated a dose-dependent telomere shortening with increasing smoking and recalculated for each pack-year smoked an additional telomere length loss of 18 % (Valdes et al. 2005), however, to quit smoking seemed to increase LTL, depending on the past time of smoking cessation (Wulaningsih et al. 2016). On the other hand beneficial behaviors for humans’
health were linked to longer LTL than humans with poor health behaviors like eating few
13 polyunsaturated fatty acids (Cassidy et al. 2010; Tiainen et al. 2012), performing a Mediterranean diet (Boccardi et al. 2013), higher vegetable consumption (Lian et al. 2015), having enough physical activity (Puterman et al. 2010; Song et al. 2013; Borghini et al. 2015) or enough sleep (Prather et al.
2015) were associated with longer LTL.
Stress to the human body may negatively influence telomere length. Beside the lifestyle impact on LTL, the physical and psychological stress exposure was manifold revered to have a critical influence on LTL. Various studies in adults showed accelerated LTL erosion with increased life stress. For instance, shorter LTL was associated with the posttraumatic stress disorder, (O'Donovan et al. 2011;
Zhang et al. 2014; Roberts et al. 2017), depression, anxiety and adjustment disorders (Wang et al.
2017), perceived stress during caregiving of a chronically ill children (Epel et al. 2004), unemployment (Ala-Mursula et al. 2013), experienced discrimination (Lee et al. 2017), or stressful and threatening life events within the previous 6 month like illness, social difficulties or loss of an intimate relationship because of death or separation (van Ockenburg et al. 2015; Verhoeven et al.
2015; Lopizzo et al. 2017). Additionally, the accelerated decrease of LTL due to stressful events (like violence, low socioeconomic status, maternal depression, family disruption, and institutionalization) was also obtained in children (Coimbra et al. 2017) and even in newborns the accelerated LTL erosion was associated with increased maternal perceived stress during pregnancy (Send et al. 2017).
Obesity and telomere shortening is related to psychological and physical stress. Being obese may be both a psychological and physiological stress determinant to the human body. Obesity is the extreme accumulation of adipocyte tissue which has negative impact to the health state. According to the World Health Organization obesity is defined by a body mass index (BMI: m/l2 [kg/m2]) equal or higher than 30 kg/m2 (WHO 2000). Due to the increased body mass obese people have movement restriction, are often bullied, may suffer from the western slim ideal of beauty and suffer more often from depressions (Reeves et al. 2008; Luppino et al. 2010). Furthermore, Furukawa et al. suggested that obesity induces systemic oxidative stress and provided evidence that adipose tissue selectively increases the ROS production in mice and humans. This was further supported by an increased expression of NADPH oxidases and a decreased expression of antioxidant proteins (Furukawa et al.
2004). Linking the increase of several inflammation and oxidative stress markers to LTL, Bekaert et al. showed a negative correlation of increased oxidative stress and LTL (Bekaert et al. 2007). Based on the physiological and physiological factors it was not surprising that many researchers found evidence for shorter LTL in obese humans (Muezzinler et al. 2014; Mundstock et al. 2015). Onset of the 21st century, for the first time it was shown that obese woman had shorter LTL than non-obese women (Valdes et al. 2005; Kim et al. 2009). But also at young age, Buxton and co-workers found a shorter mean LTL in children between 2 and 17 years with early onset obesity (Buxton et al. 2011).
Interestingly, in an population based study Bischoff and colleagues could not detect an association between shorter LTL and obesity in elderly and old people (73-94 years) (Bischoff et al. 2006). Five
Introduction and Aim
14 years later, similar results were published by Njajou and co-workers. Here too, they did not find a correlation between obesity or LTL of participants between 70 and 79 years, however, they found LTL to be negatively associated with increasing subcutaneous body fat (Njajou et al. 2012).
Non-smoking obese men with a starting mean BMI of 31.9 kg/m2 lost on average 10.6 kg after a 12-week energy-restricted diet. Biopsies of the rectal mucosa before and after weight-loss program revealed a significant increase in mucosa telomere length, which appeared to be larger with increasing weight reduction (O'Callaghan et al. 2009). However, a study with overweight or obese post-menopausal women did not demonstrate a leukocyte telomere change after one year through a weight reduction of 10 % with dietary weight loss and/or aerobic exercise (Mason et al. 2013). In a gender-mixed study with 5-year dietary weight reduction reported to an increase of LTL (Garcia-Calzon et al.
2014a). This effect was also seen in overweight/obese adolescents. Here a 2 month-long intervention of dietary habits, physical activity and psychological constitution was already enough to receive a significant LTL increase after 6 month of follow up (Garcia-Calzon et al. 2014b). Similarly, obese adults and adolescents revealed a weight-loss-dependent leukocyte telomere lengthening 6 month after a bioenteric intragastric balloon (BIB) placement (Carulli et al. 2016). In 2014 Formichi and colleagues first exhibited a study of weight reduction through bariatric surgery and LTL. The obese patients, with a BMI between 33 and 79 kg/m2, obtained either sleeve gastrectomy, gastric banding, gastric bypass, biliopancreatic diversion or a gastric plication. Even though a weight reduction was received no telomere lengthening was seen. Instead, a LTL decline was found after 3, 6, 9 and 12 months after the surgery (Formichi et al. 2014). However, after 10 years Laimer and co-workers provided evidence for an LTL increase induced bariatric surgery (Laimer et al. 2016).
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