Telomerase as a Therapeutic Target in Cardiovascular Disease.

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.

Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis.

In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time-avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies.

Loving-kindness meditation slows biological aging in novices: Evidence from a 12-week randomized controlled trial.

Combinations of multiple meditation practices have been shown to reduce the attrition of telomeres, the protective caps of chromosomes (Carlson et al., 2015). Here, we probed the distinct effects on telomere length (TL) of mindfulness meditation (MM) and loving-kindness meditation (LKM). Midlife adults (N = 142) were randomized to be in a waitlist control condition or to learn either MM or LKM in a 6-week workshop. Telomere length was assessed 2 weeks before the start of the workshops and 3 weeks after their termination. After controlling for appropriate demographic covariates and baseline TL, we found TL decreased significantly in the MM group and the control group, but not in the LKM group. There was also significantly less TL attrition in the LKM group than the control group. The MM group showed changes in TL that were intermediate between the LKM and control groups yet not significantly different from either. Self-reported emotions and practice intensity (duration and frequency) did not mediate these observed group differences. This study is the first to disentangle the effects of LKM and MM on TL and suggests that LKM may buffer telomere attrition.

Obstructive sleep apnea, nighttime arousals, and leukocyte telomere length: the Multi-Ethnic Study of Atherosclerosis.

STUDY OBJECTIVES: Sleep disturbances and sleep apnea are associated with increased vulnerability to age-related disease, altering molecular pathways affecting biological aging. Telomere length captures one component of biological aging. We evaluated whether objectively assessed sleep and sleep apnea relate to leukocyte telomere length (LTL) in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Men and women aged 44-84 years (n = 672) from the MESA Stress and MESA Sleep studies underwent polysomnography and 7 day actigraphy (at Exam 5) and assessment of LTL (at baseline [Exam 1] and about 10 years later [Exam 5]). RESULTS: General linear models adjusting for age, sex, race/ethnicity, BMI, physical activity, and smoking found that severe obstructive sleep apnea (OSA; apnea-hypopnea index > 30) was cross-sectionally associated with shorter LTL (p = 0.007). Modest associations of shorter LTL with less rapid eye movement sleep, more stage 1 sleep, wake after sleep onset >30 min, and long sleep duration were found, but these effects were diminished after adjusting for lifestyle and OSA. Exploratory analyses found that higher arousal index at Exam 5 was associated with greater LTL decline over the prior 10 years (p = 0.004). CONCLUSIONS: OSA was associated with shorter LTL. Individuals with high-arousal frequency had greater leukocyte telomere attrition over the prior decade. These findings suggest that sleep apnea and sleep fragmentation are associated with accelerated biological aging.

Endocrine Conditions in Older Adults: Anti-Aging Therapies.

Interest in slowing or reversing the process of aging continues to grow and has encouraged the growth of an entire anti-aging industry. However, there is a dearth of data based on randomized trials in humans to support proposed therapies to address the various complex processes involved in aging. Hormonal therapies, in particular, have little data to support safe use and are associated with some degree of risk. Experimental data in animal models suggest possible molecular targets but their use in clinical medicine is far in the future. Observational data guide the current recommendations to maintain a healthy lifestyle, including consumption of a healthful diet and achieving adequate sleep, toward the goal of slowing the aging process. Patients may ask their physicians to offer opinions about treatments they hope will increase their health span. To counsel patients effectively, it is important for physicians to understand the basic principles of anti-aging science. Maintenance of supportive, nonjudgmental therapeutic relationships with patients is critical to avoid harmful and costly treatments while trying to present reliable evidence for available anti-aging therapies.

Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length.

Stress affects cellular aging and inflammatory and chromosomal processes, including telomere length, thereby potentially compromising health and facilitating disease onset and progression. Stress-related diseases and strategies to manage stress usually require integrative or behavioral therapeutic approaches that also operate on cellular levels. Mind-body medicine (MBM) uses the interaction between the mind, body, behavior, and the environment to correct physical and psychological malfunctions, thus ameliorating disease states and improving health. The relaxation response (RR) is a physiological opponent of stress and the stress response (SR) (i.e., fight-or-flight response), also invoking molecular anti-stress processes. Techniques that elicit the RR are at the core of practically all MBM interventions. We surmise that these techniques can also affect chromosomal and telomere processes, molecular aging, and the modulation of inflammatory states on cellular levels.

Association between statin drug use and peripheral blood leukocyte telomere length in the National Health and Nutrition Examination Survey 1999-2002: a cross-sectional study.

PURPOSE: To evaluate the association between statin drug use and peripheral blood leukocyte telomere length in a U.S. nationally representative sample of adults. METHODS: We conducted a cross-sectional analysis of data from National Health and Nutrition Examination Survey 1999-2002, representative of the noninstitutionalized U.S. POPULATION: The analytic study population included 3496 men and women aged 40-84 years without a history of cancer and who had information of telomere length and statin use. RESULTS: Compared with nonusers, statin users were more likely to be former smokers, older, white, male, and had more comorbidities. Statin users did not have longer telomeres than nonusers after age (coefficient -0.013, p = .30) and multivariable (0.0003, p = .98) adjustment. After multivariable adjustment, log-transformed telomere length nonstatistically significantly increased with increasing duration of use (0.003, p-trend = .11), which did not differ by number of comorbidities (p-interaction = 0.18). Compared with nonuse, more than 5 years of use had an odds ratio of telomere length above the 75th percentile of 1.62 (95% confidence interval 0.90-2.92; p-trend = .10). CONCLUSIONS: Although telomere length appeared to be longer with longer duration of use of a statin, this association was not statistically significant, and we could not rule out bias as the explanation.

Weight Loss Maintenance and Cellular Aging in the Supporting Health Through Nutrition and Exercise Study.

OBJECTIVE: The aim of the study was to determine, within a weight loss clinical trial for obesity, the impact of intervention arm, weight change, and weight loss maintenance on telomere length (TL). METHODS: Adults (N = 194) with a body mass index between 30 and 45 were randomized to a 5.5-month weight loss program with (n = 100) or without (n = 94) mindfulness training and identical diet-exercise guidelines. We assessed TL at baseline and 3-, 6-, and 12-month postbaseline in immune cell populations (primarily in peripheral blood mononuclear cells [PBMCs], but also in granulocytes and T and B lymphocytes). We defined weight loss maintenance as having lost at least 5% or 10% of body weight (tested in separate models) from preintervention to postintervention, and having maintained this loss at 12 months. We predicted that greater weight loss and weight loss maintenance would be associated with TL lengthening. RESULTS: Neither weight loss intervention significantly predicted TL change nor did amount of weight change, at any time point. Across all participants, weight loss maintenance of at least 10% was associated with longer PBMC TL (b = 239.08, 95% CI = 0.92 to 477.25, p = .049), CD8+ TL (b = 417.26, 95% CI = 58.95 to 775.57, p = .023), and longer granulocyte TL (b = 191.56, 95% CI = -4.23 to 387.35, p = .055) at 12 months after accounting for baseline TL. Weight loss maintenance of 5% or more was associated with longer PBMC TL (b = 163.32, 95% CI = 4.00 to 320.62, p = .045) at 12 months after accounting for baseline TL. These tests should be interpreted in light of corrections for multiple tests. CONCLUSIONS: Among individuals with obesity, losing and maintaining a weight loss of 10% or more may lead to TL lengthening, which may portend improved immune and metabolic function. TL lengthening in this study is of unknown duration beyond 12 months and requires further study. TRIAL REGISTRATION: Clinicaltrials.govidentifierNCT00960414; Open Science Framework (OSF) preregistration: https://osf.io/t3r2g/.

Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality.

A growing body of evidence suggests that meditation training may have a range of salubrious effects, including improved telomere regulation. Telomeres and the enzyme telomerase interact with a variety of molecular components to regulate cell-cycle signaling cascades, and are implicated in pathways linking psychological stress to disease. We investigated the effects of intensive meditation practice on these biomarkers by measuring changes in telomere length (TL), telomerase activity (TA), and telomere-related gene (TRG) expression during a 1-month residential Insight meditation retreat. Multilevel analyses revealed an apparent TL increase in the retreat group, compared to a group of experienced meditators, similarly comprised in age and gender, who were not on retreat. Moreover, personality traits predicted changes in TL, such that retreat participants highest in neuroticism and lowest in agreeableness demonstrated the greatest increases in TL. Changes observed in TRGs further suggest retreat-related improvements in telomere maintenance, including increases in Gar1 and HnRNPA1, which encode proteins that bind telomerase RNA and telomeric DNA. Although no group-level changes were observed in TA, retreat participants' TA levels at post-assessment were inversely related to several indices of retreat engagement and prior meditation experience. Neuroticism also predicted variation in TA across retreat. These findings suggest that meditation training in a retreat setting may have positive effects on telomere regulation, which are moderated by individual differences in personality and meditation experience. (ClinicalTrials.gov #NCT03056105).

Infant HPA axis as a potential mechanism linking maternal mental health and infant telomere length.

Maternal depression has been suggested to be an independent risk factor for both dysregulated hypothalamic-pituitary-adrenal axis (HPA) functioning and shorter telomere length in offspring. In contrast, research suggests that individual differences in mindfulness may act as a protective factor against one's own telomere degradation. Currently, research has yet to investigate the association between longitudinal changes in maternal mental health (depressive symptoms and mindfulness) and salivary infant telomere length, and whether such changes might be mediated by alterations in infant cortisol response. In 48 mother-infant dyads, we investigated whether the changes in maternal mental health, when infants were 6-12 months of age, predicted change in infant cortisol reactivity and recovery over this period. We also investigated whether these changes in infant HPA functioning predicted subsequent infant salivary telomere length at 18 months of age. Furthermore, we investigated whether change in infant HPA functioning provided a potential pathway between changes in maternal mental health factors and infant salivary telomere length. Analyses revealed that increases in maternal depressive symptoms over that six-month period indirectly related to subsequent shorter infant telomere length through increased infant cortisol reactivity. Implications for the ways in which maternal mental health can impact offspring stress mechanisms related to aging and disease trajectories are discussed.

Analysis of the age of Panax ginseng based on telomere length and telomerase activity.

Ginseng, which is the root of Panax ginseng (Araliaceae), has been used in Oriental medicine as a stimulant and dietary supplement for more than 7,000 years. Older ginseng plants are substantially more medically potent, but ginseng age can be simulated using unscrupulous cultivation practices. Telomeres progressively shorten with each cell division until they reach a critical length, at which point cells enter replicative senescence. However, in some cells, telomerase maintains telomere length. In this study, to determine whether telomere length reflects ginseng age and which tissue is best for such an analysis, we examined telomerase activity in the main roots, leaves, stems, secondary roots and seeds of ginseng plants of known age. Telomere length in the main root (approximately 1 cm below the rhizome) was found to be the best indicator of age. Telomeric terminal restriction fragment (TRF) lengths, which are indicators of telomere length, were determined for the main roots of plants of different ages through Southern hybridization analysis. Telomere length was shown to be positively correlated with plant age, and a simple mathematical model was formulated to describe the relationship between telomere length and age for P. ginseng.

Control of nuclear activities by substrate-selective and protein-group SUMOylation.

Reversible modification of proteins by SUMO (small ubiquitin-like modifier) affects a large number of cellular processes. In striking contrast to the related ubiquitin pathway, only a few enzymes participate in the SUMO system, although this pathway has numerous substrates as well. Emerging evidence suggests that SUMOylation frequently targets entire groups of physically interacting proteins rather than individual proteins. Protein-group SUMOylation appears to be triggered by recruitment of SUMO ligases to preassembled protein complexes. Because SUMOylation typically affects groups of proteins that bear SUMO-interaction motifs (SIMs), protein-group SUMOylation may foster physical interactions between proteins through multiple SUMO-SIM interactions. Individual SUMO modifications may act redundantly or additively, yet they may mediate dedicated functions as well. In this review, we focus on the unorthodox principles of this pathway and give examples for SUMO-controlled nuclear activities. We propose that collective SUMOylation is typical for nuclear assemblies and argue that SUMO serves as a distinguishing mark for functionally engaged protein fractions.