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Life Extension Magazine June 2012

Stress Relief

Short telomeres in depression and the general population are associated with a hypocortisolemic state.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls. METHODS: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires. RESULTS: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (r(s) = -.258, p = .003). CONCLUSIONS: Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population.

Biol Psychiatry. 2012 Feb 15;71(4):294-300

Telomere shortening in chronic obstructive pulmonary disease.

Chronic oxidative stress and systemic inflammation contribute to the pathology of several chronic diseases, one among which is chronic obstructive pulmonary disease (COPD). In addition, increased oxidative stress and inflammation have been observed to be negatively associated with telomere length (TL). Our aim was to investigate the TL in COPD patients in relation to pulmonary and extrapulmonary disease severity. Furthermore, based on experimental evidence suggesting the effects of oxidative stress on telomere shortening, we studied the association of TL with the antioxidant enzyme superoxide dismutase (SOD). One hundred and two COPD patients with moderate to severe COPD were studied and compared with 19 healthy age-matched controls. Patients were characterized by elevated levels of inflammatory markers (CRP, sTNF-receptors) and lower SOD-activity than the controls (p

Respir Med. 2009 Feb;103(2):230-6

Study of telomere length and different markers of oxidative stress in patients with Parkinson’s disease.

BACKGROUND: Many studies have shown that short telomere length (TL) is associated with high oxidative stress and various age-related diseases. Parkinson’s disease (PD) is an age-related disease, and although its pathogenic mechanism is uncertain, oxidative stress is believed to be implicated in this pathology. The aim of this case-control study was to assess both TL and the different markers of oxidative stress in elderly patients with PD compared to age control subjects. METHODS: 20 PD patients and 15 age-matched controls, >65 years were studied. TL was measured by Southern blotting from DNA samples extracted from white blood cells. Superoxide dismutase (SOD) activity and plasma levels of total glutathione and protein carbonyls were determined. RESULTS: There was a trend for lower TL in PD patients: 6.06 ± 0.81 kb in PD versus 6.45 ± 0.73 kb in controls (p = 0.08). No significant difference was found between the two groups in terms of oxidative stress markers. In controls, age was the main determinant of telomere shortening (r = -0.547; p = 0.03) whereas, in PD patients, telomere shortening was mainly dependent on plasmatic concentrations of carbonyl proteins (r= -0.544; p=0.044). In PD patients, a negative association was observed between plasma carbonyl protein levels and SOD activity (r= -0.622, p=0.004). CONCLUSIONS: In PD, TL is shorter in presence of high oxidative stress as measured by carbonyl protein levels. The absence of telomere attrition with age among patients with PD could reflect a telomere regulation by mechanisms other than age.

J Nutr Health Aging. 2011 Apr;15(4):277-81

Telomeres, telomerase, and aging: origin of the theory.

In 1971 I published a theory in which I first formulated the DNA end replication problem and explained how it could be solved. The solution to this problem also provided an explanation for the Hayflick Limit, which underpins the discovery of in vitro and in vivo cell senescence. I proposed that the length of telomeric DNA, located at the ends of chromosomes consists of repeated sequences, which play a buffer role and should diminish in dividing normal somatic cells at each cell doubling. I also proposed that the loss of sequences containing important information that could occur after buffer loss could cause the onset of cellular senescence. I also suggested that for germline cells and for the cells of vegetatively propagated organisms and immortal cell populations like most cancer cell lines, an enzyme might be activated that would prevent the diminution of DNA termini at each cell division, thus protecting the information containing part of the genome. In the last few years, most of my suggestions have been authenticated by laboratory evidence. the DNA sequences that shorten in dividing normal cells are telomeres and the enzyme that maintains telomere length constant in immortal cell populations is telomerase.

Exp Gerontol. 1996 Jul-Aug;31(4):443-8

Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans.

OBJECTIVE: Life stress is hypothesized to alter the dynamic regulation of the autonomic, neuroendocrine, and immune systems. This study examined the effects of antecedent chronic life stress on psychological and physiological responsivity after acute challenge with a psychological stressor. METHOD: Using a within-subject mixed design, male volunteers with (N = 12) and without chronic life stress (N = 11) were administered a 12-minute laboratory stressor (mental arithmetic) vs a video control. RESULTS: Acute psychological stress induced subjective distress, increases of circulating concentrations of epinephrine, norepinephrine, beta-endorphin, adrenocorticotropic hormone (ACTH), and cortisol, and a selective redistribution of natural killer (NK) cells into the peripheral blood as compared with the video control condition. Although the two groups were almost identical at baseline in psychological, sympathetic, neuroendocrine, and immune domains, the chronic stress group showed greater subjective distress, higher peak levels of epinephrine, lower peak levels of beta-endorphin and of NK cell lysis, and a more pronounced redistribution of NK cells in response to the acute psychological challenge than the controls. Furthermore, the acute stressor induced a protracted decline in NK lysis per NK cell in the chronic stress group but had no effect in the controls. CONCLUSIONS: In summary, when persons who are undergoing chronic life stress are confronted with an acute psychological challenge, an exaggerated psychologic and peak sympathomedullary reactivity occurs that is associated with decrements in individual NK cell function and is protracted beyond termination of the stressor and sympathomedullary recovery.

Psychosom Med. 1997 Jul-Aug;59(4):447-57

Neural correlates of epigenesis.

The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression. We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination. Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress. Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals’ level of rumination. These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.

Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16033-8

Mechanism of anti-stress activity of Ocimum sanctum Linn, eugenol and Tinospora malabarica in experimental animals.

Effects of restraint stress (RS) and its modulation by O. sanctum (Os), eugenol and T. malabarica (Tm) were evaluated on some biochemical and biophysical parameters in rats. RS induced elevations in blood glucose and urea levels, were unaffected by either Os, eugenol or Tm pretreatment. However, both Os and eugenol lowered RS-induced cholesterol levels. RS also caused a generalized increase in enzyme activity and Os, eugenol or Tm effectively lowered the RS-induced elevations in lactate dehydrogenase (LDH) and alkaline phosphatase. RS also induced (a) increased membrane protein clusterization, (b) increased membrane fluidity and (c) reduced membrane thickness--in RBC membrane, whereas, the effects on the synaptosomal membrane were less marked. The RS-induced changes in RBC membrane dynamics were attenuated/reversed by Os, eugenol or Tm, in a differential manner. These biochemical and membrane changes during Rs and their modulation by the adaptogens are discussed in light of the possible mechanisms of action of these agents, during such aversive stimuli.

Indian J Exp Biol. 1992 Jul;30(7):592-6

Circadian rhythm of hormones is extinguished during prolonged physical stress, sleep and energy deficiency in young men.

The circadian rhythm of hormones (N = 10) and mental performance (N = 18) was investigated in male cadets during a 5-day military training course with continuous heavy physical activities corresponding to 35% of the maximal oxygen uptake, with almost total lack of food and sleep. The 24-h means for androstenedione, dihydroepiandrosterone (DHEA), 17 alpha-hydroxyprogesterone, testosterone and thyroid-stimulating hormone decreased strongly during the course, and the circadian rhythm was extinguished below the minimum levels measured during the control experiment. The 24-h means for cortisol, dihydroepiandrosterone sulfate (DHEA-S) and progesterone increased during the course, and the circadian rhythm was abolished above the maximum levels of the control experiment. A gradual increase was found in thyroxine, free thyroxine and triiodothyronine during the first 12 h of activities, followed by a constant decrease for the rest of the course. Mental performance decreased during the course and the amplitude of its circadian rhythm increased from +/- 10% to +/- 30% of the 24-h mean. The circadian rhythms investigated were almost normalized after 4-5 days of rest. However, the nocturnal rise for cortisol, androstenedione and DHEA appeared earlier, and the plasma levels of thyroid hormones, estradiol and DHEA-S were lower during the recovery experiment than in the control experiment. The responses to stress of the circadian rhythm for mental performance and steroid hormones during the course indicate a differential regulation.

Eur J Endocrinol. 1994 Jul;131(1):56-66