***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In this paper , Choi and colleagues analyzed levels of mitochondrial DNA in two prospect i ve observational cohort studies and found that increased mtDNA levels are associated with ICU mortality , and improve risk prediction in medical ICU patients . The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients We propose a model wherein chronic stress results in glucocorticoid receptor resistance ( GCR ) that , in turn , results in failure to down-regulate inflammatory response . Here we test the model in two viral-challenge studies . In study 1 , we assessed stressful life events , GCR , and control variables including baseline antibody to the challenge virus , age , body mass index ( BMI ) , season , race , sex , education , and virus type in 276 healthy adult volunteers . The volunteers were subsequently quarantined , exposed to one of two rhinoviruses , and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold . In study 2 , we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus  and monitored at baseline and for 5 d after viral challenge for the production of local ( in nasal secretions ) proinflammatory cytokines ( IL-1β , TNF-α , and IL-6 ) . Study 1 : After covarying the control variables , those with recent exposure to a long-term threatening stressful experience demonstrated GCR ; and those with GCR were at higher risk of subsequently developing a cold . Study 2 : With the same controls used in study 1 , greater GCR predicted the production of more local proinflammatory cytokines among infected subjects . These data provide support for a model suggesting that prolonged stressors result in GCR , which , in turn , interferes with appropriate regulation of inflammation . Because inflammation plays an important role in the onset and progression of a wide range of diseases , this model may have broad implication s for underst and ing the role of stress in health Objective Mitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses . This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function . Methods A systematic review of the literature investigating the effects of psychological stress on mitochondrial function was conducted . The review focused on experimentally controlled studies allowing us to draw causal inference about the effect of induced psychological stress on mitochondria . Results A total of 23 studies met the inclusion criteria . All studies involved male laboratory animals , and most demonstrated that acute and chronic stressors influenced specific facets of mitochondrial function , particularly within the brain . Nineteen studies showed significant adverse effects of psychological stress on mitochondria and four found increases in function or size after stress . In humans , only six observational studies were available , none with experimental design s , and most only measured biological markers that do not directly reflect mitochondrial function , such as mitochondrial DNA copy number . Conclusons Overall , evidence supports the notion that acute and chronic stressors influence various aspects of mitochondrial biology , and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria . Limitations of current animal and human studies are discussed . Maladaptive mitochondrial changes that characterize this subcellular state of stress are termed mitochondrial allostatic load . Prospect i ve studies with sensitive measures of specific mitochondrial outcomes will be needed to establish the link between psychosocial stressors , emotional states , the result ing neuroendocrine and immune processes , and mitochondrial energetics relevant to mind-body research in humans Mitochondrial components , including mitochondrial DNA ( mtDNA ) , when released extracellularly , can act as " damage-associated molecular pattern " ( DAMP ) agents and cause inflammation . As many elderly people are characterized by a low- grade , chronic inflammatory status defined " inflamm-aging , " we evaluated if circulating mtDNA can contribute to this phenomenon . Eight hundred and thirty-one Caucasian subjects were enrolled in the study , including 429 siblings aged 90 - 104 ( 90 + siblings ) .  mtDNA plasma levels increased gradually after the fifth decade of life . In 90 + subjects , mtDNA values of two members of the same sibling relationship were directly correlated , suggesting a role for familiar/genetic background in controlling the levels of circulating mtDNA . The subjects with the highest mtDNA plasma levels had the highest amounts of TNF-α , IL-6 , RANTES , and IL-1ra ; the subjects with the lowest mtDNA levels had the lowest levels of the same cytokines . In vitro stimulation of monocytes with mtDNA concentrations similar to the highest levels observed in vivo result ed in an increased production of TNF-α , suggesting that mtDNA can modulate the production of proinflammatory cytokines . Our findings therefore show that circulating mtDNA increases with age , and can significantly contribute to the maintenance of the low- grade , chronic inflammation observed in elderly people BACKGROUND Decreased hippocampal volume is observed in patients with Cushing 's syndrome and other conditions associated with elevated cortisol levels , stress , or both . Reversibility of hippocampal neuronal atrophy result ing from stress occurs in animals . Our study investigated the potential for reversibility of human hippocampal atrophy . METHODS The study included 22 patients with Cushing 's disease .  Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment . RESULTS Following treatment , hippocampal formation volume ( HFV ) increased by up to 10 % . The mean percent change ( 3.2 + /- 2.5 ) was significantly greater ( p < .04 ) than that of the comparison structure , cau date head volume ( 1.5 + /- 3.4 ) . Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol ( r = -.61 , p < .01 ) . This relationship strengthened after adjustments for age , duration of disease , and months elapsed since surgery ( r = -.70 , p < .001 ) . There was no significant correlation between cau date head volume change and magnitude of cortisol decrease . CONCLUSIONS Changes in human HFV associated with sustained hypercortisolemia are reversible , at least in part , once cortisol levels decrease . While many brain regions are likely affected by hypercortisolemia , the human hippocampus exhibits increased sensitivity to cortisol , affecting both volume loss and recovery Objective : To investigate progression of MRI-assessed manifestations of cerebral degeneration related to cognitive changes in a population of elderly patients with diabetes mellitus ( DM ) compared to age-matched control subjects . Methods : From a r and omized controlled trial ( PROSPER study ) , a study sample of 89 patients with DM and 438 control subjects without DM aged 70–82 years were included for brain MRI scanning and cognitive function testing at baseline and reexamination after 3 years . Changes in brain atrophy , white matter hyperintensities ( WMHs ) , number of infa rct ions , and cognitive function test results were determined in patients with DM and subjects without DM . Linear regression analysis was performed with correction for age , gender , hypertension , pravastatin treatment , educational level , and baseline test results . In patients with DM , baseline MRI parameters were correlated with change in cognitive function test result using linear regression analysis with covariates age and gender . Results : Patients with DM showed increased progression of brain atrophy ( p < 0.01 ) after follow-up compared to control subjects . No difference in progression of WMH volume or infa rct ions was found . Patients with DM showed increased decline in cognitive performance on Stroop Test ( p = 0.04 ) and Picture Learning Test ( p = 0.03 ) . Furthermore , in patients with DM , change in Picture Learning Test was associated with baseline brain atrophy ( p < 0.02 ) . Conclusion : Our data show that elderly patients with DM without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without DM . Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity The hippocampus shrinks in late adulthood , leading to impaired memory and increased risk for dementia . Hippocampal and medial temporal lobe volumes are larger in higher-fit adults , and physical activity training increases hippocampal perfusion , but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown . Here we show , in a r and omized controlled trial with 120 older adults , that aerobic exercise training increases the size of the anterior hippocampus , leading to improvements in spatial memory .  Exercise training increased hippocampal volume by 2 % , effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF , a mediator of neurogenesis in the dentate gyrus . Hippocampal volume declined in the control group , but higher preintervention fitness partially attenuated the decline , suggesting that fitness protects against volume loss . Cau date nucleus and thalamus volumes were unaffected by the intervention . These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood , which is accompanied by improved memory function BACKGROUND Pre clinical studies demonstrate that the neonatal environment can permanently alter an individual 's responses to stress . To demonstrate a similar phenomenon in humans , we prospect ively examined the relationships of maternal stress beginning in infancy and concurrent stress on preschoolers ' hypothalamic-pituitary-adrenal activity and later mental health symptoms . METHODS  Salivary cortisol levels  were assessed in 282 4.5-year-old children and 154 of their siblings . Maternal reports of stress were obtained when the children were ages 1 , 4 , and 12 months , and again at 4.5 years . Children 's mental health symptoms were assessed in first grade . RESULTS A cross-sectional analysis revealed that preschoolers exposed to high levels of concurrent maternal stress had elevated cortisol levels ; however , a longitudinal analysis revealed that concurrently stressed children with elevated cortisol also had a history of high maternal stress exposure in infancy . Importantly , children exposed only to high levels of concurrent or early stress had cortisol levels that did not significantly differ from those never exposed to stress . Further analysis of the components of stress indicated that maternal depression beginning in infancy was the most potent predictor of children 's cortisol . We also found that preschoolers with high cortisol levels  exhibited greater mental health symptoms in first grade . CONCLUSIONS These results link the findings of pre clinical studies to humans by showing that exposure to early maternal stress may sensitize children 's pituitary-adrenal responses to subsequent stress exposure OBJECTIVE — We determined whether reduced insulin sensitivity , mitochondrial dysfunction , and other age-related dysfunctions are inevitable consequences of aging or secondary to physical inactivity . RESEARCH DESIGN AND METHODS — Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and ATP production in mitochondria isolated from vastus lateralis biopsies of 42 healthy sedentary and endurance-trained young ( 18–30 years old ) and older ( 59–76 years old ) subjects . Expression of proteins involved in fuel metabolism was measured by mass spectrometry .  Citrate synthase activity , mitochondrial DNA ( mtDNA ) abundance , and expression of nuclear-encoded transcription factors for mitochondrial biogenesis were measured . SIRT3 , a mitochondrial sirtuin linked to lifespan-enhancing effects of caloric restriction , was measured by immunoblot . RESULTS — Insulin-induced glucose disposal and suppression of endogenous glucose production were higher in the trained young and older subjects , but no age effect was noted . Age-related decline in mitochondrial oxidative capacity was absent in endurance-trained individuals . Although endurance-trained individuals exhibited higher expression of mitochondrial proteins , mtDNA , and mitochondrial transcription factors , there were persisting effects of age . SIRT3 expression was lower with age in sedentary but equally elevated regardless of age in endurance-trained individuals . CONCLUSIONS — The results demonstrate that reduced insulin sensitivity is likely related to changes in adiposity and to physical inactivity rather than being an inevitable consequence of aging . The results also show that regular endurance exercise partly normalizes age-related mitochondrial dysfunction , although there are persisting effects of age on mtDNA abundance and expression of nuclear transcription factors and mitochondrial protein . Furthermore , exercise may promote longevity through pathways common to effects of caloric restriction Chronic stress in non-human animals decreases the volume of the hippocampus , a brain region that supports learning and memory and that regulates neuroendocrine activity . In humans with stress-related psychiatric syndromes characterized by impaired learning and memory and dysregulated neuroendocrine activity , surrogate and retrospective indicators of chronic stress are also associated with decreased hippocampal volume . However , it is unknown whether chronic stress is associated with decreased hippocampal volume in those without a clinical syndrome . We tested whether reports of life stress obtained prospect ively over an approximate 20-year period predicted later hippocampal grey matter volume in 48 healthy postmenopausal women . Women completed the Perceived Stress Scale repeatedly from 1985 to 2004 ; in 2005 and 2006 , their hippocampal grey matter volume was quantified by voxel-based morphometry . Higher Perceived Stress Scale scores from 1985 to 2004 - an indicator of more chronic life stress - predicted decreased grey matter volume in the right orbitofrontal cortex and right hippocampus . These relationships persisted after 
    Output:
    
Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and other metabolites .
At the cellular level , mitochondrial signaling influences gene expression and epigenetic modifications , and modulates the rate of cellular aging .
Conclusions This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing psychosocial experiences and the result ing emotional responses — both adverse and positive — into clinical ly meaningful biological and physiological changes .