Human aging is associated with stochastic somatic mutations of mitochondrial DNA

Kadenbach, Bernhard; Münscher, C.; Frank, Viola; Müller‐Höcker, Josef; Napiwotzki, Jörg

doi:10.1016/0921-8734(95)00021-w

Cited by 122 publications

(81 citation statements)

References 85 publications

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“…Because the frequency of the 4977-bp deletion increases with age (11,27), we investigated whether the lower detection in UC IECs was related to this variable. This was accomplished by analyzing the data in Fig.…”

Section: Resultsmentioning

confidence: 99%

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Fukushima¹,

Fiocchi²

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Fukushima, Kouhei, and Claudio Fiocchi. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients. Am J Physiol Gastrointest Liver Physiol 286: G804-G813, 2004; 10.1152/ajpgi.00398.2003.-Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition. epithelium; energy metabolism ALTHOUGH THE ETIOLOGY OF ULCERATIVE colitis (UC) is still uncertain, colonic epithelial cells (EC) have long been considered central to its pathophysiology. In addition to the restriction of the inflammatory process and associated dysplastic changes to the epithelial lining (43), there is abundant experimental evidence pointing to colonocytes as likely targets and mediators of key pathogenic events. Detection of circulating colon antibodies and cytotoxic mononuclear cells in UC patients initially suggested that colonocytes could be targets of autoimmune reactivity (6, 49). Subsequent studies demonstrated that in UC, EC express high levels of human leukocyte antigen D-related antigens (48), secrete abnormal mucin glycoconjugates (41), produce increased amounts of cytokines and chemokines (4,42,57), express costimulatory molecules (39), display autoantigens recognized exclusively by UC tissueeluted antibodies (53), and fail to mediate induction of suppressor T cells (36). Additional reports demonstrated cyclooxygenase 2 and NF-B activation (46, 51), as well as an increased rate of EC apoptosis in UC (...

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Section: Resultsmentioning

confidence: 99%

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Fukushima¹,

Fiocchi²

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Diminished oxygen extraction with age has been shown previously 15,16 and may be related to aging-induced mutations of mitochondrial DNA. 17 A prior report has suggested that attenuated MSNA response to handgrip in the aged is due to higher resting MSNA and not to muscle reflex attenuation per se. 18 Our study also demonstrates higher resting MSNA in older subjects.…”

Section: Discussionmentioning

confidence: 99%

Aging and the Exercise Pressor Reflex in Humans

et al. 2003

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Background-Blood flow limitation to exercising muscles engages the muscle reflex during exercise, evoking an increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Methods and Results-In the current study, we examined forearm flow and autonomic responses to ischemic handgrip in young and older subjects. We studied 6 younger subjects (mean age 23.5Ϯ2.2 years) and 7 older subjects (mean age 65.0Ϯ2.4 years). Subjects performed rhythmic handgrip (thirty 1-sec contractions/min) at 30% maximal voluntary contraction during six 1-minute stages: freely perfused exercise (E1) and exercise with forearm pressure of ϩ10, ϩ20, ϩ30, ϩ40, and ϩ50 mm Hg (E2 through E6). We measured HR, BP, MSNA, forearm flow velocity, forearm venous oxygen saturation, H ϩ , and lactate. Compared with E1, ischemic exercise (E2 through E6) increased HR, BP, and MSNA, reduced forearm velocity, lowered venous oxygen saturation, and raised venous lactate and H ϩ . Compared with the younger subjects, the older subjects had attenuated BP at E6, attenuated MSNA indices (%⌬bursts, bursts/100 heart beats and signal averaged MSNA), attenuated H ϩ at E6, a trend toward higher levels of oxygen saturation, and similar forearm velocity and HR responses. Key Words: aging Ⅲ exercise Ⅲ reflex Ⅲ blood flow D uring exercise, the sympathetic nervous system is activated. This helps redistribute blood flow to active muscle and aids in preventing blood pressure (BP) from falling. 1 Two neural systems contribute to sympathetic activation: central command, 2 a feed-forward process, and a muscle reflex termed the exercise pressor reflex. 3 The muscle reflex is engaged when mechanically or metabolically sensitive thin fiber afferents within contracting muscle increase their discharge. 4 During forearm exercise, the muscle reflex is engaged when the muscle fatigues and/or when a mismatch occurs between blood supply and metabolic demand. 5 In the present study, we examined the effects of aging on the exercise pressor reflex in humans. Despite the fact that this reflex is an important determinant of exercise flow regulation, little is known about the effects of aging on this reflex. The reflex is evoked by a muscle work/blood flow mismatch. Therefore, to engage the reflex, a paradigm was employed in which the level of work was kept constant as external impedance to muscle flow was progressively increased. We examined whether age affects the BP response to reflex engagement and if sympathetic nerve responses to reflex engagement is different in young and older subjects. The results of these studies support the concept that the muscle reflex becomes attenuated with age. Conclusions-Aging Methods SubjectsSix young (4 males, 2 females; mean age 23.5 years; mean body mass index 23.5) and 7 older subjects (4 males, 3 females; mean age 65.0; body mass index 26.2) were studied. All were normotensive non-smokers on no medications. Each signed an Institutional Review Board-approved consent. Forearm PressureSubjects performed handgrip in a sealed...

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“…If the combination of these point mutations is not sufficient to obtain accurate ageing indicators, other mutations in the coding region, whose rate also seems to increase with age in muscle tissues, may possibly complete the study. More specifically, the 8344, 3243 and 10006 [23,28] positions as well as modification types like mini-duplications could be also tested [29].…”

Section: Discussionmentioning

confidence: 99%

Detection of the A189G mtDNA heteroplasmic mutation in relation to age in modern and ancient bones

Lacan

Thèves

Amory³

et al. 2008

Int J Legal Med

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Abstract:The aim of this study was to demonstrate the presence of the A189G age-related point mutation on DNA extracted from bone. For this, a PNA/DNA sequencing method which can determine an age threshold for the appearance of the mutation was used.Initially, work was done in muscle tissue in order to evaluate the sensitivity of the technique and afterwards in bone samples from the same individuals. This method was also applied to ancient bones from 6 well preserved skeletal remains. The mutation was invariably found in muscle, and at a rate of up to 20% in individuals over 60 years old.In modern bones, the mutation was detected in individuals aged 38 years old or more, at a rate of up to 1%, but its occurrence was not systematic (only 4 out of 10 of the individuals over 50 years old carried the heteroplasmy). For ancient bones, the mutation was also found in the oldest individuals according to osteologic markers. The study of this type of age-related mutation and a more complete understanding of its manifestation has potentially useful applications. Combined with traditional age markers, it could improve identification accuracy in forensic cases or in anthropological studies of ancient populations.

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Human aging is associated with stochastic somatic mutations of mitochondrial DNA

Cited by 122 publications

References 85 publications

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Aging and the Exercise Pressor Reflex in Humans

Detection of the A189G mtDNA heteroplasmic mutation in relation to age in modern and ancient bones

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