Age and sex influence on oxidative damage and functional status in human skeletal muscle

A reduction in muscle mass, with consequent decrease in strength and resistance, is commonly observed with advancing age. In this study we measured markers of oxidative damage to DNA, lipids and proteins, some antioxidant enzyme activities as well Ca²⁺ transport in sarcoplasmic reticulum membranes in muscle biopsies from vastus lateralis of young and elderly healthy subjects of both sexes in order to evaluate the presence of age- and sex- related differences. We found a significant increase in oxidation of DNA and lipids in the elderly group, more evident in males, and a reduction in catalase and glutathione transferase activities. The experiments on Ca²⁺ transport showed an abnormal functional response of aged muscle after exposure to caffeine, which increases the opening of Ca²⁺ channels, as well a reduced activity of the Ca²⁺ pump in elderly males. From these results we conclude that oxidative stress play an important role in muscle aging and that oxidative damage is much more evident in elderly males, suggesting a gender difference maybe related to hormonal factors.This revised version was published online in September 2005 with corrections to the Cover Date.     

Impact of the earthquake of September 26, 1997 in Umbria, Italy on the socioenvironmental and psychophysical conditions of an elderly population

The consequences of natural disasters on the social and health status of older people have not been deeply considered. The aim of this study was to evaluate the socioenvironmental and psychophysical conditions of an elderly population after a devastating earthquake. A randomly selected group of 332 older people (> or =64 years) was selected among 1548 eligible subjects living in the city of Nocera Umbra four months after an earthquake of 5.6 magnitude on the Richter scale. Three geriatricians evaluated the study subjects by means of a structured interview, and standardized scales, which considered physical and mental status, mood and anxiety, and self-perception of well-being, as well as the characteristics of family composition and social interactions. Of the study subjects, 11.1% lived alone, and 33.4% with the spouse only. Most were self-sufficient in the basic activities of daily life. Musculoskeletal diseases and hypertension were the most frequently observed pathologies in this geriatric population. In addition, 47.9% of the subjects lived in temporary houses; this group more frequently suffered from hypertension, and had a higher score of comorbidity as measured by Cumulative Illness Rating Scale (CIRS) compared to people who remained at home. People living in the pre-fabricated huts also showed a higher score on the Geriatric Depression Scale and the Hamilton scale for anxiety, and complained more often of their health status, evaluated as self-perception of well-being, when compared to the home dwellers. Although all the studied subjects suffered from the discomforts caused by the earthquake, the precariousness of living in temporary houses, whose structural characteristics do not take the needs of elderly subjects into account, could justify the higher distress experienced by persons housed in the huts. These observations suggest that, after natural disasters, emergency programs should be more adapted to elderly people, whose needs and expectations are often different from those of young adults.     

Abridged version of the severe impairment battery (SIB)

Until recently, severe dementia has received little attention on the part of clinicians and researchers. Yet, it represents a major problem from the point of view of Public Health because it is always accompanied by marked functional impairment with, in addition, frequent psychiatric and behavioural problems. These deficits are associated with impairment in activities of daily living that result in marked loss of autonomy and lead inevitably to the need to seek outside assistance, at least on a part-time basis. The arrival of new drugs with a potential to palliate some of the symptoms makes the assessment of severe dementia even more important. The Severe Impairment Battery (SIB) has been proposed in 1990 in order to evaluate the cognitive abilities of patients for whom standard cognitive measures are no longer adapted. Its purpose was to analyze different cognitive domains, based on the residual capacities of these patients. It evaluates the following domains: social interaction, orientation, attention, language, memory, praxis, constructional abilities and visuo spatial functions. The original SIB consisted of 51 items with a maximum score of 152. The battery was later shortened with a score of 133 and later 100. The latter version, which included 40 items, has been validated and published in France by Boller et al. However, clinical experience suggests that even this version is too long and includes some redundancies. We have therefore prepared an abridged version, which only includes 26 items with a maximum score of 50. It can be administered in 10 to 15 minutes. The selection was based mainly on clinical experience. We wanted to keep all of the domains included in the original version. Finally the selection was justified by a factorial analysis. The present version is based on a consensus reached by an US and Italian research group, in addition to ours.     

Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease

CONTEXT: A large body of experimental evidence suggests that in Alzheimer disease (AD) pathogenesis an important role is played by oxidative stress, but there is still a lack of data on in vivo markers of free radical-induced damage. OBJECTIVES: To evaluate levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage to DNA, in peripheral lymphocytes; to measure plasma concentrations of several nonenzymatic antioxidants; and to assess the relationships between any observed changes in lymphocyte DNA 8-OHdG content and plasma antioxidant levels in patients with AD and healthy aged control subjects. SUBJECTS: Forty elderly outpatients with AD and 39 healthy age- and sex-matched controls were studied. MAIN OUTCOME MEASURES: The level of 8-OHdG was determined in DNA extracted from lymphocytes and plasma levels of vitamin C, vitamin A, vitamin E, and carotenoids (zeaxanthin, beta-cryptoxanthin, lycopene, lutein, and alpha- and beta-carotene) were measured by high-performance liquid chromatography. RESULTS: Lymphocyte DNA 8-OHdG content was significantly higher and plasma levels of antioxidants (with the exception of lutein) were significantly lower in patients with AD compared with controls. In patients with AD, a significant inverse relationship between lymphocyte DNA 8-OHdG content and plasma levels of lycopene, lutein, alpha-carotene, and beta-carotene, respectively, was observed. CONCLUSIONS: Markers of oxidative damage are increased in AD and correlate with decreased levels of plasma antioxidants. These findings suggest that lymphocyte DNA 8-OHdG content in patients with AD reflects a condition of increased oxidative stress related to a poor antioxidant status.     

Dietary habits are major determinants of the plasma antioxidant status in healthy elderly subjects

Previous studies indicate that regular consumption of a diet rich in fruits and vegetables is associated with a lower risk for age-related diseases. The aim of the present study was to evaluate whether the often-reported age-related decrease of plasma antioxidants in man depends on differences in dietary intake or on other age- and gender-related factors. In this observational case-control study, thirty-nine community-dwelling healthy subjects aged 65 years and older consuming high intakes of fruits and vegetables daily (HI) and forty-eight healthy subjects aged 65 and older consuming low intakes of fruit and vegetables daily (LI) were enrolled. Plasma levels of retinol, tocopherols, carotenoids and malondialdehyde (MDA) as well as content of protein carbonyls in Ig G were measured. Plasma levels of retinol, tocopherols and carotenoids were significantly higher in group HI than in group LI subjects independent of age and gender. MDA levels were inversely correlated with vitamin A and alpha-carotene. Protein carbonyls were inversely correlated with gamma-tocopherol. In the elderly, a higher daily intake of fruits and vegetables is associated with an improved antioxidant status in comparison to subjects consuming diets poor in fruits and vegetables. Modification of nutritional habits among other lifestyle changes should be encouraged to lower prevalence of disease risk factors in later life.     

Cognitive impairment is the major risk factor for development of geriatric syndromes during hospitalization: results from the GIFA study

OBJECTIVE: To detect the main factors associated with the occurrence of specific geriatric syndromes (namely pressure sores, fecal incontinence, urinary incontinence and falls) in elderly patients during hospitalization. DESIGN: Observational prospective study. Setting: Eighty-one community and university hospitals throughout Italy. PARTICIPANTS: 13,729 patients aged 65 years and more, consecutively admitted to medical or geriatric acute wards during 20 months in the period between 1991 and 1998. MEASUREMENTS: Occurrence of pressure sores, fecal incontinence, urinary incontinence and falls during the stay in hospital. RESULTS: Pressure sores were already present in 3% of hospitalized subjects, fecal incontinence in 7.3%, while urinary incontinence, evaluated on a subgroup of total population (4,268 subjects), had a prevalence of 22.3%. During hospitalization (mean stay of 15 days), 74 subjects developed new pressure sores, 55 became fecal and 35 urinary incontinent, and 279 subjects had at least one episode of fall. In multivariate analyses, cognitive impairment, advanced age (85+ years), length of stay (more than 3 weeks) and severe disability were the main independent predictors of development of the four geriatric syndromes, with cognitive impairment as the most significant risk factor for all the four outcomes (OR 4.9, 95% CI 2.4-9.9 for pressure sores; OR 6.3, 95% CI 3.0-13.0 for fecal incontinence; OR 5.3, 95% CI 2.3-12.0 for urinary incontinence; OR 1.6, 95% CI 1.2-2.3 for falls). CONCLUSION: Very old people have a significant increased risk of several geriatric syndromes during the stay in hospital, particularly if it is long and they are cognitively impaired. A standardized comprehensive geriatric evaluation at admission could be helpful in detecting all subjects at risk and preventing the development of hospital-acquired geriatric syndromes.     

Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of beta-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature-vascular or degenerative-dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.     

Cigarette smoking cessation increases plasma levels of several antioxidant micronutrients and improves resistance towards oxidative challenge

Cigarette smoking is associated epidemiologically with increased risk of cardiovascular diseases, but the pathophysiological mechanisms are still not fully understood. There is evidence that smoking is related to increased free radical production and antioxidant depletion, but the effects of smoking cessation on plasma concentrations of antioxidants and susceptibility to oxidative stress are largely unknown. Plasma levels of vitamins A, C, E, uric acid, total thiols, carotenoids (including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) and malondialdehyde (MDA, a biomarker of lipid peroxidation) were measured in fifteen healthy, normolipidaemic subjects (seven males, eight females, 35.2 (sd 2.3) years) before and 4 weeks after smoking cessation. To determine plasma resistance towards oxidative challenge, plasma was incubated for up to 5 h with the peroxyl radical-generator 2,2'-azobis(2-amidinopropane) (AAPH); MDA and ascorbate levels were measured at various time points. The concentrations of all plasma antioxidants were lower before smoking cessation than afterwards; MDA levels were higher before than after termination of smoking. Upon AAPH exposure, the consumption of plasma ascorbate and the production of MDA occurred at a significantly faster rate before smoking cessation as compared with afterwards. Cigarette smoking cessation is followed by a marked increase in plasma antioxidant concentrations and substantially improves plasma resistance towards oxidative challenge. Given the importance of cigarette smoking as a risk factor for cardiovascular diseases and the pathophysiological role played by oxidative stress in these illnesses, quitting smoking represents an irreplaceable preventive strategy against tobacco-induced oxidative stress and vascular damage.     

Elevated lipid peroxidation biomarkers and low antioxidant status in atherosclerotic patients with increased carotid or iliofemoral intima media thickness.

OBJECTIVES: Lipid peroxidation plays an important role in the development of atherosclerosis, a chronic, age-related disease process of the arterial wall with onset decades prior to its clinical manifestations. The aim of the study was to assess the association between the intima media thickness (IMT) of the major arteries as a clinical marker of atherosclerosis and markers of lipid peroxidation along with the antioxidant status in humans. DESIGN: Case-control study. SETTING: A university-affiliated outpatient clinic. SUBJECTS: Thirty patients (22 males, 8 females; 70.4 +/- 7.3 years) with atherosclerosis of the carotid or iliofemoral arteries and 62 healthy controls (30 males, 32 females; 68.3 +/- 4.3 years). METHODS: Plasma levels of 8,12-isoprostane F2alpha-VI (8,12-IPF2alpha-VI) were measured by gas chromatography/mass spectrometry, whereas levels of malondialdehyde (MDA), vitamins A (retinol) and E (alpha- and gamma-tocopherol), and carotenoids were determined by high-performance liquid chromatography. The IMT was measured by B-mode ultrasonography. RESULTS: Patients showed, independent of fruit and vegetable intake, significantly lower plasma levels of retinol, alpha-tocopherol, and all carotenoids excluding beta-cryptoxanthin compared with controls. On the contrary, plasma 8,12-IPF2alpha-VI levels were almost doubled (p < .001) and MDA levels increased by one-third (p < .01) in atherosclerotic patients compared with controls. CONCLUSIONS: The analyses of isoprostanes and antioxidant nutrients in plasma as markers of oxidative stress and the parallel evaluation of IMT as a structural marker of atherosclerosis are suitable tools for investigating the role of antioxidants and oxidative stress in atherosclerosis.     

Protective variant for hippocampal atrophy identified by whole exome sequencing

We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552