Current Aging Science (v.5, #2)
Longevity Pathways: HSF1 and FoxO Pathways, a New Therapeutic Target to Prevent Age-Related Diseases by Felipe P. Perez (87-95).
Modern medicine is directed towards the prevention, detection and cure of individual diseases. Yet, current medical models inadequately describe aging-associated diseases. We now know that failure in longevity pathways including oxidative stress, multisystem dysregulation, inflammation, sarcopenia, protein deposition and atherosclerosis are associated with age-related diseases. Such longevity pathways are potential targets for therapeutic intervention. Interventions in specific pathways have been shown to ameliorate and postpone the aging phenotype by activation of multiple genes. The strategy that we propose in this paper is to apply interventions simultaneously on complementary longevity pathways to achieve a synergistic result. For instance, aging is known to attenuate the HSF1 pathway leading to production of very toxic beta-amyloid fibrils. Consequently, the FoxO pathway is activated, resulting in the formation of less toxic high molecular weight aggregates as a defense mechanism. Thus the simultaneous upregulation of the HSF1 and FoxO pathways could potentially decrease protein deposition and proteotoxicity, thereby retarding or possibly preventing the onset of neurodegenerative diseases. Modulating these two pathways may also delay the onset of other age-related pathologies including cognitive decline, cancer, diabetes and cardiovascular disease due to its multi-gene effect. In this paper, we will discuss the role of several agents on the simultaneous modulation of these two central longevity pathways. The aging of western societies makes prevention of age-related diseases a pressing priority.
Epidermal Cell Proliferation in Calorie-Restricted Aging Rats by Tapan Kumar Bhattacharyya (96-104).
Calorie restriction (CR) has been known to produce many beneficial health effects, and lowered cell proliferation from CR has been shown to produce anti-cancer effects in some tissues. In this study the rate of epidermal cell proliferation in aging Fischer 344 rats from ad libitum fed (AL) and CR colonies was assessed in relation to changes in epidermal thickness with age. Proliferating cell nuclear antigen (PCNA) was detected using immunohistochemical method on paraffin sections in the epidermis of dorsal skin and footpad in these animals obtained from the National Institute on Aging. The proliferating cell index was compared with morphometric measurement of epidermis in young, young adult and old animals (six per group). Data were analyzed by Excel and SPSS 14.0 softwares for statistical evaluation. Two-way analysis of variance (ANOVA) was applied to data to test the effects of age, diet, and age-diet interaction. The following significant effects were noted: (I) age and age-diet effects in dorsal skin epidermal width, and PCNA; (II) age, and diet effect on footpad epidermal thickness, and PCNA index. There was a trend of increasing epidermal thickness in the dorsal skin in normally feeding aging rats which was depressed with CR in the two younger groups. PCNA index showed a trend of attrition from young to old. The thickness of epidermis in foot pad showed a curvilinear trend in both AL and CR groups with lowest mean values in the old group, and more predominant effect in CR-exposed animals. The proliferation index in the foot pad demonstrated a trend of reduction in old specimens with lower mean values in each corresponding CR age group. This report agrees with CR-inhibited cell proliferation reported in many organs by other investigators, and the observed results might have been caused by physiological or endocrine mechanisms affecting the epithelium in these calorie-restricted animals.
Two Age-Related Accumulation Profiles of Toxic Metals by Hiroshi Yasuda (105-111).
In order to investigate the body burden levels of toxic metals in Japanese, five toxic metal concentrations in scalp hair samples from 28,424 subjects from infant to elderly were determined with inductively coupled plasma mass spectrometry (ICP-MS). The geometric mean of hair mercury concentrations showed a high-significant age-correlated increase (r = 0.341, p < 0.0001) with a peak at the 6th decade of life and then decreased with further aging in both sexes. The mean mercury concentrations in male adults were significantly higher than those in female (p < 0.001), indicating the gender difference (male > female) in mercury accumulation. Arsenic also showed a similar accumulation profile with agedependency and gender difference in adult subjects. In contrast, cadmium, lead and aluminium exhibited another type of accumulation profile: the highest burden level was observed in infants aged 0-3 years old for every element in both sexes. In addition, cadmium was found to have a character accumulating in aged females, with significant age-dependency (r = 0.134, p < 0.0001) and gender difference (female > male). These findings suggest that toxic metals are classified into two families on the basis of their accumulation profiles, and that the three elements of mercury, arsenic and cadmium which accumulate age-dependently in adults, may play a role in aging process and higher burden with them may lead to acceleration of aging.
Influence of Essential Trace Minerals and Micronutrient Insufficiencies on Harmful Metal Overload in a Mongolian Patient with Multiple Sclerosis by Fumio Komatsu (112-125).
Parkinson’s disease and other neurological disorders are prevalent in Mongolia. Our previous studies revealed a significant correlation of these diseases with high oxidative stress due to a high body burden of harmful metals, such as manganese, iron, lead, cadmium, and aluminum. This report describes a 37-year-old male Mongolian patient with multiple sclerosis and essential micronutrient deficiency. This patient demonstrated high oxidative stress, as shown by high urinary 8-hydroxy-2'-deoxyguanosine levels of 14.7 and 14.3 ng/mg creatinine (crea), although his hair levels of these toxic metals were markedly lower than other Mongolians. In addition, this patient was deficient not only in various essential minerals, including selenium, magnesium, copper, cobalt, vanadium, and nickel, but also in micronutrients such as vitamin B6, C, E, folic acid, niacin, and β-carotene. Furthermore, after taking 2,3-dimercaptosuccinic acid, a chelating agent, urinary excretion of lead, cadmium, manganese, aluminum, iron, copper, and lithium were increased 156-, 8.4-, 7.6-, 4.3-, 3.3-, 2.1-, and 2.1-fold, respectively. These results suggest that this patient suffered from a deficiency in micronutrients such as essential minerals and vitamins, which resulted in a disturbance in the ability to excrete harmful metals into the urine and hair. It is possible that a deficiency of micronutrients and a high burden of heavy metals play a role in the pathogenesis of multiple sclerosis. Nutritional treatment may be an effective approach to this disease.
Aging and Regenerative Capacity of Skeletal Muscle in Rats by Priit Kaasik (126-130).
The objective of the study was to examine skeletal muscle regeneration capacity of young and very old rats during autotransplantation. In 3.5 and 30 month-old Wistar rats, gastrocnemius muscle was removed and grafted back to its original bed. Incorporation of 3H leucine into myofibrillar and sarcoplasmic protein fractions, their relative contents in autografts and synthesis rate of MyHC and actin were recorded. The relative muscle mass of old rats was about 67% of that of young rats; the absolute mass of autografted muscle was 61% intact in the young rat group and 51% in the old rat group. Content of myofibrillar protein in the autografts of young rats was 46% of the intact muscle content, and 39% in the old rat group. In conclusion, the difference in skeletal muscle regeneration capacity of young and very old rats is about ten percent. In the autografts of both young and old rats, the regeneration of the contractile apparatus is less effective in comparison with the sarcoplasmic compartment.
Cognition in Non-Demented Diabetic Older Adults by Sirisha Nandipati (131-135).
Evidence links diabetes mellitus to cognitive impairment and increased risk of Alzheimer's disease (AD) and suggests that insulin therapy improves cognition. With an increasing percentage of the US elderly population at high risk for diabetes and AD, the evidence of an association between diabetes and poor cognition in non-demented elderly may have implications for diagnosis, prevention and treatment of cognitive decline including AD. In our study, we hypothesized that diabetic elders with normal cognition would demonstrate poorer cognitive outcomes than non-diabetic elders and that diabetic elders receiving diabetes treatment would demonstrate better outcomes than those not receiving treatment. Data were evaluated from the National Alzheimer’s Coordinating Center’s Uniform Data Set (UDS). The UDS consists of clinical and neuropsychological assessments of a sample of elderly research subjects recruited from thirty-one Alzheimer’s Disease Centers nationwide. The UDS provides a unique opportunity to study cognition in a nationally recruited sample with structured neuropsychological tests. We examined the impact of diabetes and diabetes treatment on cognitive measures in 3421 elderly research subjects from 2005-2007 with normal cognition. We performed linear regression analyses to compare cognitive scores between diabetic subjects and non-diabetic subjects. Diabetic subjects had lower scores than non-diabetic subjects including attention, psychomotor function and executive function, but no differences in memory or semantic memory language. There was no association between diabetes treatment and cognitive scores. These subtle but significant cognitive deficits in diabetic subjects compared to non-diabetic subjects may contribute to difficulty with compliance with complex diabetes medication regimens. A specific role of diabetes as a risk for cognitive impairment will require longitudinal study.
Mini-Mental Parkinson (MMP) as a Dementia Screening Test: Comparison with the Mini-Mental State Examination (MMSE) by Andrew J. Larner (136-139).
Background: As populations age, screening instruments for cognitive impairment and dementia will become of increasing importance in clinical practice. Mini-Mental Parkinson (MMP), a derivative of the Mini-Mental State Examination (MMSE), was originally described as a cognitive screening instrument for use in Parkinson’s disease. Its item content addresses some of the acknowledged shortcomings of the MMSE. Pragmatic use of MMP in general cognitive clinics has not previously been examined. Aim: To compare the performance of two scales, Mini-Mental Parkinson (MMP) and the Mini-Mental State Examination (MMSE), as cognitive screening instruments for dementia in a memory clinic population. Methods: MMP was administered prospectively to 201 consecutive new patient referrals independent of other tests used to establish dementia diagnosis according to standard diagnostic criteria (DSM-IV). Diagnostic utility of MMP for dementia was measured and compared with MMSE. Results: MMP proved easy to use and acceptable to patients. Optimal test accuracy (0.86) was at MMP cutoff of ≤ 17/32, with sensitivity 0.51, specificity 0.97, positive predictive value 0.83, negative predictive value 0.87, and area under Receiver Operating Characteristic curve 0.89. Using a higher cutoff (≤ 29/32), MMP sensitivity was 1.00 with specificity 0.70. MMP scores correlated with MMSE (r = 0.93) and diagnostic agreement was high (κ = 0.85). Conclusions: MMP is a useful screening instrument in the memory clinic setting, with patients who fall below the designated cutoff requiring further investigation to ascertain a cause for their cognitive impairment.
Influence of Genetic Factors on the Development of Breast Cancer in the Older Woman by Christianne S.H. Bouwens (140-147).
Although the major part of the burden of disease for female breast cancer occurs at older age, less is known about the development and progression in this age group than in women under 60 years of age. As the world population continues to age, the percentage of elderly is increasing in all communities and the incidence of breast cancer will rise accordingly. Improving detection and diagnosis, and a better understanding of the mechanisms that play a role in this age group, will not only improve quality of life in older sufferers but could also contribute to the management of this disease in the adult population as well. Development of breast cancer in the older woman is influenced by many variables that may differ from the risk factors that are involved in younger women. In addition to well-described variables at younger ages such as family history, hormonal exposure, lifestyle factors and pre-existing benign breast disease, in older women age-related changes in breast tissue, biochemistry, inflammatory responses and the immune system, as well as accumulation of DNA damage and spontaneous mutations are suspected to contribute to the complex relationship between ageing and breast cancer. We review the available data on the role of age-related changes and genetic mutations in the development of breast cancer in older women as well as their effects on estrogen metabolism and free oxygen radical inactivation.
High Doses of In vitro Beta-carotene, Alpha-Tocopherol and Ascorbic Acid Induce Oxidative Stress and Secretion of IL-6 in Peripheral Blood Mononuclear Cells from Healthy Donors by Barbara Fonseca de Oliveira (148-156).
Background: Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species (ROS) and a biological system's ability to readily detoxify the reactive intermediates or repair the resulting damage. Our objective was to verify the existence of an in vitro dual effect of alpha-tocopherol, beta-carotene and ascorbic acid in peripheral blood mononuclear cells (PBMNC) of healthy donors and the inflammatory capacity by IL-6 production. Methods: PBMNC were incubated with two concentrations of vitamin complex: [A] = Ascorbic Acid = 0.08μM, α- tocopherol = 0.04μM, β-carotene = 0.0008 μM and [20A] = Ascorbic Acid = 1.6μM, α-tocopherol = 0.82μM, β-carotene = 0.016μM. Oxidizing and reducing response were measured by chemiluminescence and MTT assays, respectively. IL-6 production was measured by sandwich ELISA. Results: Ours results demonstrated that PBMNC (from 20-39-year-old donors) incubated with vitamins activated free radical production only in [20A] concentration. However, in the age groups of 40-59 and 60-80 years old, there was a significant reduction and activation of the oxidizing response with both concentrations, respectively. The inflammatory profile showed an elevation of IL-6 production in pro-oxidant and a decrease in antioxidant conditions. Correlation between ROS production and IL-6 releasing was observed. Conclusions: With this experiment we concluded that vitamins can exert an antioxidant effect and a pro-oxidant effect according to their concentration, and could be an inductor of an inflammatory process in vitro generating severe complications to the body in cellular levels.
Cerebral Vascular Aging: Extending the Concept of Pulse Wave Encephalopathy Through Capillaries to the Cerebral Veins by Marie Cecile Henry-Feugeas (157-167).
The recent concept of pulse wave encephalopathy helps understanding the cerebral venous remodeling in aging. This so-called periventricular venous collagenosis is an expected mechanical consequence of the age-related changes in arterial pulsations and the mechanical fatigue of vascular smooth muscles. Unlike arteriolar mechanical stress, venular mechanical stress depends on both the blood pulse wave amplitude and the mechanical properties of the environment tissue. Thereby, there is a preferential periventricular location of venous collagenosis and a mechanistic link between venous collagenosis and foci of white matter rarefaction or leukoaraiosis. The recent concept of pulse wave encephalopathy also helps understanding the widening of retinal venules, the “mirror” of cerebral venules, in various manifestations of pulse wave encephalopathy, including progressive leukoaraïosis, lacunar and hemorrhagic “pulse wave” strokes, and dementia. Indeed, the age-related chronic increase in arterial pulsations explains subsequent arteriolar myogenic “fatigue”, marked attenuation in the arteriolar myogenic tone and abnormal penetration of the insufficiently dampened arterial pulse wave into the venules. Thus, retinal venular widening, a biomarker of advanced pulse wave encephalopathy, is also increasingly recognized as a biomarker for high cardiovascular risk. All these data support a shift in the concept of chronic cerebrovascular disease, from the classical model which is restricted to steno-occlusive cerebrovascular diseases to an enlarged model which would include the pulse wave encephalopathy concept. Thereby, preventing damage to the cerebral microvasculature by an undampened arterial pulse wave will become a logical target for the prevention and treatment of late-onset cognitive decline.