Current Aging Science (v.4, #2)

Role of the Immune System in Aging and Longevity by Patricia Alonso-Fernandez, Monica De la Fuente (78-100).
The aging process is a universal, intrinsic, progressive accumulation of deleterious changes in cells and tissues that increases morbidity and leads to death. The heterogeneity of the age-related physiological changes is shown by the and#x201C;biological ageand#x201D;, which determines the rate of ageing experienced by each individual and therefore his life expectancy. According to the recent theory of oxidation-inflammation to explain the aging process, the immune system seems to be involved in the chronic oxidative and inflammatory stress conditions of aging. It has been proposed that several agerelated changes in immune cell functions, which depend on the redox state of these cells, could be good markers of health, biological age and longevity. In order to identify parameters of the functional and redox situation of immune cells as markers of biological age and predictors of longevity, we have studied those parameters in human healthy centenarians, in extreme long-living mice, as models of successful aging, and in immune cells from murine models of premature immunosenescence. The aim of the present work is to review the results in humans and rodents on those parameters and their relationship with biological age and longevity, as well as to propose several strategies of lifestyle useful to improve the immune function and thus to increase the mean life span.

Oxidative Stress and Skeletal Muscle Dysfunction with Aging by Wataru Aoi, Kunihiro Sakuma (101-109).
With advanced of age, production of reactive oxygen species increases in muscle tissues, which causes a continuous elevation of oxidative stress in the muscle. Such oxidative stress brings damage by oxidation of cell components such as lipids, proteins, and DNA. Growing evidences suggest that oxidative stress affects energy metabolism, protein degradation, and apoptosis in the muscle via transcriptional and posttranslation regulation of key proteins, which results in loss of muscle mass and metabolic dysfunction. On the other hand, regular exercise and proper nutrition containing some antioxidant can improve the muscle function by a reduction of excessive oxidative stress. This article describes the influence of oxidative stress on the progress of age-related muscle dysfunction and reviews the effect of countermeasures such as exercise and diet.

Glaucoma and Aging by Guilherme Guedes, James C. Tsai, Nils A. Loewen (110-117).
Age is an established major risk factor for glaucoma that can be used along with other data to compute chances of developing glaucoma. This leading cause of blindness is becoming increasingly more prevalent in the aging population. The characteristic progressive degeneration of the optic nerve in glaucoma is primarily caused by increased intraocular pressure yet the cause for the reduced outflow is not well understood. Early diagnosis of glaucoma remains difficult. Classic treatment can delay progression of glaucomatous optic neuropathy by lowering intraocular pressure medically or surgically. Recent insights into the age-related molecular changes of the outflow tract and retinal ganglion cells have encouraged search for new treatment approaches. New findings suggest that age related tissue changes themselves contribute significantly and are not just associated. Interdisciplinary research will be necessary to advance understanding, diagnosis and treatment of this neurodegenerative disease that has been known for more than thousand years but to this date remains a challenge.

Role of Insulin Signaling in the Interaction Between Alzheimer Disease and Diabetes Mellitus: A Missing Link to Therapeutic Potential by Naoyuki Sato, Shuko Takeda, Kozue Uchio-Yamada, Hironori Ueda, Tomomi Fujisawa, Hiromi Rakugi, Ryuichi Morishita (118-127).
Diabetes mellitus (DM) is one of the major non-genetic risk factors for Alzheimer disease (AD). However, the mechanism by which DM increases the risk of AD has not been elucidated. Here, we summarize recent findings to address this question. Whereas neuropathological studies in humans suggest that DM does not increase Aand#946; accumulation in the brain (a major hallmark of AD), earlier works in animal models show that Aand#946; does accumulate. Therefore, alternate mechanisms might exist. Recent studies using the human brain indicate that insulin signaling is impaired in the AD brain. In neurons, this insulin signaling plays a key role in modulating synaptic function and neuronal senescence besides regulating tau phosphorylation, another hallmark of AD. On the other hand, in cerebrovessels, DM causes vascular remodeling, which involves increased RAGE (receptor for advanced glycation endproducts) expression, and AD is associated with cerebrovascular amyloid angiopathy (CAA). Our recent study involving AD mice with DM has revealed that a vicious circle underlies the interaction between AD and DM. Interestingly, in our mouse model, AD increased RAGE expression, and DM worsened CAA. The contribution of vascular factors such as RAGE expression and CAA to the impairment of insulin signaling will be discussed. This impaired insulin signaling might be a possible link between AD and DM. Moreover, insulin signaling is also involved in the mechanism of aging, decreasing with an increase in age. An identification of the mechanism whereby DM modifies the pathological condition of AD through the modulation of insulin signaling is required to develop potential therapeutics for AD not only with but also without DM.

Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events. Vascular calcification refers to the deposition of calcium phosphate mineral, most often hydroxyapatite, in arteries. Extensive calcification of the vascular system is a key characteristic of aging. In this article, we outline the mechanisms governing vascular calcification and highlight its association with cellular senescence. This review discusses the molecular mechanisms of cellular senescence and its affect on calcification of vascular cells, the relevance of phosphate regulation and the function of FGF23 and Klotho proteins. The association of vascular calcification and cellular senescence with the rare human aging disorder Hutchison-Gilford Progeria Syndrome (HGPS) is highlighted and the mouse models used to try to determine the underlying pathways are discussed. By understanding the pathways involved in these processes novel drug targets may be elucidated in an effort to reduce the effects of cellular aging as a risk factor in cardiovascular disease.

The nature of knowledge, i.e. sensory-dependent or abstract, is controversial. Growing evidence supports the existence of sensory-dependent knowledge in young individuals, but this question remains unexplored in elderly individuals. Thus the first objective of this study was to assess sensory-dependent knowledge in normal aging using a cross-modal priming paradigm. The cross-modal priming is a way to verify the nature of knowledge. However, contradictory results are reported about the existence of a cross-modal priming effect in normal aging. One possible explanation for the controversial findings is the priming task difficulty that would require too much executive resources in elderly participants and would prevent them to obtain a priming effect. Therefore, the second objective was to assess the executive involvement in the priming task. The method was based on a cross-modal priming paradigm with familiar bimodal items. First, all the sound primes were presented. For half of them, a visual abstract mask was presented simultaneously. Then, all the visual targets were processed. A battery of neuropsychological tests was administered to assess the involvement of executive functions in the priming paradigm. The results demonstrated a priming effect in the young and elderly participants, but only for the primes presented without the visual mask. The mask interference demonstrated the perceptual nature of the priming effect which supports the sensory-dependent theory of knowledge. The executive functions were correlated with the priming task only in the elderly participants. These results therefore support the task difficulty hypothesis.

Effects of a Long-Term Treatment with an Antioxidant Pyridoindole on Vascular Responsiveness in Diabetes-Induced Aging Rats by Asli F. Ceylan-Isik, Nuray Ari, Milan Stefek, Ruzena Sotnikova, Gulgun Ozansoy, Lubica Horakova, Cimen Karasu (150-157).
Impaired vascular reactivity is a hallmark of cardiovascular diseases induced by diabetes, which is also an accelerated aging model. This study was designed to investigate the effect of chronic treatment of stobadine, a pyridoindole antioxidant, on vascular responsiveness in diabetic animals. Age- (13-week old) and gender-matched Wistar rats were randomly divided into control and diabetic groups. Streptozotocin (55mg/kg, i.p.) was used to induce experimental diabetes. After induction of diabetes, rats were randomly assigned for receving stobadine (24.7 mg/kg/day, p.o.) or vehicle for 8-10 months. Stobadine treatment significantly reduced the severity of hyperglycemia, heart and kidney weights, systolic blood pressure, and attenuated diabetes-induced loss in body weight gain. Increased vasoconstriction responses to phenylephrine (PE; 10-8-10-5 M) and BayK-8644 (3x10-7-3x10-5 M) were significantly decreased by stobadine treatment in diabetes. Although stobadine treatment increased acetylcholine (ACh; 10-9-10-5 M)-induced relaxation responses, sodium nitroprusside (10-11-10-6 M)-induced relaxations were not affected by the treatment or diabetes. Stobadine treatment markedly reduced A23187 (10-9-3x10-6 M)-induced relaxation responses while it remained unchanged in diabetics compared to controls. The transient vasoconstriction to PE was reduced by cyclopiazonic acid (10-6 M) or thapsigargin (TH; 10-6 M) in all groups. TH also inhibited the relaxation to ACh (3x10-6 M) in control and stobadine-treated diabetic groups. These results suggest that antioxidative and Ca2+ current regulatory effects of stobadine, contribute to the mechanisms responsible for its beneficial effects in aged diabetic rats.

Vitamin E and All-Cause Mortality: A Meta-Analysis by Erin L. Abner, Frederick A. Schmitt, Marta S. Mendiondo, Jennifer L. Marcum, Richard J. Kryscio (158-170).
The current analysis reexamines the relationship between supplemental vitamin E and all-cause mortality. All randomized, controlled trials testing the treatment effect of vitamin E supplementation in adults for at least one year were sought. MEDLINE, the Cochrane Library, and Biological Abstracts databases were searched using the terms and#x201C;vitamin E,and#x201D; and#x201C;alpha-tocopherol,and#x201D; and#x201C;antioxidants,and#x201D; and#x201C;clinical trial,and#x201D; and and#x201C;controlled trialand#x201D; for studies published through April 2010; results were limited to English, German, or Spanish language articles. Studies were also obtained through reference mining. All randomized controlled trials using vitamin E, with a supplementation period of at least one year, to prevent or treat disease in adults were identified and abstracted independently by two raters. Mortality data from trials with a supplementation period of at least one year were pooled. The selected trials (n = 57) were published between 1988 and 2009. Sample sizes ranged from 28 to 39,876 (median = 423), yielding 246,371 subjects and 29,295 all-cause deaths. Duration of supplementation for the 57 trials ranged from one to 10.1 years (median = 2.6 years). A random effects meta-analysis produced an overall risk ratio of 1.00 (95and#x25; confidence interval: 0.98, 1.02); additional analyses suggest no relationship between dose and risk of mortality. Based on the present meta-analysis, supplementation with vitamin E appears to have no effect on all-cause mortality at doses up to 5,500 IU/d.

The present work addresses one of the currently most controversial aspects of early detection of Alzheimer's disease (AD) and other dementias; that is, the identification of the Mild Cognitive Impairment (MCI) syndrome