Current Aging Science (v.8, #3)

Meet Our Editorial Board Member by Stephen C. Bondy (215-215).

Commentary: What is Aging? Can it be Eliminated? by Michael A. Singer (216-219).

Background: The nature of the life-extending effect of calorie restriction (CR) is an unsolved problem in biology since 30 years of the last century. Furthermore, many different factors that cause analogous life-extending effect, so called CR-mimetic factors, have been found. They increase the lifespan of different animal species (repeatedly in invertebrates) and therefore remain in the forefront of anti-aging researches. The aims of this paper is to find an overarching solution for the nature of CR and all CR-mimetic factors and to analyze the consequences following this phenomenon.
Methods: The analysis of empirical scientific data, which concern aging process and boundary areas from the point of view of the bioenergetics theory of aging.
Results: "Anything that affects a living system that slows (accelerates) the rate of cell division entails extending (reducing) life duration" is this overarching solution. CR is one of such factors that cause a retardation in the rate of cell divisions due to the shortage in 'construction materials' necessary for doubling cell mass during reduplication. This put a brake on realization of the aging program. To draw this conclusion, a new concept of the proliferative aging clock based on bioenergetics theory of aging was put forward. This clock governs the rate of the aging process via programmed, proliferativedependent and stepwise bioenergetics decline.
Conclusion: The mechanism of the life-extending effect of CR and CR-mimetic factors is not related to that of natural aging, therefore this unable to be the basis for elaboration of radical remedy for senescence. However, both the CR and some of CR-mimetic factors can undoubtedly lead to human life extension: our organism differs from that of the other mammals only slightly. It is the wellbeing and vulnerability of such extended life that are under consideration. To achieve a healthy and unlimited life it is necessary to reprogram gene expression so that cell bioenergetics levels either remain at a previous level after cell division, which will stop aging, or else grow, which will result in organism rejuvenation.

The process of aging is a continuum of degeneration which eventually leads to loss of function and clinically manifest disease. Yet, in the purely therapeutic sense, there is a distinct clinical and practical separation between age-related degenerative diseases and the background process of aging itself. It is quite possible that biomedical technologies will prove invaluable in treating or alleviating the impact of distinct age-related degenerative diseases such as cardiovascular disease, arthritis or dementia. However, when it comes to addressing the fundamental, background stochastic nature of aging, it is unlikely that regenerative biotechnologies will have any appreciable impact in continually counteracting the process. In this paper we discuss some essential conceptual obstacles, both functional and translational, which will prove overwhelming and which preclude the notion that aging can be eliminated by using physical therapies. Our reasoning is two-fold: 1. Disruptive regenerative biotechnologies interfere with the complex, dynamic topological architecture of the human organism, in a manner that will render them unsuitable for clinical use against all age-related degeneration. 2. Even if some regenerative biotechnological treatments are developed in the laboratory, the translational issues will be insurmountable, and the treatments will thus be practically unusable by the general public at large. Predictions about the near or mid-term development of rejuvenating biotechnologies are not sufficiently grounded, and do not provide a framework for effective practical achievement of negligible senescence. Instead, the answer must lie in more global and abstract methods which align well with evolutionary mechanisms based on techno-cultural societal necessities. These are likely to operate in a way which ultimately may downgrade the importance of human aging and make it an evolutionarily unnecessary process.

Association between amyloid-β (Aβ) toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage has been demonstrated in the pathophysiology of Alzheimer's disease (AD). In the early stages of the disease, the defect in energy metabolism was found to be severe. This may probably due to the Aβ and ROS-induced declined activity of complexes in electron transport chain (ETC) as well as damages to mitochondrial DNA. Though clinically inconclusive, supplementation with antioxidants is reported to be beneficial especially in the early stages of the disease. A mild to moderate improvement in dementia is possible with therapy using antioxidants viz coenzyme Q10 (ubiquinone), α-lipoic acid, selenium, omega-3 fatty acids and vitamin E, emphasize their possible role as an adjuvant with the existing conventional treatment. Since mitochondrial dysfunction has been observed, a new therapeutic strategy called as 'Mitochondrial Medicine' which is aimed to maintain the energy production as well as to ameliorate the enhanced apoptosis of nerve cells, has been developed. Mitochondrial CoQ10, Szeto-Schiller peptide-31 and superoxide dismutase/ catalase mimetic, EUK-207 were the mitochondrial targeted agents demonstrated in experimental studies. This article discusses the mitochondrial impairment and the possible mitochondria targeted therapeutic intervention in AD.

Objective: This study seeks to examine the applicability of the Dual-Process Model of Ideology, Politics, and Prejudice (DPM) as a theoretical explanatory frame-work to ageism.
Methods: The study is based on a secondary analysis of the European Social Survey (ESS), a quantitative project established in 2001 that includes 34 European countries. The sample was a representative random sample of the adult population of eight participating countries, and included a total of 19,073 participants.
Main Findings: In general, this study's findings point to the fact that no statistically significant correlation exists between the personality variables, whether authoritative or social dominant, and ageism.
Principal Conclusions: It appears that the theoretical framework of the DPM model may not be appropriate as a theoretical and explanatory model of the phenomenon of ageism. This may indicate that ageism possibly differs from similar social phenomena, such as sexism and racism, at least in its DPM model basis. More research is needed in this field to better understand the applicability of the DPM model to ageism.

Background and Objectives: Aging is associated with reduced quality and quantity of sleep. 50% of senior citizens living in the community and 70% of those living in nursing homes suffer from sleep disorders. Moreover, insomnia increases the risk of mortality and morbidity in older adults. We aimed to investigate the effect of aerobic exercise on quantity and quality of sleep among the elderly people referring to health centers of Lar city, southern Iran.
Methods and Patients: We enrolled 60 elderly people whose age range was 60-75 years and (mean ±SD) age was (64.8±5.2). Participants were randomly assigned into two groups of 30 each (case group= 30 and control group=30). The patients in the case group participated in exercise trainings consisted of three one-hour sessions per week for 12 consecutive weeks. Sleep quantity and quantity in the participants was evaluated before and after intervention using Pittsburgh Sleep Quality Index (PSQI).
Results: Independent t-test showed that sleep quality score was improved by 44.46% in the case group (p<0.0001). Furthermore, sleep duration was improved by 98/16% (p=0.038) and sleep latency was improved by 76/6% in the case group; while, the difference between the two groups regarding the changes in the sleep latency was not statistically significant (p=0.089).
Conclusion: Aerobic exercise program could improve the sleep quality and quantity in the elderly. It could also be used as a cost effective and long lasting method of therapy with no side effect which could be used for the treatment of insomnia in older people.

Age-related Decrease of Sirtuin 2 Protein in Human Peripheral Blood Mononuclear Cells by Kazuo Yudoh, Rie Karasawa, Junji Ishikawa (256-258).
Sirtuin 2, which is mainly present in cytoplasm, plays an important role in mammalian development, caloric restriction, metabolic regulation cellular antioxidant potential and the regulation of aging. We found that the protein level of sirtuin 2 in human peripheral blood mononuclear cells (PBMCs) decreases with an advance in donor age in men and women. Our data suggest that sirtuin 2 level in PBMCs decreases with age in both men and women and may have a potential as a useful biomarker monitoring health conditions and aging.

Withaferin A Regulates LRRK2 Levels by Interfering with the Hsp90- Cdc37 Chaperone Complex by Malathi Narayan, Juan Zhang, Kaitlyn Braswell, Chelsea Gibson, Ashley Zitnyar, Daniel C. Lee, Sheeba Varghese-Gupta, Umesh K. Jinwal (259-265).
Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multi-domain protein that has been found to be mutated in patients with familial and sporadic Parkinson's disease, Alzheimer's disease and Crohn's disease. While the functions of LRRK2 are still largely unclear and mutations in LRRK2 are associated with adverse gain-of-function activities such as increased kinase activity, increased levels of LRRK2 alone are associated with toxicity in neurons. Consequently, exploring mechanisms to decrease levels of LRRK2 using pharmacological inhibitors would be highly advantageous. Previous work has shown that the chaperone heat shock protein 90 (Hsp90) and its co-chaperone Cdc37 interact with and stabilize LRRK2. In the current study, we explore the regulation of LRRK2 by withaferin A (WA), a potent inhibitor of the interaction between Hsp90 and Cdc37. We report that treatment of the microglial cell line N9 with WA causes a decrease in cellular levels of LRRK2 in a dose- and time-dependent manner. We also find that treatment with WA disrupts the interaction between Hsp90, its co-chaperone Cdc37 and LRRK2, which leads to the destabilization and decreased levels of LRRK2. Additionally, treatment with celastrol, which is also an inhibitor of the Hsp90-Cdc37 complex, decreased LRRK2 levels. Interestingly, treatment with WA in the presence of celastrol enhanced the clearance of LRRK2. Overall, our data suggest that LRRK2 levels can be regulated by targeting the Hsp90-Cdc37 complex, which may have implications in the search for therapeutic strategies for Alzheimer's disease, Parkinson's disease and other LRRK2 proteinopathies.

Differentiating Walking from other Activities of Daily Living in Older Adults Using Wrist-based Accelerometers by Amy Papadopoulos, Nicolas Vivaldi, Cindy Crump, Christine Tsien Silvers (266-275).
There is a significant body of literature demonstrating that accelerometers placed at various locations on the body can provide the data necessary to recognize walking. Most of the literature, however, either does not consider accelerometers placed at the wrist, or suggests that the wrist is not the ideal location. The wrist, however, is probably the most socially-acceptable location for a monitoring device. This study evaluates the possibility of using wrist accelerometers to recognize walking in the elderly during everyday life to evaluate the amount of time spent walking and, moreover, potentially recognize changes in stability that might lead to falls. Thirty elderly individuals aged 65 years and older were asked to wear a wrist accelerometer for four hours each while simultaneously being videorecorded as they went about their normal daily activities. Accelerometer data were then analyzed using both frequency- and time-domain analyses. Particular attention was given to methods capable of being calculated on the wrist device so that future work will not require streaming large amounts of data from the device to the central server. Frequencybased analysis to characterize walking in the test set yielded results of 98% area under the receiver operating characteristic curve (AUC). Using a time-series algorithm limited to features calculable on the wrist device, moreover, achieved an AUC of 90%. A small, socially-acceptable, wrist-based device, therefore, can successfully be used to differentiate walking from other activities of daily living in older adults. These findings may enable improved gait monitoring and efforts in falls prevention.

Association Study of IL-4 -590 C/T and DDX39B -22 G/C Polymorphisms with the Risk of Late-Onset Alzheimer's Disease in Iranian Population by Mohsen Soosanabadi, Hadi Bayat, Koorosh Kamali, Kioomars Saliminejad, Mehdi Banan, Hamid Reza Khorram Khorshid (276-281).
Interleukin-4 (IL-4), an important anti-inflammatory cytokine, is elucidated to regulate amyloid β-induced production of the inflammatory cytokines such as IL-1 and IL-6. It is assumed that IL-4 may involve in the inflammation pathology of surrounding senile plaques in Alzheimer's disease (AD) patients. DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B), appears to be involved in regulation of the inflammatory cytokines which are in correlation with AD pathology. This study was conducted to investigate the two single nucleotide polymorphisms (SNPs), IL-4 -590 C/T and DDX39B -22 G/C, association with the risk of late-onset AD (LOAD) in Iranian population.
In the present study, therefore, a cohort of 153 LOAD cases and 153 age-matched unrelated, non-dementia control subjects were analyzed for the two polymorphisms by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).
Our results successfully demonstrate a protective association between the IL-4 -590 T allele, IL-4 -590 C/T heterozygous genotype (P= 0.01, OR= 0.53 and P= 0.041; OR= 0.56, respectively) and LOAD in Iranian population. A resemblance significant association was detected in female population when subjects were stratified by sex: the IL-4 -590 T allele (P= 0.02, OR= 0, 40) and the heterozygous genotype (P= 0.009, OR= 0.29). However, no significant association was observed between the DDX39B -22 G/C polymorphism in the cases and controls. Furthermore, it is clarified that the protective effect of IL-4 -590 is independent from APOE protective genotypes.
Accordingly, the IL-4 -590 T allele may be applied as a protective marker in the development of LOAD in Iranian population.

A Population-Based Study of Cholesterol Measurements in the Oldest Old by Charlotte Gils, Kaare Christensen, Mads Nybo (282-287).
Background: Effect of lipid-lowering treatment in the oldest old is a matter of debate as there is no unequivocal evidence of statins being beneficial among the oldest. The need for cholesterol measurements is therefore also questionable, but the frequency of cholesterol measurements in the oldest old has not been described on a population basis. Therefore, the number of lipid measurements in the period 2002-2012 was evaluated for people aged 85+ years.
Methods: The Laboratory Information System and the Population Register at Statistics Denmark were used for retrieving data on people aged 85+ living on the Island of Funen. The development in trends for cholesterol measurements was analysed in age groups of 5-years interval using linear regression analysis.
Results: A total of 30,424 persons with a cholesterol measurement entered the study. The total number of cholesterol measurements increased by 246% during the observation period. The percentage of people having a cholesterol measurement increased significantly (p < 0.001) from 2002 to 2012 for all groups except males over 100 years of age. The increase was only due to requests from general practitioners, not from hospital units.
Conclusion: Despite the uncertainty regarding lipid-lowering treatment in the oldest old, the percentage of people having a cholesterol measurement increased significantly during the study period. Whether this increase in cholesterol measurements leads to increased prescription of lipid-lowering medication in this cohort and/or better outcomes warrants future research.