Therapeutic potential and challenges of targeting sirtuins in neurodegenerative diseases

Aging is the predominant risk factor for major neurodegenerative diseases. The underlying mechanisms are largely unknown. Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend lifespan when upregulated. Sirtuins are involved in fundamental mechanisms in age-related neurodegenerative diseases, including protein aggregation and homeostasis, survival and stress responses, and inflammatory processes. In this review, we will discuss the neurobiology of sirtuins and their multifaceted roles in the pathogenesis of neurodegenerative diseases. We will also examine the potential and challenges of targeting sirtuin pathways to treat these devastating conditions.     

Mammalian sirtuins and energy metabolism

Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases that can extend the lifespan of several lower model organisms including yeast, worms and flies. The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response. Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals. This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.     

去乙酰化酶Sirtuin与衰老的研究进展

Sirtuin蛋白是一组具有NAD⁺依赖性的组蛋白去乙酰基转移酶,该家族成员具有高度保守的催化结构域,可以通过对多种底物进行去乙酰化作用,从而在机体内参与一系列的生物学活动,包括维持细胞抗胁迫能力和基因组稳定性以及参与能量代谢等．Sir2参与了酵母的交配型基因、端粒和rDNA 重复序列的沉默以及细胞寿命等生理功能．在哺乳动物中,SIRT1是该家族中目前研究最为广泛且较为透彻的成员,而SIRT6的功能研究成为近年来继SIRT1后的又一新热点．综述了sirtuin蛋白的结构及其与衰老关系的研究进展．     

神经生长因子与神经系统老化

老化通常指生物体生长发育成熟以后,随年龄增加生理机能逐渐减退,内环境稳定性下降,组织器官逐渐发生退行性改变,最终走向衰老、死亡的过程。神经系统老化是神经元退行性病变形成的基础和条件。由于神经生长因子（nerve growth factor,NGF）与中枢神经系统胆碱能神经元的存活和可塑性调节密切相关,所以NGF在神经系统老化和神经退行性变疾病如老年性痴呆（Alzheimer’s disease,AD）的发生发展过程中发挥重要作用。本文综述了NGF在脑老化中的变化及其与AD发病机制的关系。     

Focus: The Aging Brain: The Knowledge of Memory Aging Questionnaire: Factor Structure and Correlates in a Lifespan Sample

The authors examined the factor structure of the Knowledge of Memory Aging Questionnaire (KMAQ) [1] using confirmatory factor analysis in a lifespan sample of 933 individuals who ranged in age from 18 to 101. Participants were college students at Louisiana State University and adults from the community enrolled in the Louisiana Healthy Aging Study (LHAS). A two-factor solution was expected, consistent with the normal and pathological memory aging dimensions that comprise the KMAQ. A bi-factor solution with items loading on a general response bias factor and either a normal or pathological knowledge-specific factor showed good model fit. Knowledge scores were correlated with demographic and cognitive performance variables. Implications of these data for clinical settings and research are considered.     

端粒、端粒酶与衰老

古往今来,“长生不老”成为人们一直追求的梦想,曾经有多少人用各种方法来延缓衰老,但终未取得显著效果。近年来研究证实,端粒缩短导致衰老。     

DNA 与衰老

衰老是生物体各种功能的普遍衰弱,以及抵抗环境伤害和恢复生理稳态的降低过程。衰老、衰老的原因、衰老的机理及衰老与疾病、衰老与死亡的关系,一直是生物及医学领域的科学家们积极探讨的问题。衰老这一极其复杂的生物学过程,涉及物理、化学、生物、医学诸领域。现已发展的近300种衰老学说分别从整体、器官、细胞、分子水平对生物衰老的机制进行了阐述。本文将从分子的角度阐述生物信息分子－DNA及其相关物质与生物衰老的关系。     

Ecological Aging: The Settings Approach in Aged Living and Care Accommodation

As the proportion of older people increases within populations, financial demands related to the cost of health service delivery threaten global stability. This population trend challenges the traditional approach to health service delivery to older populations. This article presents the Australian context as a case study to argue that the application of a health promoting settings approach to aged care may lead to improved well-being for older people to the extent that the periods of chronic morbidity often associated with aging can be compressed into an ever shorter period of time. Promoting an ecological perspective to aged care suggests that there is no need to manage older people in isolation, as is common practice, but as integral to the way society lives, works, and plays. The article maps parallels between characteristics of health promoting settings such as Health Promoting Schools and the aged living and care industry, arguing that the setting encompassing services for the elderly is a prime location for the establishment of a new health promotion setting. Supporting life opportunities for our aged is central to such an approach. More broadly, an ecological approach orients us toward the connection between environment and health, and encourages increased attention and action within the aged living and care sector on reducing environmental impacts of this growing population. As such, the application of this approach to the aged living and care sector has the potential to reduce the threat that a dependant older population has on global sustainability.     

Aging and epigenetics: longitudinal changes in gene-specific DNA methylation

DNA methylation has been associated with age-related disease. Intra-individual changes in gene-specific DNA methylation over time in a community-based cohort has not been well described. We estimated the change in DNA methylation due to aging for nine genes in an elderly, community-dwelling cohort of men. Seven hundred and eighty four men from the Veterans Administration Normative Aging Study who were living in metropolitan Boston from 1999-2009 donated a blood sample for DNA methylation analysis at clinical examinations repeated at approximately 3-5 year intervals. We used mixed effects regression models. Aging was significantly associated with decreased methylation of GCR, iNOS and TLR2 and with increased methylation of IFNγ, F3, CRAT and OGG. Obstructive pulmonary disease at baseline modified the effect of aging on methylation of IFNγ (interaction p = 0.04). For participants who had obstructive pulmonary disease at their baseline visit, the rate of change of methylation of IFNγ was -0.05% 5-methyl-cytosine (5-mC) per year (95% CI: -0.22, 0.13), but was 0.14% 5-mC per year (95% CI: 0.05, 0.24) for those without this condition. Models with random slopes indicated significant heterogeneity in the effect of aging on methylation of GCR, iNOS and OGG. These findings suggest that DNA methylation may reflect differential biological aging.     

Development and Aging of the Liver and Pancreas in the Domestic Carp, Cyprinus Carpio: From Embryogenesis to 15-year-old Fish

The cytology of development and aging of the liver and pancreas in domestic carp was studied in a large sample of EM and LM sections from larvae juveniles 1–10 year old adults and 15 year old experimentally stunted fish weighing 20g and of 110–120mm TL. The primordium of the two glands appears in embryos 3–4 days after fertilization as buds from the gut wall. Formation of the hepatic tubules is first seen in larvae 10 days after fertilization. Two types of hepatocytes are discernable: one with a pale cytoplasm and the other with a dense opaque cytoplasm; both extend microvilli into the sinusoidal space of Disse and bear intracellular bile canaliculi. With maturation and branching of the hepatic tubules a complicated hepatic muralium is formed. The pancreatic cells develop in 5–6mm TL embryos primarily along the blood capillaries and in 10–11 day old larvae exocrine A and B cells are seen prominent by their zymogen granules and spires and stacks of rough endoplasmic reticulum. Ripening of the Islets of Langerhans begin in larvae of 10mm TL. By 16mm TL two types of endocrine cells are visible. With aging three processes are recognizable in the liver: (1) increased branching of the blood net displaces the hepatic units and complicates the structure of the liver parenchyma; (2) a gradual increase in lipid vacuoles and debris deposition in secretory cells takes place; and (3) the number of melano-macrophage cells and melano-macrophage centers gradually increases. In 15-year-old experimentally stunted fish (110–120mm TL) the liver and pancreas resemble those of juvenile fish appearing much healthier than those of 8–10 year old large carp from commercial ponds. These findings provide evidence that aging is not a simple time-dependent mechanism but is also strongly modulated by environmental factors.     

Aging bone score and climatic factors

Hand radiograms for osseographic assessment of bone aging status were taken from more than 7,500 individuals residing in 31 different localities and belonging to 20 ethnic groups. Multiple regression analysis was used to evaluate possible associations between bone aging parameters and several climatic factors, to wit: hours of daylight in January and July, average monthly humidity and partial vapor pressure in January and July, and one climatic index pertaining to comfort conditions in life, namely, the Bioclimatic Index of Severity of Climatic Regime. Multiple regression analysis clearly pointed to significant correlations between climatic characteristics and indices defining the relative rate of bone aging in humans; it also evinced an independent contribution of July's humidity and January's mean temperature to earliest age at which first signs of bone aging can be found. In sum, there are grounds for concluding that temperature and humidity are key factors in triggering initial bone changes in individuals within the human populations prone to environmental effects. The combination of humidity and temperature with other factors which reflect the sharpness of the interseasonal differences in climatic conditions predispose the populations to early onset of bone changes. Am J Phys Anthropol 106:349–359, 1998. © 1998 Wiley-Liss, Inc.     

心血管老化和心力衰竭

老年人心血管系统的老化是很明显的,动脉硬化改变了后负荷以及左心室的形状.尽管左心室的心脏收缩功能仍然能够维持,但是左心室的舒张功能则大大改变.运动时老年人的心血管功能产生明显的改变,老年人可以通过运动训练改善心血管功能.老化引起心血管结构和功能改变,从而降低心脏疾病出现的阈值.对老年人在运动或休息时心血管结构和功能的改变进行了综述.     

衰老及相关基因群

综述20世纪与基因相关的衰老原理的探索及其进展,整体动物水平的衰老研究归纳了衰老了诸多表象但疏于对衰老本质的探讨。线粒体－自由基衰老学说阐述了线粒体DNA的损伤与衰老有很大的相关性,由Hayflic k分裂限制衍生的端粒衰老学说给衰老机制提供了重要信息,目前狭隘的基因程序化衰老学说已和损伤衰老概念有机的联系在了一起。总之,自由基衰老学说得到了氧化衰老学说和糖基化衰老学说的补充逐渐形成了生化副反应与基因衰老学说的大统一衰老机制板块理论。