Inhibition of DNA methyltransferase aberrations reinstates antioxidant aging suppressors and ameliorates renal aging

DNA methylation alterations play mechanistic roles in aging; however, the epigenetic regulators/mediators causally involved in renal aging remain elusive. Here, we report that natural and D‐galactose (D‐gal)‐induced aging kidneys display marked suppression of antiaging factor NRF2 (nuclear factor erythroid‐derived 2‐like 2) and KLOTHO, accompanied by upregulations of DNA methyltransferase (DNMT) 1/3a/3b and NRF2/KLOTHO gene promoter hypermethylations. Administration of a DNMT inhibitor SGI‐1072 effectively hypomethylated the promoters, derepressed NRF2/KLOTHO, and mitigated the structural and functional alterations of renal aging in D‐gal mice. Moreover, oleuropein (OLP), an olive‐derived polyphenol, also displayed similar epigenetic modulation and antiaging effects. OLP inhibited the epigenetic NRF2/KLOTHO suppressions in a gain of DNMT‐sensitive manner in cultured renal cells, demonstrating a strong DNA‐demethylating capacity. In NRF2 knockout and KLOTHO knockdown D‐gal mice, OLP exhibited reduced antiaging effects with KLOTHO displaying a prominent gene effect and effect size; consistently in KLOTHO knockdown mice, the antiaging effects of SGI‐1027 were largely abrogated. Therefore, the KLOTHO recovery is critical for the antiaging effects of DNA demethylation. Collectively, our data indicate that aberrant DNMT1/3a/3b elevations and the resultant suppression of antiaging factors contribute significantly to epigenetic renal aging, which might be targeted for epigenetic intervention by synthetic or natural DNA‐demethylating agents.     

An Integrated Framework for Risk Management and Population Health

The traditional medical model of health and health policy development has focused on individuals and the role of medical care in preventing and treating disease and injury. Recent attention to health inequities and social determinants of health has raised the profile of population heath and evidence-based strategies for improving the health of whole populations. At the same time, risk science has emerged as an important new discipline for the assessment and management of risks to health. This article reviews historical developments in the fields of risk management and population health and proposes a joint population health risk management framework that integrates the key elements of both fields. Applying this integrated approach to managing population health risks will facilitate the development of evidence-based health policy. It will encourage a more systematic and comprehensive evaluation of population health issues and promote the use of a broader suite of interventions to reduce health risks and enhance population health status.     

Dietary antiaging phytochemicals and mechanisms associated with prolonged survival

Aging is well-known an inevitable process that is influenced by genetic, lifestyle and environmental factors. However, the exact mechanisms underlying the aging process are not well understood. Increasing evidence shows that aging is highly associated with chronic increase in reactive oxygen species (ROS), accumulation of a low-grade proinflammatory phenotype and reduction in age-related autophagy, suggesting that these factors may play important roles in promoting aging. Indeed, reduction of ROS and low-grade inflammation and promotion of autophagy by calorie restriction or other dietary manipulation can extend lifespan in a wide spectrum of model organisms. Interestingly, recent studies show that some food-derived small molecules, also called phytochemicals, can extend lifespan in various animal species. In this paper, we review several recently identified potential antiaging phytochemicals that have been studied in cells, animals and humans and further highlight the cellular and molecular mechanisms underlying the antiaging actions by these molecules.     

Antiaging Action of Caloric Restriction: Endocrine and Metabolic Aspects

Restricting the energy intake of mice and rats slows the rate of actuarial aging, delays or prevents most age-associated disease processes, and maintains physiological processes in a youthful state at advanced ages. This manipulation is effective when initiated in young animals or in adult life. Although body fat is decreased by this reduction in energy intake, the reduction in body fat is not causally related to the antiaging action. Nor does this reduction in energy intake slow the aging processes by decreasing the metabolic rate, but it may do so by altering the characteristics of fuel use. Another possible mechanism underlying the antiaging action is the general protection restriction of energy intake provides against harmful agents, an action which may be the result of an alteration in adrenal glucocorticoid physiology.     

The ongoing saga of sirtuins and aging

Sirtuins are known to slow aging in simple eukaryotes; however, viewing mammalian sirtuins as antiaging proteins may be overly simplistic. In this issue of Cell Metabolism, Li et al. (2008) provide evidence that SirT1 has properties consistent with both pro- and antiaging functions in mice.     

Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity

One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here, we report that celecoxib, a nonsteroidal anti-inflammatory drug widely used to treat pain and inflammation, extends Caenorhabditis elegans lifespan and delays the age-associated physiological changes, such as motor activity decline. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent cyclooxygenase-2 (COX-2) inhibitor. However, the result from a structural-activity analysis demonstrated that the antiaging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack COX-2 inhibitory activity produce a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3'-phosphoinositide-dependent kinase-1, a component of the insulin/IGF-1 signaling cascade to increase lifespan.     

Dietary restriction and longevity extension as a manifestation of Hormesis

Restricting the food intake of rats and mice to 60% of ad libitum intake has been shown to significantly slow their aging processes and markedly extend length of life. Evidence is presented that indicates the antiaging action of this dietary restriction is a manifestation of hormesis and acts by enabling the animal to cope with stressors, including the low‐intensity, long‐term intrinsic and extrinsic stressors conjectured to cause aging. A hypothesis is offered for the evolutionarily adaptive basis of the antiaging action of dietary restriction: It proposes that this antiaging action is a byproduct of the evolution of mechanisms that enabled animals living in the wild to survive unpredictable and relatively brief periods of food scarcity. Likely proximate mechanisms of antiaging action of dietary restriction are considered. Enhancement of the stress response genes, particularly the heat shock protein genes, appears to be importantly involved. Evidence indicates that moderate hyperadrenocorticism also plays a significant role. These proximate mechanisms may well be major players in other examples of hormesis.     

Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation

The free radical theory of aging is currently one of the most popular. In parallel, many studies have demonstrated the association of fibrosis and increased oxidative stress in the pathogenesis of some chronic human diseases, and fibrosis is often characteristic of aging tissues. One of the few interventions that effectively slow aging is calorie restriction and the protection against the age-associated increase of oxidative stress remains one of the foremost hypotheses to explain this action. As an alternative to traditional calorie restriction, another dietary regimen, termed alternate-day fasting, has also been tested, whose antiaging mechanisms have not been explored so much extensively. We thus studied the effects of alternate-day fasting, started at 2 months of age, on oxidative stress and fibrosis in the heart during aging. In the left ventricle of the heart of elderly (aged 24 months) versus young (aged 6 months) male rats we found a significant increase in oxidative stress paralleled by increased fibrosis. In parallel there was a significant increase in inflammatory cytokine levels and in NF-kB DNA binding activity with advancing age. Alternate-day fasting protected against all these age-related phenomena. These data support the hypothesis that this kind of dietary restriction protects against age-related fibrosis, at least in part by reducing inflammation and oxidative damage, and this protection can thus be considered a factor in the prevention of age-related diseases with sclerotic evolution.     

Clinical oxidation parameters of aging

Aging is a complex progressive physiological alteration of the organism which ultimately leads to death. During the whole life a human being is confronted with oxidative stress. To measure how this oxidative stress is developing during the aging process and how it changes the cellular metabolism several substances have been pronounced as biomarkers including lipid peroxidation (LPO) products, protein oxidation products, antioxidative acting enzymes, minerals, vitamins, glutathione, flavonoids, bilirubin and uric acid (UA).

But none of them could develop to the leading one which is accepted by the whole scientific community to determine the life expectancy of the individual person or biological age or age-related health status. Further there are many conflicting data about the changes of each single biomarker during the aging process.

There are so many different influences acting on the concentration or activity of single substances or single enzymes that it is not possible to measure only one clinical marker and determine how healthy an individual is or to predict the life expectancy of the corresponding person. Therefore, always a set or pattern of clinical biomarkers should be used to determine the oxidation status of the person. This set should include at least one marker for the LPO, the protein oxidation and the total antioxidative status and ideally also one for DNA damages.     

Clinical oxidation parameters of aging

Aging is a complex progressive physiological alteration of the organism which ultimately leads to death. During the whole life a human being is confronted with oxidative stress. To measure how this oxidative stress is developing during the aging process and how it changes the cellular metabolism several substances have been pronounced as biomarkers including lipid peroxidation (LPO) products, protein oxidation products, antioxidative acting enzymes, minerals, vitamins, glutathione, flavonoids, bilirubin and uric acid (UA).

But none of them could develop to the leading one which is accepted by the whole scientific community to determine the life expectancy of the individual person or biological age or age-related health status. Further there are many conflicting data about the changes of each single biomarker during the aging process.

There are so many different influences acting on the concentration or activity of single substances or single enzymes that it is not possible to measure only one clinical marker and determine how healthy an individual is or to predict the life expectancy of the corresponding person. Therefore, always a set or pattern of clinical biomarkers should be used to determine the oxidation status of the person. This set should include at least one marker for the LPO, the protein oxidation and the total antioxidative status and ideally also one for DNA damages.     

Crosstissue coexpression network of aging

Aging is characterized by the interlocking decay of biological functions over time. Microarrays have been successful in elucidating some of the genome-wide changes that occur with age. Using the AGEMAP dataset that catalogs changes in gene expression as a function of age in 16 tissues in mice, we identified tissue-specific aging genes. Coordinated aging processes across different tissues then were clarified in crosstissue coexpression networks on both the gene and pathway levels. Our findings provide more concrete information about coordinated aging across different tissues. By bridging gene-level and tissue-level research, this study could help identify targets for attenuation of critical aging-related genes, pathways, or networks for antiaging intervention.     

城市生态风险评价研究进展

随着城市化发展和城市人居环境的恶化,城市生态风险越来越受到关注,但尚缺乏有关城市生态风险评价的深入系统研究.本文依据城市生态学原理及生态风险评价框架从驱动力、风险源、风险受体与评价终点,以及生态风险综合评价方法等方面对城市生态风险评价研究进行综述.指出城市经济社会活动类型与程度是城市生态风险产生的主要驱动力;城市生态系统不同等级功能实体和城市整体是城市生态风险评价中的风险受体;城市生态风险评价终点包括城市生态系统结构、过程、功能要素,以及城市整体水平的性质和功能变化;耦合了社会经济需求的生态系统模型是城市生态风险评价方法的发展方向.未来城市生态风险评价研究应明确生态风险管理具体目标,确定综合性评价终点,建立多指标评价体系和综合评价方法.     

Interactions between mitochondrial dysfunction and other hallmarks of aging: Paving a path toward interventions that promote healthy old age

Current research on human aging has largely been guided by the milestone paper “hallmarks of aging,” which were first proposed in the seminal 2013 paper by Lopez-Otin et al. Most studies have focused on one aging hallmark at a time, asking whether the underlying molecular perturbations are sufficient to drive the aging process and its associated phenotypes. More recently, researchers have begun to investigate whether aging phenotypes are driven by concurrent perturbations in molecular pathways linked to not one but to multiple hallmarks of aging and whether they present different patterns in organs and systems over time. Indeed, preliminary results suggest that more complex interactions between aging hallmarks must be considered and addressed, if we are to develop interventions that successfully promote healthy aging and/or delay aging-associated dysfunction and diseases. Here, we summarize some of the latest work and views on the interplay between hallmarks of aging, with a specific focus on mitochondrial dysfunction. Indeed, this represents a significant example of the complex crosstalk between hallmarks of aging and of the effects that an intervention targeted to a specific hallmark may have on the others. A better knowledge of these interconnections, of their cause-effect relationships, of their spatial and temporal sequence, will be very beneficial for the whole aging research field and for the identification of effective interventions in promoting healthy old age.     

Chronic Physical Illness: A Psychophysiological Approach for Chronic Physical Illness

Growing evidence demonstrates that psychological risk variables can contribute to physical disease. In an effort to thoroughly investigate potential etiological origins and optimal interventions, this broad review is divided into five sections: the stress response, chronic diseases, mind-body theoretical models, psychophysiological interventions, and integrated health care solutions. The stress response and its correlation to chronic disorders such as cardiovascular, gastrointestinal, autoimmune, metabolic syndrome, and chronic pain are comprehensively explored. Current mind-body theoretical models, including peripheral nerve pathway, neurophysiological, and integrative theories, are reviewed to elucidate the biological mechanisms behind psychophysiological interventions. Specific interventions included are psychotherapy, mindfulness meditation, yoga, and psychopharmacology. Finally, the author advocates for an integrated care approach as a means by which to blur the sharp distinction between physical and psychological health. Integrated care approaches can utilize psychiatric nurse practitioners for behavioral assessment, intervention, research, advocacy, consultation, and education to optimize health outcomes.     

Is the secret for a successful aging to keep track of cancer pathways?

A successful aging could be gained by life satisfaction, social functioning, or psychological resources and, definitely, by increasing resistance to diverse age‐related pathologies. Nowadays, cancer can be considered an age‐related disease since the incidence of most cancers increases with age, rising more rapidly beginning in midlife. Although adults with extended longevity are less likely to develop cancer, it is now emerging that aging and cancer share common molecular links, and thus targeting these mechanisms may be suitable to treat multiple disorders, for the prolonging of healthy aging. At present, one of the cornerstones of antiaging is hormone‐replacement therapy to treat diseases associated with a state of age‐related sex‐hormone deficiency in women and men; however, many studies question the relationship of hormone replacement to cancer recurrence. Here, we discuss signaling and metabolic molecular crossroad linking aging and cancer. This is useful to argue about the current knowledge of prolongevity and druggable targets and to motivate specific intervention strategies that could modify practices of the aging population, activating multiple longevity pathways but keeping track of cancer pathways, thereby potentially preserving health status.     

Uncouplers of oxidation and phosphorylation as antiaging compounds

Food restriction causes a set of physiological changes that reduce the rate of aging. At the level of an organism, these changes are initiated by a hormonal response, which in turn activates certain intracellular signaling cascades. As a result, cells increase their antioxidant capacities and decrease the risk of cancerous transformation. A number of small molecule compounds activating these signaling cascades have been described. One could expect that direct pharmacological activation of the signaling can produce a stronger antiaging effect than that achieved by the indirect hormonal stimulation. Data from the literature point to the opposite. Possibly, a problem with pharmacological activators is that they cause generation of mitochondrial reactive oxygen species. Indeed, hyperpolarized mitochondria are known to induce oxidative stress. Such hyperpolarization could happen because of artificial activation of cellular response to caloric restriction in the absence of energy deficit. At the same time, energy deficit seems likely to be a natural consequence of the shortage of nutrients. Thus, there is a possibility that combining the pharmacological activators with compounds that decrease mitochondrial transmembrane potential, uncouplers, could be a powerful antiaging strategy.