Anti-aging Interventions Research Articles

Application of Kinase Inhibitors for Anti-aging Intervention.

Protein phosphorylation, mediated by protein kinases, has important physiological and pathological implications in our lives. Targeting kinase is one of the most interesting of the emerging topics in the pharmaceutical industry, especially since there is a focus on cancer therapy. Given that kinases may be involved in the aging process the focus will be on using the kinase inhibitor for anti-aging intervention to enhance healthspan and increase longevity. In this review, we will summarize: (i) the impact of the phosphoproteomic approach to elucidate molecular mechanisms of diseases; (ii) importance of the drug discovery approach for targeting kinases; (iii) the dysregulation of Janus kinase (JAK) / signal-transducing adapter molecules (STAT) and p70 ribosomal protein S6 kinase (S6Ks) pathway in aging and the age-related process; (iv) the epidemiological studies available in order to see whether a correlation between JAK/STAT and S6Ks mRNA expression levels exist in cancer and in patient outcome; (v) finally, we will show selected inhibitors of these kinases approved by the US Food and Drug Administration (FDA).

New phytochemicals as potential human anti-aging compounds: Reality, promise, and challenges

ABSTRACTAging is an inevitable process influenced by genetic, lifestyle, and environmental factors. Indirect evidence shows that several phytochemicals can have anti-aging capabilities, although direct evidence in this field is still limited. This report aims to provide a critical review on aspects related to the use of novel phytochemicals as anti-aging agents, to discuss the obstacles found when performing most anti-aging study protocols in humans, and to analyze future perspectives. In addition to the extensively studied resveratrol, epicatechin, quercetin, and curcumin, new phytochemicals have been reported to act as anti-aging agents, such as the amino acid L-theanine isolated from green tea, and the lignans arctigenin and matairesinol isolated from Arctium lappa seeds. Furthermore, this review discusses the application of several new extracts rich in phytochemicals with potential use in anti-aging therapies. Finally, this review also discusses the most important biomarkers to test anti-aging interventions, the necessity of conducting epidemiological studies and the need of clinical trials with adequate study protocols for humans.

Terapias antienvejecimiento aplicadas a la enfermedad de Alzheimer

Alzheimer's disease is the most common cause of dementia in the elderly population. Currently, there are no effective treatments to prevent or delay the natural course of the disease. Numerous studies have provided information about the molecular processes underlying biological ageing and, perhaps more importantly, potential interventions to slow ageing and promote healthy longevity in laboratory model systems. The main issue addressed in this review is whether an intervention that has anti-ageing properties can alter the appearance and/or progression of Alzheimer's disease, a disease in which age is the biggest risk factor. Different anti-ageing interventions have been shown to prevent (and in some cases possibly restore) several parameters recognised as central symptoms to the development of Alzheimer's disease. In addition, they are taking the first steps towards translating these laboratory discoveries into clinical applications.

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice.

There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2years. Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.

The Ethics of Anti-aging Clinical Trials.

Interventions aiming to slow, stop, or reverse the aging process are starting to enter clinical trials. Though this line of research is nascent, it has the potential to not only prevent prolonged human suffering, but also to extend human well-being. As this line of research develops, it is important to understand the ethical constraints of conducting such research. This paper discusses some of these constraints. In particular, it discusses the ethical difficulties of conducting this research in a way that would produce reliable data regarding the effectiveness of an anti-aging intervention. Clinical trials of such interventions, I argue, will be faced with a dilemma between two confounding variables. Eliminating the variables requires introducing ethically problematic research practices. Thus, researchers must either perform research in ethically problematic ways, or forego the conduct of high-impact clinical research on anti-aging interventions.

Markers of arterial health could serve as accurate non-invasive predictors of human biological and chronological age.

The decline in functional capacity is unavoidable consequence of the process of aging. While many anti-aging interventions have been proposed, clinical investigations into anti-aging medicine are limited by lack of reliable techniques for evaluating the rate of ageing. Here we present simple, accurate and cost-efficient techniques for estimation of human biological age, Male and Female Arterial Indices. We started with developing a model which accurately predicts chronological age. Using machine learning, we arrived on a set of four predictors, all of which reflect the functioning of the cardiovascular system. In Arterial Indices models, results of carotid artery duplex scan that show the thickness of the intima media complex and quantitatively describe the degree of stenosis are combined with pulse wave velocity and augmentation index measurements performed by applanation tonometry. In our cohort, the age of men was determined with MAE = 6.91 years (adjusted R-squared = 0.55), and the age of women with MAE = 5.87 years (adjusted R2 = 0.69). The Epsilon-accuracies of age-predicting models were at 86.5% and 80% for women and men, respectively. Substantially higher differences between the predicted age and the calendar age were noted for patients with Type 2 Diabetes Mellitus (T2D) as compared to non-T2D controls, indicating that the model could serve as a good approximation for an elusive biological age. Notably, in females with chronological and biological ages mismatching by 5 or more years, significant increases in in Framingham CVD scores and lower levels of IGF-1 were observed.Proposed Male and Female Arterial Indices derive biological age from the results of functional tests which do not require specialized laboratory equipment and, therefore, could be performed in hospitals and community health clinics.

563 Mechanistic modeling facilitates identification of key pathways involved in dermal aging and potential new targets for anti-aging intervention

563 Mechanistic modeling facilitates identification of key pathways involved in dermal aging and potential new targets for anti-aging intervention

A Holistic Approach to Antiaging as an Adjunct to Antiaging Procedures: A Review of the Literature.

Aging is a multifactorial process and depends on both intrinsic and extrinsic factors. Procedural options for diminishing signs of intrinsic aging and cosmetic rejuvenation have expanded dramatically. However, less attention is paid to counseling patients on options for mitigating extrinsic factors related to aging. The objective of this study was to review changes that occur with intrinsic and extrinsic aging, and provide evidence-based holistic counseling recommendations that can be used synergistically with aesthetic procedures to maximize antiaging interventions. A PubMed search was conducted for articles on intrinsic and extrinsic aging as it relates to skin, fat, muscle, and bone. Key clinical trials and studies on the effect of diet, hormones, exercise, sleep, stress, dental hygiene, smoking, pollution, and oxidative stress on the aging process are reviewed, and treatment recommendations are summarized based on available evidence. Conventional cosmetic procedures and cosmeceuticals work together with nutritious diet, exercise, dental hygiene, hormonal balance, stress reduction, smoking and pollution avoidance, and healthy sleep patterns for a better effect on antiaging. A combination approach of multiple nonsurgical modalities along with healthy lifestyle recommendations to minimize intrinsic and extrinsic aging factors allows cosmetic practitioners to target multiple facets of aging concurrently and maximize the aesthetic interventions cosmetic dermatologists/practitioners provide.

Biopolitics Meets Biosemiotics: The Semiotic Thresholds of Anti-Aging Interventions

Biosemiotics and the analysis of biopower have not yet been explicitly brought together. This article attempts to find their connecting points from the perspective of biosemiotics. It uses the biosemiotic understanding of the different types of semiosis in order to approach the practices of biopower and biopolitics. The central concept of the paper is that of the ‘semiotic threshold’. We can speak of (1) the lower semiotic threshold, signifying the dividing line between non-semiosis and semiosis; and (2) the secondary semiotic thresholds, signifying the borders between different types (iconic, indexical, symbolic) of semiosis. Speaking in terms of types of semiosis means speaking in terms of different capabilities for normativity, which is why the article uses the approaches of Michel Foucault on normalization in biopower and of Georges Canguilhem on organismic normativity. As an example on which biopolitics and biosemiotics could connect, the discourse of regenerative and anti-aging medicine is used.

Cardiac Aging - Benefits of Exercise, Nrf2 Activation and Antioxidant Signaling.

Cardiovascular dysfunction and heart failure associated with aging not only impairs the cardiac function but also the quality of life eventually decreasing the life expectancy of the elderly. Notably, cardiac tissue can prematurely age under certain conditions such as genetic mutation, persistent redox stress and overload, aberrant molecular signaling, DNA damage, telomere attrition, and other pathological insults. While cardiovascular-related morbidity and mortality is on the rise and remains a global health threat, there has been only little to moderate improvements in its medical management. This is due to the fact that the lifestyle changes to molecular mechanisms underlying age-related myocardial structure and functional remodeling are multifactorial and intricately operate at different levels. Along these lines, the intrinsic redox mechanisms and oxidative stress (OS) are widely studied in the myocardium. The accumulation of reactive oxygen species (ROS) with age and the resultant oxidative damage has been shown to increase the susceptibility of the myocardium to multiple complications such as atherosclerosis, hypertension, ischemic heart disease, cardiac myopathy, and heart failure. There has been growing interest in trying to enhance the mechanisms that neutralize the ROS and curtailing OS as a possible anti-aging intervention and as a treatment for age-related disorders. Natural defense system to fight against OS involves a master transcription factor named nuclear erythroid-2-p45-related factor-2 (Nrf2) that regulates several antioxidant genes. Compelling evidence exists on the Nrf2 gain of function through pharmacological interventions in counteracting the oxidative damage and affords cytoprotection in several organs including but not limited to lung, liver, kidney, brain, etc. Nevertheless, thus far, only a few studies have described the potential role of Nrf2 and its non-pharmacological induction in cardiac aging. This chapter explores the effects of various modes of exercise on Nrf2 signaling along with its responses and ramifications on the cascade of OS in the aging heart.

Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice.

Metformin is an oral anti-diabetic used as first-line therapy for type 2 diabetes. Because benefits of metformin extend beyond diabetes to other age-related pathology, and because its effect on gene expression profiles resembles that of caloric restriction, metformin has a potential as an anti-aging intervention and may soon be assessed as an intervention to extend healthspan. However, beneficial actions of metformin in the central nervous system have not been clearly established. The current study examined the effect of chronic oral metformin treatment on motor and cognitive function when initiated in young, middle-aged, or old male mice. C57BL/6 mice aged 4, 11, or 22 months were randomly assigned to either a metformin group (2 mg/ml in drinking water) or a control group. The mice were monitored weekly for body weight, as well as food and water intake and a battery of behavioral tests for motor, cognitive and visual function was initiated after the first month of treatment. Liver, hippocampus and cortex were collected at the end of the study to assess redox homeostasis. Overall, metformin supplementation in male mice failed to affect blood glucose, body weights and redox homeostasis at any age. It also had no beneficial effect on age-related declines in psychomotor, cognitive or sensory functions. However, metformin treatment had a deleterious effect on spatial memory and visual acuity, and reduced SOD activity in brain regions. These data confirm that metformin treatment may be associated with deleterious effect resulting from the action of metformin on the central nervous system.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. Inthis study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.

The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control.

The original concept of the NAD World was proposed in 2009, providing a comprehensive framework to investigate critical issues of biological robustness and trade-offs in mammalian aging and longevity control. Significant progress has been made over the past 7 years, advancing our understanding of the mechanisms by which biological robustness is maintained, and providing extensive support to the concept of the NAD World. Three key organs and tissues have been identified as basic elements in this control system for mammalian aging and longevity: the hypothalamus as the control center of aging, skeletal muscle as an effector, and adipose tissue as a modulator. While the hypothalamus sends a signal to skeletal muscle through the sympathetic nervous system, adipose tissue remotely regulates hypothalamic function by coordinating NAD+ biosynthesis at a systemic level. Skeletal muscle might also communicate with other organs and tissues by secreting various myokines. The mammalian NAD+-dependent protein deacetylase SIRT1 and the key NAD+ biosynthetic enzyme NAMPT mediate these inter-tissue communications. In this review, the function of each organ or tissue and their inter-tissue communications will be discussed in terms of understanding mammalian aging and longevity control. With such an emphasis on the system architecture, the concept is now reformulated as the NAD World 2.0, providing several important predictions. The concept of the NAD World 2.0 will provide a new foundation to understand a control system for mammalian aging and longevity and accelerate the development of an effective anti-aging intervention for humans.

Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation.

Caloric restriction is an anti-aging intervention known to extend lifespan in several experimental models, at least in part, by stimulating autophagy. Caloric restriction increases neuropeptide Y (NPY) in the hypothalamus and plasma ghrelin, a peripheral gut hormone that acts in hypothalamus to modulate energy homeostasis. NPY and ghrelin have been shown to be neuroprotective in different brain areas and to induce several physiological modifications similar to those induced by caloric restriction. However, the effect of NPY and ghrelin in autophagy in cortical neurons is currently not known. Using a cell culture of rat cortical neurons we investigate the involvement of NPY and ghrelin in caloric restriction-induced autophagy. We observed that a caloric restriction mimetic cell culture medium stimulates autophagy in rat cortical neurons and NPY or ghrelin receptor antagonists blocked this effect. On the other hand, exogenous NPY or ghrelin stimulate autophagy in rat cortical neurons. Moreover, NPY mediates the stimulatory effect of ghrelin on autophagy in rat cortical neurons. Since autophagy impairment occurs in aging and age-related neurodegenerative diseases, NPY and ghrelin synergistic effect on autophagy stimulation may suggest a new strategy to delay aging process.

Editorial: Proceedings of the 3rd International Conference on Genetics of Aging and Longevity.

In April 2014, the 3rd International Conference ≪Genetics of aging and longevity≫ took place in Sochi, Russia. We are pleased to present a collection of articles based on or related to the topics of the Conference and published in Frontiers in Genetics of Aging in 2015. They reflect understanding complex interactions between genes and genetic pathways underlying aging that is of utmost significance for the future life of humanity. Accordingly, genetic basis of longevity remained the most important topic of the Conference. The role of genes involved in energy supply and mitochondrial integrity and function deserved a close attention in two reviews published in this collection (Morrow and Tanguay; Rogers and Rogina). The importance of redox homeostasis in aging was considered in the paper by Klichko et al. Undoubtedly, energy metabolism governed by various genes and environmental factors, such as calorie intake, represents one of the key players in longevity control. Klichko et al. also demonstrated that temporal regulation of redox status is related to the aging-associated loss of a proper circadian modulation with age. Having joined an interesting extramural discussion, Koliada et al. reviewed the current views on the telomere length as a marker and/or a cause of aging and came to the conclusion that telomere may not serve as a “clock” counting cell divisions, but that telomere shortening, rather, reflects the history of exposure to oxidative stress in cell lineages. Thereto, another article described age-associated alterations in the chromosome morphology in a particular type of cells and indicated molecular mechanisms underlying these changes (Lebedeva et al.). Aging is defined as a gradual loss of physiological functions accompanied by decreasing fertility and increasing risk of mortality. An important and challenging question for the world-wide scientific community is whether there are means allowing to combat aging and to prolong health span and life span. Therefore, it is not surprising that anti-aging interventions attracted much attention at the Conference and, therefore, a number of articles in this collection were concentrated on possible pharmacological agents aimed to slow down aging (Carretero et al.; Johnson et al.; Semenkov et al.; Sycheva). Of note, effects of treatments on age-related traits, such as weight, as well as on some pathological states, rather than on aging and longevity were often considered (Johnson et al.; Semenkov et al.; Sycheva). In two research papers (Johnson et al.; Semenkov et al.), anti-aging interventions were to apply chemical (rapamycin) and physical (temperature, UV light) agents targeted at TOR signaling and ROS production; the role of vitamins in reducing cellular damage was regarded by Sycheva; five main pharmacological classes of compounds known to extend lifespan were considered in the review written by Carretero et al.). Arguments supporting the idea that the nervous system is an important target for anti-aging prophylaxis were also discussed by Omelyanchuk et al. The wide spectrum of agents and targets considered in a restricted number of articles once again sends us a trivial, albeit important message: modulation and fine tuning of multiple molecular mechanisms are needed to ensure longevity. Likewise, analysis of genome-wide screens for polymorphisms significantly associated with human longevity (Yashin et al.) brought authors to the conclusion that genes involved in the life span control affect various molecular functions but, eventually, these functions converge in the development of aging and key age-related pathologies. In the context of the search for means that are able to prolong the life span, Baranova and Willett suggested to pay a close attention to “the world of metabolites,” arguing that metabolome might be the most effective target for anti-aging interventions. Overall, articles from this collection reflect a wide range of current aging research and highlight its prospects and future directions. We hope that they will attract the attention of a broad scientific readership.

Measures of Healthspan as Indices of Aging in Mice-A Recommendation.

Over the past decade, a large number of discoveries have shown that interventions (genetic, pharmacological, and nutritional) increase the lifespan of invertebrates and laboratory rodents. Therefore, the possibility of developing antiaging interventions for humans has gone from a dream to a reality. However, it has also become apparent that we need more information than just lifespan to evaluate the translational potential of any proposed antiaging intervention to humans. Information is needed on how an intervention alters the "healthspan" of an animal, that is, how the physiological functions that change with age are altered. In this report, we describe the utility and the limitations of assays in mice currently available for measuring a wide range of physiological functions that potentially impact quality of life. We encourage investigators and reviewers alike to expect at minimum an overall assessment of health in several domains across several ages before an intervention is labeled as "increasing healthspan." In addition, it is important that investigators indicate any tests in which the treated group did worse or did not differ statistically from controls because overall health is a complex phenotype, and no intervention discovered to date improves every aspect of health. Finally, we strongly recommend that functional measurements be performed in both males and females so that sex differences in the rate of functional decline in different domains are taken into consideration.

The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity

SummaryIdentifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals.Video

Is programmed aging a cause for optimism?

Aging is now viewed as programmed under genetic control by a growing minority of evolutionary biologists, and a larger proportion of researchers in gerontology. The hypothesis of programmed aging has been regarded as encouraging for anti-aging science. Some mechanisms of programmed aging may present ready targets for medical interference [mitigation alleviation attenuation], while other kinds of programmed mechanism may yet prove to be refractory. The most promising possibility is that the machinery responsible for maintenance of the vibrant and youthful state of the body is never really lost, but de-commissioned by hormonal signals in the aging body; restoring a youthful signaling environment should then be sufficient to prompt the body to restore itself. But it is also possible that aging may be programmed in a way that does not facilitate anti-aging interventions. We identify two possible cases: In the first, the body is programmed to age via neglect rather than by affirmative self-destruction, so that damage is accumulating that the body is beyond the body's power to repair. In the second, aging is controlled by an epigenetic clock whose workings are so intricate as to be intractable for human mastery in the foreseeable future. There is substantial evidence that first of these is not a likely scenario, but the jury is still out on the second.

Endurance Exercise and Selective Breeding for Longevity Extend Drosophila Healthspan by Overlapping Mechanisms

Endurance exercise has emerged as a powerful intervention to extend healthy physiology into advanced age. Normal, age‐associated declines in organ structure and function are alleviated in endurance‐trained individuals. Long‐term exercise also reduces age‐related pathologies. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare the effects of endurance training on Drosophila melanogaster to the effects of selective breeding for longevity. We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Microarrays indicate that 73% of transcriptional changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training. Both endurance training and longevity selection upregulate folate biosynthesis, stress defense and lipid metabolism. Conversely, both interventions downregulate multiple carbohydrate metabolism pathways. methuselah‐like 3 was also transcriptionally reduced in both groups. Altering mthl3 expression in adult flies was able to reproduce a subset of the shared phenotypes. These results provide support for endurance exercise as a broadly acting anti‐aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways. In addition, these results identify the mthl3 gene as a potential target of exercise training.