Towards a life prolonging pill? Small molecules with anti-ageing properties

While at present there is no scientific consensus on the reasons for cellular and organismal ageing--or indeed on a comprehensive definition for ageing--scientific efforts to unravel the complex biochemistry behind the ageing process have recently met with considerable success. Despite a still somewhat fragmented understanding of the phenomenon of ageing, a distinction has therefore become possible between those biochemical and physiological events that are causal to ageing, and those that merely accompany the process. Such a distinction is an important prerequisite for the selection of targets for pharmacological intervention, and for the design of "anti-ageing drugs" directed against these targets. This review looks from a chemical viewpoint at currently used model systems for the ageing process, at small molecules showing anti-ageing properties in these screens, and at their mechanisms of action.     

黄芩苷对D-半乳糖致亚急性衰老小鼠生理机能的影响

目的：研究黄芩苷对D-半乳糖致亚急性衰老小鼠生理机能的影响。方法：实验小鼠随机均分为7组,分别为对照组、模型组、香菇多糖（200mg/kg）组,黄芩苷低、中、高（50、100、200mg/kg）3个剂量组及黄芩苷（100mg/kg）＋香菇多糖（100mg/kg）组。在灌胃给予上述药物24d后,对实验小鼠的学习记忆能力进行测试,同时测定小鼠体内超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、过氧化氢酶（CAT）等酶的活性,及丙二醛（MDA）的含量。结果：高、中剂量的黄芩苷能提高衰老小鼠的学习记忆能力（P〈0.05）,能在一定程度上提高组织或血浆中SOD、GSH-Px的活性,升高血浆中CAT的活性,并降低MDA的含量,但较香菇多糖组效果略差,而黄芩苷＋香菇多糖组效果最佳（P〈0.05））。结论：黄芩苷可延缓D-半乳糖致亚急性衰老小鼠的衰老进程,其作用机制可能与其调节氧化代谢酶系统有关,可作为抗氧化衰老辅助药物。     

Rationale and methods of discovering hormetins as drugs for healthy ageing

INTRODUCTION: Mild stress-induced hormesis is becoming increasingly attractive as an ageing interventional strategy and is leading to the discovery of hormesis-inducing compounds called hormetins. Almost 50 years of modern biogerontolgical research has established a clear framework regarding the biological basis of ageing and longevity, and it is now generally accepted that ageing occurs in spite of the presence of complex pathways of maintenance, repair and defense, and there is no 'enemy within.' This viewpoint makes modulation of ageing different from the treatment of one or more age-related diseases. A promising strategy to slow down ageing and prevent or delay the onset of age-related diseases is that of mild stress-induced hormesis by using hormetins. AREAS COVERED: The article presents the rationale and a strategy for discovering novel hormetins as potential drugs for ageing intervention by elucidating multiple stress responses of normal human cells. Furthermore, it discusses the first steps in identifying prospective hormetin drugs and provides a recent example of successful product development, based on the ideas of hormesis and by following the strategy described here. EXPERT OPINION: As a biomedical issue, the biological process of ageing underlies several major diseases, and although the optimal treatment of every disease, irrespective of age, is a social and moral necessity, preventing the onset of age-related diseases by intervening in the basic process of ageing is the best approach for achieving healthy ageing and for extending the healthspan.     

Apoptosis remodeling in immunosenescence: implications for strategies to delay ageing

Immunosenescence is characterized by a peculiar remodeling of the immune system, mainly induced by lifelong antigenic burden and oxidative stress. Apoptosis or programmed cell death plays a central role in the ageing process. Both recurrent antigenic stimulations and oxidative metabolism by-products, impinging upon the immune system, modify the apoptotic capability of lymphocytes, driving immunosenescence. The apoptosis remodeling, in addition to inflamm-ageing, i.e. the upregulation of anti-stress responses and inflammatory cytokines, represents one of the major determinants of ageing rate and longevity, as well as of the most common age-related diseases. The cells of the immune system undergo two different kinds of apoptotic processes: activation-induced cell death (AICD), geared towards the elimination of unnecessary lymphocytes following clonal expansion, and damage-induced cell death (DICD), particularly important for preventing the onset of neoplastic proliferations. During senescence these apoptotic pathways are differentially modulated, with variable impacts on the ageing process. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative, inflammatory and neoplastic diseases whose incidence increases with age. This review focuses on the role of AICD and DICD dysfunction in the ageing process and highlights emerging anti-ageing therapeutical strategies offered by apoptosis re-modulation. The challenge for the future is to identify factors and signals that regulate apoptotic processes and determine if selective apoptosis manipulation in specific lymphocyte subsets could preserve immune function in the elderly, contributing to successful ageing.     

The effect of processed water on constitutive and ultraviolet-A-radiation-induced level of mitochondrial DNA mutations in human dermal fibroblasts

The integrity of the mitochondrial genome is of crucial importance for the cellular energy metabolism, and increased mutation rates are causally related to premature ageing. We demonstrate that replacement of normal deionized water with processed water in cell culture medium decreases the constitutive levels of the most frequent large-scale deletion of the mitochondrial genome in human dermal fibroblasts. In addition the presence of processed water also prevented the generation of the common deletion which was induced in these cells by repetitive UVA irradiation (3 x 8 J/cm(2) daily). Thus, processed water appears to protect the mitochondrial genome and may thus exert anti-oxidative and anti-ageing effects.     

Ageing and metabolism: drug discovery opportunities

There has recently been significant progress in our understanding of the mechanisms that regulate ageing, and it has been shown that changes in single genes can dramatically extend lifespan and increase resistance to many diseases. Furthermore, many of these genes belong to evolutionarily conserved pathways that also control energy metabolism. In this review, we describe the shared molecular machinery that regulates ageing and energy metabolism. Although drugs to slow ageing face severe regulatory hurdles, it is likely that an understanding of ageing pathways will help to identify novel drug targets to treat metabolic disorders and other age-related diseases.     

Challenging but essential targets for genuine anti-ageing drugs

Contrary to what one might conclude from the popular press, anti-ageing drugs do not yet exist, in the sense in which the term 'drug' is normally used. Since a drug is assumed to be effective against its target human pathology and since the vast majority of deaths in the developed world are from ageing-related causes, it is inappropriate to describe something as an anti-ageing drug unless one has good reason to believe that it will appreciably extend the life expectancy of those in the developed world who receive it. A drug that rejuvenates aspects of the aged body but does not increase life expectancy is an antifrailty drug, not an anti-ageing one. This distinction is critical for decision makers in the drug discovery sphere because, while the market for antifrailty drugs (even unproven ones) is large, that for genuine anti-ageing drugs - which, as the author explains, are now foreseeable - will certainly be far larger. In this article, the author surveys the main aspects of age-related degeneration that are believed to be essential targets for genuine anti-ageing drugs - that is, without whose amelioration human life expectancy probably cannot be greatly increased - and some promising strategies for the design of such drugs.     

Novel therapies for sarcopenia: ameliorating age-related changes in skeletal muscle

Among the most serious consequences of ageing are its effects on skeletal muscle structure and function. Ageing is associated with a progressive loss of muscle mass (sarcopenia) motor function, a slowing of muscle movements and a decline in muscle strength. These age-related changes in muscle properties contribute to the gradual loss of functional independence and the increased incidence of fall-related injuries in the elderly. Progressive muscle fibre denervation, the loss of motor units and subsequent motor unit remodelling have been implicated as mechanisms responsible for these deleterious effects of ageing on skeletal muscle, especially the loss of force and power output. However, the age-related reduction in the speed of contraction has been reported to occur before the onset of severe muscle wasting, indicating that age-related changes intrinsic to skeletal muscle fibres cannot be excluded. Even in the absence of disease, muscles atrophy and become functionally weaker with age. From a public health perspective, sarcopenia has widespread clinical implications. Diminished muscle mass and functional strength with age increases the risk of injury from sudden falls and increases the dependence on the frail elderly for assistance in accomplishing even the most basic tasks required for independent living, including the maintenance of personal hygiene, feeding and recreational pursuits, leading to an inability to perform even simple activities required for daily living. Research into ageing and muscle function is of increasing importance to the community as the ageing population continues to escalate. It is generally agreed that such age-related changes in skeletal muscle structure and function are inevitable, although debate exists as to whether these intrinsic changes are immutable or reversible. Clearly, there is a profound need for therapeutic intervention strategies that aim to slow the effects of ageing on muscle function and/or restore muscle size and strength in the frail elderly so as to improve or maintain their quality of life. This review examines recent (1998 - 2001) patents on novel strategies for ameliorating the effects of ageing on muscle structure and function.     

Androgen replacement therapy in the hypogonadal ageing man

In men, gonadal function is affected in a slow, progressive way as part of the normal ageing process. Recently, however, significant interest has developed on the importance of this condition, which is variously known as male climacteric, andropause or, more appropriately, androgen decline in the ageing male (ADAM). The term andropause is biologically wrong and clinically inappropriate but, it adequately conveys the concept of emotional and physical changes that, although related to ageing in general, are also associated with significant hormonal alterations. The inappropriateness of the term is based on the fact that in women, the reproductive cycle invariably ends with ovarian failure. In men, this process is not universal and when it occurs it is normally subtle in its clinical manifestations. This has led to a tendency to ignore the syndrome as an unavoidable and untreatable result of the ageing process. For the sake of simplicity and directness, this review will use the terms ADAM and andropause to denote the global hormonal alterations associated with ageing.     

Innovative cancer drug targets: genomics,transcriptomics and clinomics

In men, gonadal function is affected in a slow, progressive way as part of the normal ageing process. Recently, however, significant interest has developed on the importance of this condition, which is variously known as male climacteric, andropause or, more appropriately, androgen decline in the ageing male (ADAM). The term andropause is biologically wrong and clinically inappropriate but, it adequately conveys the concept of emotional and physical changes that, although related to ageing in general, are also associated with significant hormonal alterations. The inappropriateness of the term is based on the fact that in women, the reproductive cycle invariably ends with ovarian failure. In men, this process is not universal and when it occurs it is normally subtle in its clinical manifestations. This has led to a tendency to ignore the syndrome as an unavoidable and untreatable result of the ageing process. For the sake of simplicity and directness, this review will use the terms ADAM and andropause to denote the global hormonal alterations associated with ageing.     

Methantheline improves the reactivation by HI 6 of human erythrocyte acetylcholinesterase inhibited by soman in vitro

The effect of methantheline, a quaternary ammonium compound, on the reactivation by HI 6 of soman-inhibted human erythrocyte acetylcholinesterase (AChE) was investigated in vitro using purified human erythrocyte AChE or washed human erythrocytes. Methantheline itself was found to be a mixed competitive/non-competitive inhibitor of AChE (K_ii 360±70 μmol/l; K_i 240±10 μmol/l). In all experiments the enzyme was first inhibited by soman for 30 min under conditions preventing ageing (pH 10,0°C) and then ageing was allowed by changing the pH to 7.3 and the temperature to 37°C. Methantheline addition (0.36 or 3.6 mmol/l) at the start of ageing increased the portion of AChE which could be reactivated by HI 6 (0.32 mmol/l) added 5 min later, from 24.6±1.0% (mean±SEM) of the original activity to 42.1±1.8% or 45±2.9%, respectively. With HI 6 alone, the portion of AChE activity which could be reactivated 25 min after the start of ageing decreased rapidly with the delay of the oxime addition (100% of the original activity at immediate addition), the half-life being approximately 2.5 min. With methantheline alone (0.36 mmol/l) the AChE activity was lower after immediate addition (37% of the original value), but the loss of activity due to the increasing delay of methantheline addition exhibited a similar half-life as with HI 6. Finally, when methantheline (0.36 mmol/l) was added at the start of ageing and HI 6 at various intervals thereafter the half-life of AChE activity loss due to the delay of HI 6 addition at least doubled, compared to incubations without methantheline.     

Metolose-PEG interaction as seen by positron annihilation spectroscopy

The plasticizing effects of poly(ethylene glycol) (PEG 400) on methylcellulose (Metolose) cast films were studied by conventional physicochemical methods and positron annihilation spectroscopy. The PEG concentrations relative to the total polymer content were varied within the range 0-75% (w/w). At low concentrations (below 33.3%, w/w), the plasticizer was found to build in into the methylcellulose structure. On the other hand, at higher concentrations (above 50%, w/w), it formed small separate phases in the films. Positron annihilation spectroscopy (PALS) was applied to track the Metolose-PEG interaction. Controlled ageing of Metolose-PEG films at room temperature and at 75% RH revealed a significant difference between the ageing processes of the monophase and those of the separate phase films. The ageing involves two steps in both cases: a fast and a slow one. The PALS measurements demonstrated that the slow process is hindered in the phase-separated samples.     

Are sirtuins viable targets for improving healthspan and lifespan?

Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.     

A diet supplemented with thiolic anti-oxidants improves leucocyte function in two strains of prematurely ageing mice

1. According to previous studies, Swiss mice of the same age showed striking interindividual differences in behaviour when exposed to a T-maze test, with a slow performance being linked to an impaired immune function, hyperemotional response to stress and a shorter life span compared with mice that quickly explore the maze.These facts led us to propose the slow mice as a model of prematurely ageing mice (PAM). 2. In the present study, we investigated whether this prematurely ageing model could be found in other strains of mice, such as BALB/c mice, by analysing several lymphocytes functions, such as adherence, chemotaxis, proliferative response to the mitogen concanavalin A (Con A), interleukin (IL)-2 release and natural killer (NK) activity. In addition, we tested the probable beneficial effects on these functions of dietary supplementation with thioproline (TP) plus N-acetylcysteine (NAC; 0.1% w/w of each anti-oxidant) in female Swiss and BALB/c mice. 3. Our model of premature ageing, previously reported in Swiss mice, has also been reproduced in the inbred BALB/c mouse strain, in which PAM showing an immunosenescence in several lymphocyte functions, such as lower chemotaxis, proliferative response to Con A, IL-2 release and NK activity, as well as higher adherence, were observed. A short-term (5 week) ingestion of TP + NAC by female Swiss and BALB/c mice improved leucocyte function, increasing chemotaxis, the proliferative response to Con A, IL-2 release and NK activity and decreasing the adherence of lymphocytes.These effects are greatest in cells from PAM of both strains. 4. In conclusion, our model of premature ageing has been reproduced in an inbred strain. In addition, the ingestion of a diet supplemented with two thiolic anti-oxidants, such as NAC and TP, has been shown to be beneficial to the immune response in PAM.     

The pharmaceuticalisation of ‘healthy’ ageing: Testosterone enhancement for longevity

The United Nations estimates that the world's population will reach 8.5 billion by 2030, and the populations of most countries are expected to grow older. This is case for many developed countries, including Australia, the United Kingdom, Canada, the United States of America, and member states of the European Union. Older cohorts will comprise a larger proportion of overall populations, driven in part by our increases in life expectancy. An ageing population poses challenges for governments; notably, older people tend to have multiple, chronic health conditions which can place a burden of health budgets. At the same time, we are witnessing a shift in how we respond to the health needs of our populations, with global drug policy acknowledging that some substances are contributing to increased morbidity and mortality (e.g. opioids) while others may have beneficial therapeutic effects (e.g. psylocibin, cannabis). There is general agreement that as men age their levels of testosterone decrease, and there is some evidence to suggest that there have been population-level declines in testosterone which are not associated with age. Anecdotally, testosterone is accessed by men seeking to self-medicate in the belief that they are experiencing low testosterone levels. There has also been a rise in anti-ageing clinics in the United States, providing access to testosterone replacement therapy (TRT). The non-medical use of testosterone can result in a number of adverse health events, including complications from the use of black market or underground products. Placing testosterone under a new prescribing regime may address some of these concerns, but is society ready for this change, and if so, what would this regime look like? This paper will explore the issue of how society responds to enhancement for longevity, or how we increasingly use pharmaceuticals to address and prevent illness, with a specific focus on testosterone and testosterone deficiency.     

活性磷脂抗皮肤老化的实验研究

目的探讨活性磷脂延缓小鼠皮肤老化的作用及其机理。方法小鼠每日颈背部皮下注射D-半乳糖(1 000 mg/kg)造成小鼠老化模型,同时灌胃活性磷脂42 d后,去背部皮肤,用分光光度法测定小鼠皮肤中胶原蛋白的含量。结果活性磷脂使D-半乳糖所致的小鼠皮肤老化模型中各剂量组胶原蛋白含量均显著增加。结论活性磷脂可提高皮肤中胶原蛋白含量,提示活性磷脂具有延缓皮肤老化的作用。     

Gamma-linolenic acid ameliorated glycation-induced memory impairment in rats

Context: γ-Linolenic acid (GLA) is an important constituent of anti-ageing supplements.

Objective: The current study investigates the anti-ageing effect of GLA in Sprague-Dawley rats.

Materials and methods: GLA (0.1, 0.2, 0.4, 2, 10, 20 and 24?μM) was initially evaluated for its effect on the formation of advanced glycation end products (AGEs) in vitro. For in vivo assessment (1, 5 or 15?mg/kg), the rat model of accelerated ageing was developed using d-fructose (1000?mg/kg (i.p.) plus 10% in drinking water for 40?days). Morris water maze was used to evaluate impairment in learning and memory. The blood of treated animals was used to measure glycosylated haemoglobin (HbA1c) levels. The interaction of GLA with active residues of receptor of AGE (RAGE) was analyzed using AutoDock Vina.

Results: Our data showed that GLA inhibited the production of AGEs (IC₅₀?=?1.12?±?0.05?μM). However, this effect was more significant at lower tested doses. A similar pattern was also observed in in vivo experiments, where the effect of fructose was reversed by GLA only at lowest tested dose of 1?mg/kg. The HbA1c levels also revealed significant reduction at lower doses (1 and 5?mg/kg). The in silico data exhibited promising interaction of GLA with active residues (Try72, Arg77 and Gln67) of RAGE.

Conclusion: The GLA, at lower doses, possesses therapeutic potential against glycation-induced memory decline.     

Advances in the genetics of Parkinson＇s disease

Parkinson's disease (PD) is a neurodegenerative disorder affecting a significant proportion of the ageing population. The etiology is unknown and it is likely due to a multifactorial interaction of genes and the environment on the background of ageing. Findings in the last decade suggest that the contribution of genetics to familial forms of PD is much greater than previously appreciated. Twelve loci are now associated with highly penetrant autosomal dominant or recessive PD, and causative mutations have been identified in eight genes with mutation carriers often characterized by a phenotype indistinguishable from idiopathic disease. To date, PD pharmacotherapy is symptomatic only and does not slow disease progression. Understanding how genetic mutations cause familial PD is likely to clarify molecular mechanisms underlying PD in general and will provide a guide for the development of novel therapies, both preventative and palliative, applicable to all forms of parkinsonism. This review outlines the advances in the study of the genetic background of PD and their possible clinical implications.     

干扰素β治疗复发-缓解型多发性硬化

干扰素 β已经成功用于治疗复发 缓解型多发性硬化。其免疫调节作用表现为减少复发 缓解型多发性硬化病人临床症状和在MRI水平观察到的复发率和病灶负荷 ,以及延缓功能障碍的进展。还可以延缓相关的继发性进展型多发性硬化病人功能障碍的进展 ,以及延缓临床孤立综合征发展成临床确诊的多发性硬化。虽然干扰素治疗过程中可出现一些轻微的不良反应 ,但大多数情况下无需减量或停药。中和抗体的出现可能影响疗效 ,但尚无证据表明抗体出现后就可能会完全失效。基于该疗法的安全性和可靠性 ,可以说干扰素 β是目前多发性硬化治疗中最有希望的药物之一