Current nutritional and pharmacological anti-aging interventions

Aging is the main risk factor for chronic diseases and disablement in human societies with a great impact in social and health care expenditures. So far, aging and, eventually, death are unavoidable. Nevertheless, research efforts on aging-associated diseases with the aim not only to extend life span but also to increment health span in an attempt to delay, stop and even reverse the aging process have not stopped growing. Caloric restriction extends both health and life span in several short-lived experimental models and has brought to light the role of different molecular effectors involved in nutrient sensing pathways and longevity. This opens the possibility of modulating these molecular effectors also in humans to increase longevity and health span. The difficulty to implement caloric restricted diets in humans has led to the development of new bearable diets such as time-restricted feeding, intermittent fasting or diets with limited amounts of some nutrients and to the search of pharmacological agents, targeted to the effectors that mediate the extension of life and health span in response to these anti-aging diets. Pharmacological approaches that eliminate senescent cells or prevent primary causes of aging such as telomere attrition also emerge as potential anti-aging strategies. In the present article, we review these possible nutritional and pharmacological interventions designed to mitigate and/or delay the aging process and to increase health and life span.     

Ontogenetic variation of the human genome

The human genome demonstrates variable levels of instability during ontogeny. Achieving the highest rate during early prenatal development, it decreases significantly throughout following ontogenetic stages. A failure to decrease or a spontaneous increase of genomic instability can promote infertility, pregnancy losses, chromosomal and genomic diseases, cancer, immunodeficiency, or brain diseases depending on developmental stage at which it occurs. Paradoxically, late ontogeny is associated with increase of genomic instability that is considered a probable mechanism for human aging. The latter is even more appreciable in human diseases associated with pathological or accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). These observations resulted in a hypothesis suggesting that somatic genomic variations throughout ontogeny are determinants of cellular vitality in health and disease including intrauterine development, postnatal life and aging. The most devastative effect of somatic genome variations is observed when it manifests as chromosome instability or aneuploidy, which has been repeatedly noted to produce pathologic conditions and to mediate developmental regulatory and aging processes. However, no commonly accepted concepts on the role of chromosome/genome instability in determination of human health span and life span are available. Here, a review of these ontogenetic variations is given to propose a new "dynamic genome" model for pathological and natural genomic changes throughout life that mimic those of phylogenetic diversity.     

Sphingolipids and lifespan regulation

Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipids so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

The effect of aging on brain barriers and the consequences for Alzheimer’s disease development

Life expectancy has increased in most developed countries, which has led to an increase in the proportion of elderly people in the world’s population. However, this increase in life expectancy is not accompanied by a lengthening of the health span since aging is characterized with progressive deterioration in cellular and organ functions. The brain is particularly vulnerable to disease, and this is reflected in the onset of age-related neurodegenerative diseases such as Alzheimer’s disease. Research shows that dysfunction of two barriers in the central nervous system (CNS), the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB), plays an important role in the progression of these neurodegenerative diseases. The BBB is formed by the endothelial cells of the blood capillaries, whereas the BCSFB is formed by the epithelial cells of the choroid plexus (CP), both of which are affected during aging. Here, we give an overview of how these barriers undergo changes during aging and in Alzheimer’s disease, thereby disturbing brain homeostasis. Studying these changes is needed in order to gain a better understanding of the mechanisms of aging at the brain barriers, which might lead to the development of new therapies to lengthen the health span (including mental health) and reduce the chances of developing Alzheimer’s disease.     

JAK-STAT信号通路与衰老及衰老相关疾病

老龄化是许多慢性疾病的首要危险因素.如果老年人的疾病预防水平得不到大幅度的提高,不仅会影响老年人及家庭成员的生活质量,还会导致国家的经济以及医疗资源严重的匮乏.因此,如何延缓衰老已成为全世界关注的焦点.近些年,对衰老相关的机制也进行了广泛的研究,其中JAK-STAT信号通路吸引了大量学者的眼球.但是对JAK-STAT信...     

Three-dimensional human facial morphologies as robust aging markers

Aging is associated with many complex diseases. Reliable prediction of the aging process is important for assessing the risks of aging-associated diseases. However, despite intense research, so far there is no reliable aging marker. Here we addressed this problem by examining whether human 3D facial imaging features could be used as reliable aging markers. We collected > 300 3D human facial images and blood profiles well-distributed across ages of 17 to 77 years. By analyzing the morphological profiles, we generated the first comprehensive map of the aging human facial phenome. We identified quantitative facial features, such as eye slopes, highly associated with age. We constructed a robust age predictor and found that on average people of the same chronological age differ by ± 6 years in facial age, with the deviations increasing after age 40. Using this predictor, we identified slow and fast agers that are significantly supported by levels of health indicators. Despite a close relationship between facial morphological features and health indicators in the blood, facial features are more reliable aging biomarkers than blood profiles and can better reflect the general health status than chronological age.     

A rationally designed fluorescence probe achieves highly specific and long-term detection of senescence in vitro and in vivo

Senescent cells (SnCs) are implicated in aging and various age-related pathologies. Targeting SnCs can treat age-related diseases and extend health span. However, precisely tracking and visualizing of SnCs is still challenging, especially in in vivo environments. Here, we developed a near-infrared (NIR) fluorescent probe (XZ1208) that targets β-galactosidase (β-Gal), a well-accepted biomarker for cellular senescence. XZ1208 can be cleaved rapidly by β-Gal and produces a strong fluorescence signal in SnCs. We demonstrated the high specificity and sensitivity of XZ1208 in labeling SnCs in naturally aged, total body irradiated (TBI), and progeroid mouse models. XZ1208 achieved a long-term duration of over 6 days in labeling senescence without causing significant toxicities and accurately detected the senolytic effects of ABT263 on eliminating SnCs. Furthermore, XZ1208 was applied to monitor SnCs accumulated in fibrotic diseases and skin wound healing models. Overall, we developed a tissue-infiltrating NIR probe and demonstrated its excellent performance in labeling SnCs in aging and senescence-associated disease models, indicating great potential for application in aging studies and diagnosis of senescence-associated diseases.     

Paradoxes of Aging

Insightful articles by Kirkwood and other outstanding scientists reveal paradoxes of aging. The source of paradoxes is an assumption that aging is caused by random accumulation of molecular damage. Here I demonstrate that a concept of TOR-driven program-like aging almost automatically resolves eleven paradoxes of aging. This article discusses why the accumulation of molecular damage does not limit life span, why calorie restriction and inhibition of protein synthesis extend life span, why non-existing ‘program’ for aging is nevertheless robust, why a key gene for aging cannot be found by knocking it out, why low insulin is associated with good health but low insulin response with bad health, why aging is not a disease but can be treated as a disease, why ‘healthy’ aging is slow aging, and how do we know that calorie restriction actually slows aging in humans.     

Genetic determinants of human health span and life span: progress and new opportunities

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.     

Revisiting an age-old question regarding oxidative stress

Significant advances in maintaining health throughout life can be made through a clear understanding of the fundamental mechanisms that regulate aging. The Oxidative Stress Theory of Aging (OSTA) is probably the most well studied mechanistic theory of aging and suggests that the rate of aging is controlled by accumulation of oxidative damage. To directly test the OSTA, aging has been measured in several lines of mice with genetic alterations in the expression of enzymatic antioxidants. Under its strictest interpretation, these studies do not support the OSTA, as modulation of antioxidant expression does not generally affect mouse life span. However, the incidence of many age-related diseases and pathologies is altered in these models, suggesting that oxidative stress does significantly influence some aspects of the aging process. Further, oxidative stress may affect aging in disparate patterns among tissues or under various environmental conditions. In this review, we summarize the current literature regarding aging in antioxidant mutant mice and offer several interpretations of their support of the OSTA.     

Mammal aging: Active and passive mechanisms and their medical implications

This article compares two hypotheses regarding the mechanisms responsible for aging in humans and other mammals. In the passive mechanism, aging is the result of inadequacies in maintenance and repair functions that act to prevent or repair damage from fundamental deteriorative processes. In the active mechanism, a life span management system purposely limits life span by deactivating maintenance and repair processes beyond a species-specific age.As described here, the active mechanism provides a much better fit to observational evidence while the passive mechanism provides a much better fit to traditional evolutionary mechanics theory. However, there are many other observations that conflict with traditional theory and consequently a number of alternative evolutionary mechanics theories have been developed since 1962. Several of these alternatives support active life span management and aging theories providing a rationale for active life span management have been developed based on each of those alternatives.This issue is very important to our ability to treat age-related diseases and conditions. If indeed the passive mechanism is correct, then efforts should continue to be exerted to find treatments for each different manifestation of aging, independently of the others. If the active concept is valid it is clear that there are, in addition, substantial opportunities for finding agents that generally delay aging and simultaneously ameliorate multiple manifestations of aging.In the past, the evolutionary issues have been used as essentially the entire justification for summarily rejecting active theories. Given the public health considerations and the increasing number of issues surrounding evolutionary mechanics theory, this is no longer a reasonable or responsible path.     

Pro-Aging Effects of Glucose Signaling through a G Protein-Coupled Glucose Receptor in Fission Yeast

Glucose is the preferred carbon and energy source in prokaryotes, unicellular eukaryotes, and metazoans. However, excess of glucose has been associated with several diseases, including diabetes and the less understood process of aging. On the contrary, limiting glucose (i.e., calorie restriction) slows aging and age-related diseases in most species. Understanding the mechanism by which glucose limits life span is therefore important for any attempt to control aging and age-related diseases. Here, we use the yeast Schizosaccharomyces pombe as a model to study the regulation of chronological life span by glucose. Growth of S. pombe at a reduced concentration of glucose increased life span and oxidative stress resistance as reported before for many other organisms. Surprisingly, loss of the Git3 glucose receptor, a G protein-coupled receptor, also increased life span in conditions where glucose consumption was not affected. These results suggest a role for glucose-signaling pathways in life span regulation. In agreement, constitutive activation of the Gα subunit acting downstream of Git3 accelerated aging in S. pombe and inhibited the effects of calorie restriction. A similar pro-aging effect of glucose was documented in mutants of hexokinase, which cannot metabolize glucose and, therefore, are exposed to constitutive glucose signaling. The pro-aging effect of glucose signaling on life span correlated with an increase in reactive oxygen species and a decrease in oxidative stress resistance and respiration rate. Likewise, the anti-aging effect of both calorie restriction and the Δgit3 mutation was accompanied by increased respiration and lower reactive oxygen species production. Altogether, our data suggest an important role for glucose signaling through the Git3/PKA pathway to regulate S. pombe life span.     

Studying Age-dependent Genomic Instability using the S. cerevisiae Chronological Lifespan Model

Studies using the Saccharomyces cerevisiae aging model have uncovered life span regulatory pathways that are partially conserved in higher eukaryotes^1-2. The simplicity and power of the yeast aging model can also be explored to study DNA damage and genome maintenance as well as their contributions to diseases during aging. Here, we describe a system to study age-dependent DNA mutations, including base substitutions, frame-shift mutations, gross chromosomal rearrangements, and homologous/homeologous recombination, as well as nuclear DNA repair activity by combining the yeast chronological life span with simple DNA damage and mutation assays. The methods described here should facilitate the identification of genes/pathways that regulate genomic instability and the mechanisms that underlie age-dependent DNA mutations and cancer in mammals.     

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin

The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.     

Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging?

The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an “antiaging” action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging.     

Mitochondrial sirtuins,metabolism, and aging

Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Multiple signaling pathways that regulate metabolism also play critical roles in aging, such as PI3K/AKT, mTOR, AMPK, and sirtuins (SIRTs). Among them, sirtuins are known as a protein family with versatile functions, such as metabolic control, epigenetic modification and lifespan extension. Therefore, by understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.     

Melatonin,Longevity and Health in the Aged: An Assessment

This brief review considers the potential role of melatonin in the processes of aging, the prolongation of life span and health in the aged. Studies completed to date generally suggest that exogenously administered melatonin may serve to extend life span in invertebrates, but evidence supporting this conclusion in mammals is less compelling. Thus, any conclusion regarding a role for melatonin in extending normal longevity, particularly in mammals, would be premature. With regard to deferring the signs of chemically-induced neurodegenerative conditions in experimental animals, the data are remarkably strong and there is a modicum of evidence that in humans with debilitating diseases melatonin may have some beneficial actions. Indeed, this should be one focus of future research since as the number of elderly increases in the population, the frequency of costly age-related diseases will become increasingly burdensome to both the patient and to society as a whole.     

Environmental effects on the expression of life span and aging: an extreme contrast between wild and captive cohorts of Telostylinus angusticollis (Diptera: Neriidae)

Most research on life span and aging has been based on captive populations of short-lived animals; however, we know very little about the expression of these traits in wild populations of such organisms. Because life span and aging are major components of fitness, the extent to which the results of many evolutionary studies in the laboratory can be generalized to natural settings depends on the degree to which the expression of life span and aging differ in natural environments versus laboratory environments and whether such environmental effects interact with phenotypic variation. We investigated life span and aging in Telostylinus angusticollis in the wild while simultaneously estimating these parameters under a range of conditions in a laboratory stock that was recently established from the same wild population. We found that males live less than one-fifth as long and age at least twice as rapidly in the wild as do their captive counterparts. In contrast, we found no evidence of aging in wild females. These striking sex-specific differences between captive and wild flies support the emerging view that environment exerts a profound influence on the expression of life span and aging. These findings have important implications for evolutionary gerontology and, more generally, for the interpretation of fitness estimates in captive populations.     

Melatonin,longevity and health in the aged: an assessment

This brief review considers the potential role of melatonin in the processes of aging, the prolongation of life span and health in the aged. Studies completed to date generally suggest that exogenously administered melatonin may serve to extend life span in invertebrates, but evidence supporting this conclusion in mammals is less compelling. Thus, any conclusion regarding a role for melatonin in extending normal longevity, particularly in mammals, would be premature. With regard to deferring the signs of chemically-induced neurodegenerative conditions in experimental animals, the data are remarkably strong and there is a modicum of evidence that in humans with debilitating diseases melatonin may have some beneficial actions. Indeed, this should be one focus of future research since as the number of elderly increases in the population, the frequency of costly age-related diseases will become increasingly burdensome to both the patient and to society as a whole.