Difficulties of finding the pill of immortality (1)

Surinder Kumar, David B. Lombard
Finding Ponce de Leon’s Pill: Challenges in Screening for Anti-Aging Molecules F1000Research, 2016

Translated by Evgenia Ryabtseva

Resume

Aging is characterized by a progressive accumulation of degenerative changes, culminating in dysfunction and an increase in the likelihood of death. Aging is the main risk factor for many human pathologies, including cancer, type 2 diabetes, as well as cardiovascular and neurodegenerative diseases, and, accordingly, is the cause of a huge social and economic burden. The most important goal of research in the field of aging is to develop interventions that can delay the development of many age-related diseases and increase the duration of a healthy life. Observations according to which longevity and improvement of the health of model organisms can be achieved with the help of a low-calorie diet or simple genetic manipulations stimulated the search for chemical compounds that can increase life expectancy. Most of the signaling pathways modulating the rate of mammalian aging have homologues in yeast, fruit flies and roundworms, which indicates the expediency of primary screening to identify such pharmacological interventions on invertebrate models. In recent years, several compounds have been discovered that can increase the life expectancy of invertebrates and even rodents. This article presents basic data on search strategies and progress in identifying compounds that can increase the lifespan of organisms ranging from invertebrates to mice, as well as discusses significant difficulties preventing the transfer of the results obtained into clinical practice.

Introduction

Aging is characterized by molecular, cellular and organismal changes, culminating in the loss of the body's ability to maintain physiological integrity. Human aging is associated with a significant increase in predisposition to a wide range of diseases, including cancer, type 2 diabetes mellitus, neurodegeneration and diseases of the cardiovascular system, which leads to an increase in overall morbidity and mortality. The long-term goal of studying aging is to develop interventions that can delay the development of age-related diseases and ensure longevity. To achieve this goal, research in the field of biogerontology is devoted to elucidating the basic mechanisms of aging. The data available to date indicate that many of these mechanisms have been preserved in the course of evolution in eukaryotes, ranging from yeast to mammals.

Studies conducted over the past decades on various organisms have made it possible to identify cellular signaling pathways that modulate the rate of the aging process. Many of these pathways perform the function of registering the nutritional status of the organism (Figure 1) and initiate signaling cascades that modulate specific intracellular and intercellular pathways that appropriately change the physiology of target cells. These nutrient-sensitive pathways, including signaling mechanisms mediated by insulin and insulin-like growth factor (IGF), rapamycin target protein (mTOR), adenosine monophosphate-activated protein kinase (AMPK) and sirtuins, coordinate the processes associated with cell growth and metabolism, as well as integrate them with nutrient levels, energy, growth factors and stress. Lowering the levels of nutrients and growth factors changes the signals transmitted by these pathways. Genetic or, in some cases, pharmacological manipulations of these pathways can provide an increase in life expectancy, while age-related violation of their regulation can contribute to the physiological aging of the body.

Figure 1. Summary of various factors that can contribute to aging. Dysregulation of nutrient-recording mechanisms, proteostasis disorders, stem cell wear, accumulation of DNA damage, decreased autophagy activity, accumulation of cells that have entered the phase of physiological aging, as well as increased sterile inflammation are important mechanisms driving the aging process.

A low–calorie diet is a dietary regime that implies a reduction in the total number of calories consumed without the development of exhaustion or a reduction in the use of certain dietary components, such as amino acids, is the most well-described intervention that slows down aging and delays the development of diseases in a wide range of species. The molecular effectors involved in the manifestation of the outstanding effects of a low-calorie diet include the nutrient-recording signaling pathways listed above. Preliminary data suggest that some of these pathways may have an impact on human aging, as well as diseases affecting it. For example, the relationship between genetic variants of the FOXO3A gene encoding the transcription factor at the lower stages of the pathway mediated by insulin and insulin-like growth factor and human longevity was revealed. People with Laron dwarfism have significantly reduced levels of insulin-like growth factor in serum and pronounced resistance to the development of type 2 diabetes mellitus and cancer. Pharmacological interventions that partially reproduce the effects of a low-calorie diet by modulating the activity of these nutrient-sensitive mechanisms have the potential to increase the duration of a healthy life and longevity in general. For example, the ability of rapamycin, which is a specific mTOR inhibitor, to exert some of the positive effects of a low-calorie diet under conditions of standard feeding and nutrient intake has been described. Similarly, several other molecules, such as metformin and resveratrol, have been shown to modulate nutrient-sensitive signaling mechanisms and contribute to increasing the healthy lifespan of numerous model organisms. These effects will be described in more detail below.

In addition to disrupting the regulation of nutrient-sensitive signaling pathways, other mechanisms involved in the destructive manifestations of aging include (Figure 1):

1. mitochondrial dysfunction leading to disruption of respiratory metabolism, increased generation of reactive oxygen species (ROS), as well as other consequences,
2. increased accumulation of DNA damage induced by exogenous influences and endogenous failures, including DNA replication errors and reactive oxygen species,
3. reduced proteostasis associated with an increase in the frequency of improper folding and aggregation of protein molecules,
4. physiological aging of cells, contributing to the disruption of tissue functioning,
5. increased sterile inflammation,
6. depletion of stem cell stocks and
7. epigenetic rearrangements.

Pharmacological agents acting on some of these changes are candidates for anti-aging drugs. This review provides general information on pharmacological interventions that have a proven or potential ability to delay aging and contribute to maintaining health in old age. First, we summarize the main points of the contribution made by research on invertebrate model systems to the attempts made to conduct screening aimed at identifying small molecules capable of acting as anti-aging drugs. After that, we consider in detail the molecules whose potential ability to increase life expectancy and delay the development of diseases is currently being studied. And at the very end we discuss the difficulties accompanying the search for new anti-aging drugs and the transfer of this work into clinical practice.

Continuation: Invertebrates as model systems for screening small molecules promoting longevity.