Aging and development of geroprotectors
Aging and drug discovery
Daniela Bakula et al., Aging, 2018.
Translated by Evgenia Ryabtseva
For references and references, see the original article.
To date, quite a lot of methods of intervention in the aging process are already known, allowing to increase the duration of healthy life of model organisms. Therefore, both industry and the scientific community are studying promising compounds that affect aging and age-related diseases.
This review summarizes the presentations and discussion topics discussed at the 5th Annual Forum on Aging and Drug Development, held in Basel, Switzerland, in September 2018. At the forum, representatives of the scientific community and industry gathered together to discuss the latest achievements and challenges in the field of aging research. The forum featured presentations on the mechanistic cause of aging, the possible highly conservative molecular profiles of longevity, identifiable biomarkers of aging, possible interventions in the aging process, as well as the use of artificial intelligence in the study of aging and the development of drugs. It should be noted that both in the scientific community and in industry, experts come to a consensus that molecules that influence the aging process are potentially capable of making a revolution both in society and in the healthcare system.
Introduction
Why are we getting old? Can we intervene in the aging process? And if we can, what approaches should scientists studying aging take in order to transform research results into viable therapeutic interventions to improve public health? Understanding the mechanisms of aging is a prerequisite for getting answers to these questions. However, there are a number of obstacles to the development of effective and safe interventions that increase the duration of a healthy life.
At the 5th Annual Forum on Aging and Drug Development, held within the framework of the Basel Life Congress held on September 12-13, 2018 in Basel, leading experts of the scientific community and industry gathered together to discuss the main issues of the study of aging. The Congress was organized by Alex Zhavoronkov, Executive Director of Insilico Medicine (Baltimore, Maryland, USA), specializing in the implementation of artificial intelligence solutions in the development of drugs and biomarkers, as well as Morten Scheibye-Knudsen, head of the laboratory of aging Interventions at the University's Center for Healthy Aging Copenhagen (Denmark). Below is a brief overview of the reported results and discussion topics.
What is the engine of the aging process?
Aging is a multifactorial process leading to the loss of cellular homeostasis, which, in turn, increases the susceptibility to the development of diseases. Functional extinction occurs under the influence of highly conservative signaling pathways, the effects of which can be used to manipulate the aging process.
Judith Campisi from the Buck Institute for the Study of Aging (California, USA) highlighted the role of physiological cell aging as an evolutionary compromise in relation to aging. Cells that have entered the phase of physiological aging accumulate over time and stimulate the aging process through the loss of tissue functionality and the secretion of pro-inflammatory factors that form a complex known as the secretory phenotype. Physiological aging is a double-edged knife, as it suppresses the processes of malignant transformation. However, over time, their accumulation leads to the formation of degenerative phenotypes and triggers the development of tumors. Therefore, exposure to cells that have entered the phase of physiological aging can help in preventing age-related extinction of functions. Unambiguous markers of such cells are still missing due to their high heterogeneity. In search of a solution to this problem, Campisi's group applied the method of single cell analysis to identify expression profiles specific to different cell types that have entered the phase of physiological aging. The results of this work can help in the search for more specific targets.
Michael Ristow from the Higher Technical School of Zurich (Switzerland) presented his work on the regulation of redox processes important for life expectancy and metabolism. The data previously obtained by this group formed the basis of the concept of mitohormesis as a signaling pathway contributing to the maintenance of good health, in which low concentrations of reactive oxygen species (ROS) ensure the development of an adaptive response. The concept of mitohormesis was also confirmed by the observation that limiting the amount of glucose in the diet of C.elegans roundworms leads to an increase in ROS production, which, in turn, provides protection from endogenous stress and increases life expectancy. The ROS-induced increase in tissue sensitivity to insulin was also observed in a clinical study of physical activity, and this effect was inhibited by the introduction of antioxidants into the diet. Moreover, the researchers compared the gene expression levels of young, mature and old worms C.elegans, freshwater fish D.rerio and house mice M.musculus to identify aging-associated genes preserved during evolution. Branched chain amino acid transferase (bcat-1) proved to be a strong regulator of life expectancy, and, accordingly, knockout of the bcat-1 gene increased the lifespan of C.elegans.
Both exogenous and endogenous stress factors, such as ROS, continuously affect the human genome. Different molecular mechanisms have evolved to repair various types of DNA damage. DNA damage accumulates with age, and it is generally believed that the body's ability to repair it fades with age. The effect of DNA repair mechanisms on aging was presented at the congress in two presentations. In discussing the phenotypic landscape of aging, Morten Scheibye-Knudsen from the University of Copenhagen drew attention to the fact that the mechanisms causing various age-related pathologies are poorly understood. He stressed the importance of using hierarchical groupings and machine learning algorithms to compare analogies of different diseases based on their clinical manifestations. This approach can help in the search for cellular mechanisms associated with the pathological manifestations of certain diseases. It should be noted that diseases caused by defects in the DNA damage repair system have many features similar to the aging process, which confirms the key role of maintaining the integrity of the genome in aging. Thus, disorders associated with premature aging may be good model systems for studying aging.
Martijn Luijsterburg from the Medical Center of the University of Leiden (the Netherlands) in his speech further reinforced this observation. He presented the results of his latest research on DNA repair coupled with transcription, a mechanism for repairing DNA damage that removes damaged fragments that block the transcription of active genes. An interesting fact is that mutations of genes responsible for DNA repair associated with transcription cause a variety of phenotypes. Mutations of the CSA and CSB genes can cause Coccain syndrome (progeroid nanism), a disease characterized by premature aging and manifested by severe neurodegeneration. At the same time, mutations of the UVSSA gene can cause a syndrome of sensitivity to ultraviolet radiation – a disease that has no neurological manifestations. An accurate interpretation of the molecular functions of the components of the DNA repair complex associated with transcription can help in understanding the mechanisms of the development of Coccain syndrome and the manifestations of aging. Martijn Luijsterburg presented his latest results, bringing us closer to understanding this issue.
Longevity Profiles
In recent years, the concerted efforts of researchers have been aimed at identifying biological markers that allow determining the biological age of a person. It has been demonstrated that there is a strong correlation between chronological age and various types of prognostic factors of aging, including telomere length, changes in gene expression and epigenetic changes – the so-called epigenetic clock. Vadim Gladyshev from Brigham Women's Hospital, Harvard University Medical School (Boston, Massachusetts, USA) and Moscow State University (Moscow, Russia) stated that since aging is a systemic process, a combination of different approaches can provide a more reliable prediction of biological age. His research team studied the DNA methylome of blood cells from mice of different age groups to develop an epigenetic clock suitable for testing the results of anti-aging interventions. This analysis showed that both animals on a low-calorie diet and long-lived mutant mice of the Snell dwarf line demonstrate delayed epigenetic aging. In the framework of subsequent studies of this group, transcriptomic changes associated with longevity were identified in 33 species of mammals and 14 different varieties of fruit flies of drosophila, which can be used to predict the effectiveness of new interventions to increase longevity.
Collin Ewald from the Higher Technical School of Zurich (Switzerland) presented the results of his recent work on the study of transcriptomic longevity profiles in C.elegans roundworms, which demonstrated that the composition of the extracellular matrix undergoes changes as it ages. It is important to note that potential anti-aging interventions, such as rapamycin therapy, modulate the expression of extracellular matrix genes. Moreover, it has been shown that the increase in life expectancy induced by a decrease in the activity of the signaling mechanism mediated by insulin/insulin-like growth factor-1 depends on the expression of the collagen gene. These observations indicate that a change in the composition of the extracellular matrix may be a very promising target. Collin Ewald's work demonstrates the value of C.elegans as a powerful model system for studying aging and anti-aging interventions, due to their relatively short lifespan and easily manipulated genome.
Stuart Maudsley from the University of Antwerp (Belgium) discussed the identification of multidimensional regulators of aging. In addition to epigenetic changes and changes in gene expression, deep age-related remodeling of protein expression can also be observed with aging. In a number of recent studies, his group, using a combination of classical analysis of signaling pathways and information methods of text processing in natural languages, studied age-related changes in the proteome in the hypothalamus, potentially a key organ coordinating global somatic aging. Using this innovative approach, it was found that the kinase of the G-protein coupled receptor, interacting protein (interactor)-2 (G protein-coupled receptor kinase interacting protein 2, GIT2) is a potential key regulator of aging. Subsequently, the researchers demonstrated that the expression of the GIT2 protein varies greatly over time in the hypothalamus and many other regions of the brain, as well as in various peripheral tissues associated with the regulation of energy metabolism. GIT2 acts as a scaffold protein for a variety of signaling pathways, therefore, a decrease in its functionality affects several significant manifestations of aging, including metabolic disorders, reactions to DNA damage, reactions to oxidative damage and physiological aging of the immune system. Thus, GIT2 can be a promising multidimensional therapeutic target for the treatment of age-related diseases.
Interventions in the aging process and age-related diseases
Dudley Lamming from the University of Wisconsin (Madison, Wisconsin, USA) presented the results of his work dedicated to ensuring healthy aging by reducing the content of certain dietary macronutrients in the diet.
In recent years, many interventions have been identified to increase life expectancy. Specialists are actively discussing interventions, both pharmacological (for example, rapamycin, resveratrol, metformin) and non-pharmacological (for example, a low-calorie diet, exercise). However, the mechanisms of the potential impact of these interventions on human health are not completely clear. The results of an increasing number of studies indicate that the macronutrient composition of the diet, and in particular, the protein content in it, can also play a critical role in regulating metabolic health and life expectancy. However, the question remains open as to whether changing the use of certain amino acids mediates the positive effects of reducing the protein content in the diet. In this regard, Lamming's research team has obtained data according to which reducing the use of branched chain amino acids improves the metabolic health of both lean mice and C57BL/6J animals with diet-induced obesity. This approach will reproduce the many positive effects of a low-protein diet. It should be noted that a selective decrease in the leucine content in the diet stimulated the growth of white adipose tissue, which indicates the different roles belonging to individual branched chain amino acids in the regulation of metabolic health.
Joseph Baur from the University of Pennsylvania (Philadelphia, Pennsylvania, USA) and his colleagues believe that reducing the number of calories consumed is a daunting task, so a promising strategy is the use of compounds that mimic the effects of a low-calorie diet. Modulating nicotinamide adenine dinucleotide (NAD+) levels is a promising strategy for the treatment of age-related decline in physiological functions. The results of a recent study by Baur showed that selective knockout in muscle cells of nicotinamide phosphoribosyltransferase– an enzyme necessary to maintain normal NAD+ concentration, leads to progressive loss of muscle function. The observed phenotype was neutralized by the introduction of a precursor of NAD+ – nicotinamidriboside. An interesting fact is that the increased expression of nicotinamide phosphoribosyltransferase throughout life prevented an age-related decrease in the concentration of NAD+ and improved the physical performance of old mice. Despite the well-known fact that the mitochondrial NAD+ reserve contributes to the maintenance of cell metabolism, the source of mitochondral NAD+ is still not clear. The recently published results of the work of the Baur group indicate the existence of a previously unknown NAD+ transporter, which may be another potential target for modulating the compartmentalization (distribution to different compartments) of NAD+ inside the cell.
Alexey Moskalev from the Moscow Institute of Physics and Technology (Moscow, Russia) emphasized the potential of using natural compounds as anti-aging interventions. He presented data on the potential geroprotective function of the carotenoid fucoxanthin against roundworms C.elegans and drosophila D.melanogaster. Fucoxanthin increased the median lifespan of these model organisms, which was accompanied by a number of changes in age-related processes, such as increased resistance to stress. At the molecular level, the reaction of the drosophila organism to fucoxanthin occurs simultaneously with transcriptional changes in aging-associated signaling pathways, including those mediated by MAPK and mTOR, as well as autophagy mechanisms. Preliminary results of experiments on human fibroblasts demonstrate the antisenogenic (preventing physiological aging) effects of fucoxanthin.
Olga Kovalchuk from the University of Lethbridge (Lethbridge, Canada) provided an overview of the skin aging processes triggered by internal and external factors, the impact of which leads to a violation of the regulation of the functions of matrix metalloproteinases, activation of enzymes under the influence of ultraviolet radiation, the development of inflammation and other processes. Matrix metalloproteinases promote the breakdown of collagen with simultaneous inhibition of the formation of new collagen and violation of cytokine regulation, which may be a promising target for new drugs. She listed the effects that ultraviolet and terahertz radiation have on the skin and presented new plant extracts with very powerful anti-inflammatory and anti-aging properties that can be used to neutralize the harmful effects of external factors on the skin and potentially eliminate the manifestations of its aging. The patent application is under consideration.
Alejandro Martín-Montalvo from the CABIMER Andalusian Center for Molecular Biology and Regenerative Medicine (Seville, Spain) discussed the potential of interventions based on the use of thyroid hormones against aging and age-related diseases. The key role of the levels of these hormones in the regulation of longevity is confirmed by the observation that people with exceptional longevity, as well as other long-lived animals, are characterized by low levels of circulating thyroid hormones. Despite this, Martin-Montalvo demonstrated that thyroid hormones enhance glucose excretion, which prompted him to study the possibility of using these hormones in the treatment of various types of diabetes mellitus. In a study on experimental models of diabetes, his group showed that thyroid hormones effectively inhibit the development of the disease and increase the survival rate of mice. The data obtained indicate the potential success of the use of thyroid hormones and/or their mimetics in the treatment of type 1 diabetes mellitus.
Artificial intelligence to facilitate the development of anti-aging drugs
Alexander Pickett, Executive Director for the production of the company Juvenescence (Boston, Massachusetts, USA), engaged in the development of anti-aging drugs, outlined the obstacles standing in the way of the development of anti-aging interventions. Compared to the development of traditional drugs, the development and commercialization of aging-affecting pharmaceuticals causes additional difficulties. The lack of reliable technologies to prove the effectiveness of drugs is one of the main difficulties in planning clinical trials of such interventions. In this regard, Pickett stressed the importance of developing new reliable biomarkers and confirming that they not only predict aging, but also respond to known interventions. Another obstacle will be the commercialization of drugs to interfere with aging, since today health systems are mainly aimed at treating diseases, rather than preserving people's health. The creators of the company Juvenescence believe that the development of anti-aging interventions aimed at treating existing diseases and requesting cost recovery based on the result is the fastest way to provide large populations with access to anti-aging interventions. To address these issues, Juvenescence has invested in several biotech startups working on a range of approaches, including Insilico Medicine.
Ivan Ozerov from Insilico Medicine (Baltimore, Maryland, USA) introduced the approach of an artificial intelligence-controlled computational process in the field of identification of new small molecules that prevent the progression of physiological aging of cells. This approach is based on 5 "R" (Rescue – identify, Remove – highlight, Replace – supplement, Reinforce – strengthen, Repeat – reproduce) and uses the recently published iPANDA method (in silico Pathway Activation Network Decomposition Analysis) – virtual analysis of activation mechanisms and destruction of systems. This process can accelerate the identification of targets and drugs for the development of anti-aging interventions.
Garik Mkrtchyan from the laboratory of Scheibi-Knudsen (University of Copenhagen, Denmark) He further emphasized the power of artificial intelligence to facilitate the development of drugs. An increase in the number of unrecoverable DNA damage is a sign of aging. A promising approach to eliminating this manifestation is the stimulation of DNA damage repair mechanisms. Mkrtchan presented the results of the work devoted to the application of deep learning algorithms in the screening of a library of small molecules for the identification of compounds that stimulate the restoration of DNA damage. The success of this approach is proved by the identification of drugs that induce cell resistance to ionizing radiation, but do not cause DNA damage.
Jay Olshansky from the University of Illinois (Chicago) and co-founder of Lapetus Solutions further emphasized the need to search for biomarkers to facilitate the search and development of anti-aging interventions. He justified the point of view that the target for intervention should not be the duration of life in general, but the duration of a healthy life. Olshansky demonstrated that biological age is reflected in facial features, and emphasized the value of photographic phenotypic biomarkers for assessing health status. Face photos allow you to accurately determine the age and gender of a person, but other risk factors, such as smoking and body mass index, should also be taken into account.
Anastasia Georgievskaya, co-founder of Youth Laboratories (Moscow), further emphasized the importance of facial features analysis as a promising biomarker of aging. The company uses artificial intelligence to study aging and search for a new class of non-invasive photographic biomarkers of aging. Currently, its employees are compiling a collection of photographs of laboratory mice for the development of the first mouse photographic biomarker. Since mice are still the main model for studying aging, the photographic clock of aging mice can facilitate the identification of anti-aging interventions in aging for their subsequent transfer to clinical practice.
Expert discussion on key trends in longevity biotechnology
The expert discussion on the biotechnology industry of longevity was held with the participation of Vadim Gladyshev, Morten Scheibi-Knudsen, Judith Campisi, Alexander Pickett, Mikhail Antonov, Joseph Baur and Stuart Maudsley, Alex Zhavoronkov acted as chairman.
During the discussion, the following areas were selected as the most promising for commercialization: repurposing of drugs already available on the market, senolytics, mTOR inhibitors, activators and modulators of NAD+, reprogramming and regeneration approaches, artificial intelligence and data analysis, as well as digital healthcare.
During the discussion, experts highlighted the great potential of repurposing drugs for research in the field of aging. Repurposing drugs or expanding the range of targets makes it possible to identify new indications for drugs with low risk profiles that have already been tested on humans. Significant progress has been made in the development of approaches to the study of properties and classification of drugs potentially suitable for reprofiling. To date, several attempts have already been made to predict the possibilities of using existing drugs in the fight against aging.
Recently, several senolytics selectively inducing cell death that have entered the phase of physiological aging have been tested as drugs to prevent aging or eliminate its manifestations.
At the same time, experts stressed that such therapeutic approaches are associated with high risks, as they are at the early stages of clinical development. mTOR inhibitors and NAD+ activators were also included in the list of interventions capable of delaying the first manifestation of a variety of age-related pathologies. Therefore, in the near future they can be developed as geroprotectors. One of the experts expressed the opinion that regenerative medicine approaches can provide therapeutic opportunities for influencing aging and can be further developed for subsequent market entry.
Artificial intelligence and deep learning are now considered transformative technologies for healthcare in general. For example, significant progress has been made in identifying biomarkers of human aging using computer learning based on easily obtained data, such as DNA methylation, transcriptomics, proteomics and blood biochemistry. As a result of an exhaustive discussion, experts recognized artificial intelligence and digital healthcare as key developments capable of catalyzing the speed of innovation in the field of aging research. All experts agreed that research in the field of interventions that prevent aging and promote longevity has huge prospects to have an impact on the entire health sector.
Conclusion
It is obvious that anti-aging interventions require a multi-pronged approach that allows us to evaluate complex phenotypes using the latest generation of machine learning methods. At the meeting, it was emphasized that the development of drugs in the field of anti-aging will require efforts not only from academic researchers, but also from many industrial partners and investors. This state of the industry is especially evident in the light of the large number of emerging companies trying to find interventions in the aging process suitable for transfer to clinical practice. The emergence of all these startups inspires confidence that new life-prolonging pharmacological drugs will be found. The future looks very attractive.
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