Strategy

Research Roadmap
for Increasing Human Longevity

Research areas

Feb 3, 2020
Updated on May 30, 2022
1
The goals of this roadmap
The major goal is to define the search for ways to stop and reverse human biological aging. Thus, the roadmap’s goal is to increase the scale of scientific research in the field.

Our document is ready for implementation in grant policies, and public and private funding programs. It can become the basis of mega-collaborations, like the human genome project.

By solving the fundamental problems outlined in this roadmap, we can expect a cumulative increase in human life expectancy and healthspan. The roadmap shows the areas in research to be funded and lays out the complex task of defeating aging into several clear local goals.

Since biological aging is a complex phenomenon, our document discusses the widest possible range of fundamental research and applied developments in the field of aging and rejuvenation of the body, aimed at studying:

  • Molecular mechanisms of aging and rejuvenation;

  • Aging of individual tissues, organs, and body systems, and the search for mechanisms for their rejuvenation;

  • Population studies on aging and rejuvenation;

  • Systemic approach: databases and mathematical models;

  • Prevention of age-related diseases, which are the main causes of human death;

  • Instrumental and technological methods of rejuvenation and preservation of life;

  • The formation of clinical practice in the fight against aging;
2
Molecular mechanisms of aging and rejuvenation
The molecular mechanisms of aging are a series of biological processes that lead to age-dependent accumulation of dysfunctions of cells, tissues, and organs. Their blocking potentialy leads to a slowdown in aging and to cell rejuvenation. In particular, the molecular mechanisms of aging include:

  • Destabilization of the genome of cells;

  • Reduction of chromosome telomeres (end sections of chromosomes);

  • The emergence of aging-associated epigenetic modifications of chromatin;
  • Violations of proteostasis;

  • Mitochondrial dysfunction;

  • An increase in the number of senescent (decrepit) cells;

  • Loss of cell sensitivity to nutrients;

  • Stem cell depletion;

  • Aging of the extracellular matrix, the occurrence of protein cross-links, and impaired intercellular signaling;

The Roadmap offers research of the aging mechanisms and the development of drugs that block the molecular mechanisms of aging and promote rejuvenation of the body.
2.1.1
Cell genome destabilization
Fundamental research in this area includes studies of:

  • The mechanisms of age-dependent changes of reparation system, defects in nucleus architecture (laminopathy), amplification of transposon mutagenesis, the effects of somatic mutagenesis on cells;

  • High-capacity methods for assessing the intensity of somatic mutagenesis and the identification of cells with damaged genomes;

  • The influence of environmental factors on destabilization of the genome of the cells;

  • Identifying molecular mechanisms of increased stability of the genome in long-lived species, including naked mole rat, Brandt's bats, blue whales and other animals;

  • The therapeutic methods of selective activation of individual reparation pathways, for example, induction of repair by homologous recombination;

  • Methods for removing repair scars, expressed in the activation of repair systems in the absence of DNA damage;

Clinical research in this area includes:

  • The development of gene-therapy approaches to the treatment of diseases caused by genome destabilization and malfunction of repair systems, in particular, progeria, which is exemplified in Werner's Syndrome, Bloom's Syndrome, xeroderma pigmentosum, trichothiodystrophy, Cockayne Syndrome and Seckel Syndrome;

  • Clinical trials of gene therapy of cancer and also therapies, which perform preventive removal of cells with mutations in oncogenes;

  • The development of approaches to therapy for age-dependent destabilization of the genome, in particular, the inducible increase in the activity of DNA repair systems and the development of approaches that prevent the accumulation of DNA damage in vivo and in vitro, which arise from the divisions of cells;

  • The development of molecules of radioprotectors and antimutagenic agents;
Expected Outcome:
Understanding the contribution of mutagenesis and specific mutations to the aging process and creating tools for leveling dangerous mutations. Non-toxic drugs that activate repair processes and eliminate cells with dangerous genome damage.
2.1.2
Reduction of chromosome telomeres
(end section of chromosomes)
Fundamental and clinical research:

  • Identifying the real contribution of telomere reduction to human aging;

  • Ways of reactivating telomerase activity in cells of various tissues and organs;

  • A comparative study of the terminal sections of chromosomes in individuals of various species and phenotypes, and identifying the causes of accelerated telomere contraction;

  • The role of telomeres in the formation of pathologies and diseases;

  • The identification of diseases caused by telomere reduction;

  • The study of the clinical consequences of telomerase gene therapy in humans;

Possible approaches to the treatment of telomere reduction: Pharmacological and gene therapeutic methods for reactivating telomerase in vivo, transplanting cells with elongated or more protected telomeric sites.
Expected Outcome:
Telomerase reactivation therapy in dividing cells to the level of telomere length that does not affect the aging process.
2.1.3
The onset of aging-associated epigenetic
chromatin modifications
Fundamental and clinical research of:

  • The dynamics of the DNA epigenetic modifications occurrence and histones in different types of cells and tissues at different ages, and in normal and pathological conditions;

  • The relationship between these modifications and the functional state of cells, tissues and organs;

  • Identification of pathological epigenetic patterns and pathways associated with the restoration of the chromatin epigenetic state associated with youth and health in general;

  • The role of sirtuins and other histone-modifying enzymes in longevity;
  • The influence of factors, affecting the change in DNA methylation, chromatin architecture, synthesis of non-coding RNA and changes in transcription patterns for longevity;

  • The age-related dynamics of transcriptome changes in different tissues and organs;

  • The transcriptome profile stabilization;

  • The epigenetic hours of aging, in particular, at the level of different organs, taking into account the population characteristics of a person. The study of epigenetic cell reprogramming factors;

  • Clinical studies of the role of epigenetic modifications of chromatin in the formation of pathologies and age-related diseases, study of the contribution of epigenetic factors to oncogenesis;

  • The development of epigenetic therapies for aging;
Expected Outcome:
Understanding the contribution of epigenetics to the overall aging phenotype, targeted therapies correcting epigenetic alterations.
2.1.4
Proteostasis disorder
Fundamental research in this area includes studies of/understanding of:

  • The dynamics of changes in the cells' proteome in various tissues during aging and in the case of age-related pathologies;

  • The relationship of proteomic changes with the functional state of cells, tissues, and organs;

  • The role of proteotoxicity factors in aging, including heat shock, endoplasmic stress and oxidative stress;

  • The pathways of regulation and activation of autophagy, proteasomal degradation, chaperone-mediated protection and protein refolding;

  • The role of protein aggregates in aging, as well as the pathways of induced degradation of aggregated proteins;

  • The role of activation of stress tolerance factors, including FOXO transcription factors, on proteostasis and life expectancy;

  • The search for the pharmacological inducers of autophagy and proteasomal degradation of damaged proteins;

  • The state of the proteome in patients with various age-related diseases;
Expected Outcome:
Proteome stabilization and stress resilience therapy.
2.1.5
Mitochondrial dysfunction
Research in this area includes studies of:

  • Age-dependent disorders that occur in mitochondria in cells of different types and of different tissues;

  • The role of free radicals and antioxidant systems in maintaining cell homeostasis, cell damage and cell aging;

  • Relationship between stress, reactive oxygen species and cell proliferation;

  • Mitochondrial dysfunctions, that are not associated with free radicals, in particular:
——— The destabilization of the mitochondrial genome,
——— The disturbance of the relationship between mitochondria and other
cell organelles;
——— Mitochondrial-induced inflammation;
——— Permeabilization of the mitochondrial membrane during stress;
——— Impaired mitochondrial bioenergetics;
——— Mitochondrial division disorders;
——— Mitochondrial dysregulation and calcium signaling — induced apoptosis;

  • The balance of fusion and fragmentation of mitochondria in various physiological conditions, the role of mitofusin proteins;

  • The search for ways to rejuvenate mitochondria, leading to an increase in life expectancy, specifically with regards to the activation of mitophagy, mitohormesis, the separation of the processes of oxidative phosphorylation in mitochondria;

  • The development of gene therapy for mitochondria, in particular, aimed at stimulating mitochondriogenesis through activation of the PGC-1 gene;

  • Approaches to mitochondrial rejuvenation, ex vivo growth of mitochondria, delivery of mitochondria to cells and mitochondrial transplantation;

  • The contribution of mitochondria to the formation of pathologies and age-related diseases;
Expected Outcome:
A therapy that renews mitochondria and restores their functions.
2.1.6
An increase in the number of senescent cells
Fundamental research in this area includes studies of:

  • The mechanisms of senescent cells formation, for example, cell cycle arrest, genome damage, activation of tumor suppressor genes INK4a and p53, and tissue regeneration after wounds;

  • The search for new markers of senescence and previous states of senescence;

  • The contribution of senescent cells and proteins, secreted by them, to the pathologies formation;

  • Characterization of senescence associated secretory phenotype in different tissue;

  • The relationship between senescence, oncogenesis and impaired immune function;

  • Tissue and organ specificity of senescence;

  • The search for ways to destroy senescent cells with senolytic therapies;

  • The development of therapeutic agents that return stem and differentiated cells from senescence to normal state;

  • Clinical studies of the role of senolytic therapies in preventing pathologies and increasing life expectancy, identifying diseases and pathologies caused by senescent cells, studying gene therapy methods of cleansing the body of senescent cells and rejuvenating senescent cells;
Expected Outcome:
A therapy that allows targeted and tissue-specific destruction or rejuvenation of senescent cells.
2.1.7
Loss of cell sensitivity to nutrients
Fundamental research in this area includes studies of:

  • The role of catabolic and anabolic signaling in aging and longevity;

  • Age-related dynamics of the activity of the somatotropic axis, growth hormone, insulin-like growth factor, insulin, and intracellular processes in response to these hormones in different tissues in humans of different ages and with different physiological states;

  • The disturbances in molecular pathways recognition of nutrients as a factor in the aging of the inductor and age-related diseases;

  • The mechanisms of the increase in life expectancy and healthy life expectancy by limiting nutrients in mammals;

  • The contribution of intracellular factors involved in the recognition of nutrients, e.g., mTOR, AMPK and NAD+, as targets for potential therapies of ageing and age-related diseases;

  • Clinical studies of therapies that suppress the way insulin-like growth factor and insulin signaling, in particular, the study of rapamycin and metformin to prevent age-related pathologies and to prolong life;

  • Clinical trials of various diets, including the Mediterranean diet and diets that mimic fasting, and study of the effect of fasting on changes in biomarkers of aging and the incidence of age-related diseases;

  • The role of fast carbs on the probability of development of pathologies of aging and the way to compensate for the insulin emission in response to the consumption of fast carbs;

  • People with congenital disorders of the systems sensitivity to nutrients, as well as patients with type II diabetes;
Expected Outcome:
Implementation of new approaches to normalization of the nutrient sensitivity and control cell growth, including methods of gene therapy.
2.1.8
Stem Cell depletion
Research in this area includes studies of:

  • Stem cells (SC) phenotypic description of various tissues and organs;

  • The mechanisms of self-maintenance of the pool of SC, keeping them at rest;

  • Interaction of SC and their niches;

  • The structure of stem cell niches in different tissues, as well as features age-addicted changes SC niches of various tissues, the creation of artificial niches of stem cells;

  • Factors, affecting age-dependent depletion in the number of SC, for example, the death of SC, the arrest of cell cycle of SC, the transition of SC into a state of senescence, care SC in differentiation;

  • The phenomenon of accumulation of SC with the simultaneous loss of their ability to differentiate;

  • The influence of known molecular pathways of aging on the functioning of the SC, in particular, mutagenesis, epigenetic modifications, inflammation and loss of sensitivity to nutrients;

  • Ways of rejuvenating of SC, in particular, their return from the senescent state to pluripotent state, gene-blocking specific pathways of aging SC in vivo and ex vivo;

  • To examine ways of stem cells ex vivo without loss of pluripotency and possibilities of differentiation in the characteristic cell population;

  • The potential of cryopreservation and autologous biobanking of SC;

  • The mechanisms of tissue and organs from induced pluripotent SC;

  • The therapeutic effects of injecting different types of stem cells, including autologous mesenchymal stem cells, hematopoietic stem cells, muscle stem cells;

  • The development of clinical practice on the use of SC for regenerative medicine. Introduction the practice of using induced pluripotent stem cells into clinical practice, creation of collections of cellular samples homozygous for HLA antigens;
Expected Outcome:
Implementation of new approaches to maintain the quantitative and qualitative composition of stem cells in all tissues of the human body.
2.1.9
Aging of the extracellular matrix, protein crosslinks and mpaired intercellular signaling
  • The influence of age-related changes of the extracellular substance to the functioning of cells and tissues, as well as the appearance of abnormalities and age-dependent diseases;

  • The role of matrix in the intercellular signaling;

  • Age-dependent changes and exogenous vesicular transport in various tissues;

  • The development of new therapeutic agents to be delivered in the vesicles and actsoma;

  • The ways therapeutic removal of glycated and damaged proteins of extracellular matrix, including collagens, elastin, aggrecan and crystallin;

  • The development of small therapeutic molecules with specific activity for the cleavage of certain types of cross-linking of matrix proteins and / or deletion of protein matrix containing cross-linking;

  • The mechanisms of intravenous activation the synthesis of new protein matrix and removal of damaged proteins;

  • The role of hyaluronic acid in longevity of the organism and protection against tumour growth;

  • The role of matrix in the formation of stem cell niches;

  • Molecular pathways of the effects of acute and chronic inflammation on cellular function and structure matrix of various tissues;

  • The molecular mechanisms of fibrosis, finding ways to regenerate tissues without the occurrence of fibrous formations, the search of therapeutic treatment of fibrotic formations on the functional fabric of the appropriate authority;

  • The molecular pathways of age-related loss of blood vessels, epidermis and other tissues elasticity;

  • Biomarkers for assessing age-related damage of the extracellular matrix and to identify risks of age-related pathologies, depending on these risks;

  • Clinical trials of diets with a low content of AGEs on biomarkers of biological age and indicators of health;

  • The impact of beauty therapy on the likelihood of age-related pathologies, the development of new approaches to skin rejuvenation;

  • Clinical trials of pharmacological inhibitors of hyaluronidase, matrix metalloproteinase, and pharmacological molecules decomposing crosslinking of matrix proteins, for example, alagebrium, to prevent the occurrence of age-dependent pathologies and evaluation of biomarkers of aging;
Expected Outcome:
Therapies restoring the functions of the extracellular substance and its long-lived proteins.
2.2

Prioritization of research in aging biology

To select a research model, determine the importance of potential results, and increase the value of projects, a list of recommendations has been compiled below:

2.2.1. In the case of studying the mechanisms of aging on cell lines, it is recommended to include additional experiments to verify the existence of the detected mechanisms in model animals.

2.2.2. In the case of the use of model animals, priority is given to studies of interventions that can increase the life expectancy of animals.

2.2.3. Studies on mammalian models are considered more relevant than studies on animals of other classes.

2.2.4. Priority is given to studies of interventions, that are aimed at increasing adults and old animals life expectancy.

2.2.5. In the case of the development of genetically mutant animal lines which are models of age-dependent pathologies and diseases, it is recommended to use inducible promoters that allow mutations' manifestation at a chosen age and in the selected range of tissues and organs.

2.2.6. When developing clinical approaches for treatment of certain age-dependent pathologies, it is recommended to conduct studies both on the lines of mice or rats, which are genetic models of this pathology, and on old animals in which this pathology appears with age.
3
Aging of individual tissues, organs, and body systems and the search for mechanisms for their rejuvenation
There are known aging paths specific for particular tissues and organs in the human body. They lead not only to pathology of the tissues themselves, organs and the corresponding organ systems, but also to the body as a whole. The objective of this Road Map is to support research of the aging mechanisms of various organs and tissues, of ways to prevent age-related diseases of separate organs and to prevent specific age-dependent disorders by blocking aging mechanisms, specific for particular organs or tissues.

Ultimately, the goal of all the interventions studied should be therapy development for these tissues and organs regeneration, rejuvenation, and mortality reduction of their pathologies. We need to find tools to counteract aging and maintain the functioning of the brain and nervous system as a whole, as well as other regulatory systems (endocrine and immune ones), as well as peripheral systems: respiratory, cardiovascular, digestive, genitourinary, musculoskeletal, sensory and integumentary ones. A separate area of research is the study of the effect of microbiome on the aging of the body.
3.1
The brain and the nervous system
  • Classification and study of the mechanisms by which age-dependent disorders occur in different types of cells and intercellular substances of the brain (disorders, which lead to deterioration of cognitive functions and the development of neurodegenerative diseases);

  • The study of interventions leading to long-term enhancement of cognitive function in adults and the prevention of its deterioration with aging;

  • The study of molecular mechanisms (specific to aging) role in the formation of age-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis;

  • Development of new neuroprotection methods for nervous system damaged by immune cells, particularly within hemorrhagic and ischemic stroke;

  • The study of risk prevention and treatment mechanisms of age-related brain diseases, including stroke and neurodegenerative dementia, applying the knowledge of molecular mechanisms of brain tissues aging;

  • The study of amyloids and prions in the brain; specifically, their nature, and methods for their removal;

  • The study of new means of targeted delivery of medicinal agents, including, if necessary, overcome of the blood-brain barrier; for example, nanoparticles, gene-structures and microvesicles;

  • The study of specific features of neuron function pertaining to the long lifetime of these cells;

  • The study of the neurogenesis decrease mechanisms, destruction of the chains of nerve contacts, and microfibrillar coil accumulation associated with aging;

  • To study the role of microglia in the functioning and aging of neurons;

  • The exploration of new possibilities of stitching torn neurons, including within peripheral nervous system;

  • The study of neuronal death causes, which lead to brain mass (such as hippocampus and hemispheres cortex) decrease associated with aging;

  • Development of tools for the creation and implantation of new neurons and the branching of the dendritic processes of the system to compensate for damaged neural pathways, including long neurons which innervate distant parts of the body;

  • The association of memory formation process with neuron epigenetic rejuvenation;

  • The study of regulation of neuron progenitors proliferation and identification of the role of proliferating cells in brain during aging;

  • Study of mechanisms of synaptic plasticity processes induction of and the investigation of therapeutic activators of synaptogenesis;

  • Exploring new approaches to the preservation of the integrity of brain white matter and dendritic interconnections;

  • Confirmation of the role of known molecular mechanisms of aging regarding nervous tissue, and the search for new aging mechanisms specific to the nervous system;
Expected Outcome:
Implementation of new approaches to prevent age-related degradation of neuro-architectural, biochemical and epigenetic properties of brain neurons. Therapies against specific age-related degenerative manifestations of the nervous system.
Brain research related to Cryobiology: the study of methods of freezing the brain for subsequent storage in very low temperatures and minimize the destruction of brain cells, as well as maximizing the likelihood of connectome structure and cells viability preservation during the defrosting process.

Research of the brain specifically associated with psychological function and theory of information:

  • Identify intraneuronal factors, factors of intercellular contacts, factors operating at the level of brain areas, connectome and architecture of neural networks forming the personality and identity of a person, in particular, its ability to sense of self, the experiencing of the feelings, imagination, use of language and symbolic structures, creative capacities and abilities to solve complex problems;

  • The decoding of information obtained by fixing the activity of neurons, for example, functional magnetic resonance imaging and encephalography;

  • Study of the formation of pathways and direct broadband transmission of data from nervous system to computer and from computer to brain;

  • Studies on the establishment of modern neural interfaces and wearable gadgets that can read the activity of individual regions of the cortex of the brain down to individual neurons;

  • Research on simulation of brain activity of a person depending on the set parameters of three-dimensional structure of neurons on the basis of data obtained by scanning of the brain;

  • The creation of thought systems based on neurobiological combining capacity of thinking of the nervous systems of individual people;
Expected Outcome:
Building the basis for the digitization of consciousness and principles for the restoration of a cryopreserved brain.
3.2
The endocrine system
  • Age dynamics of various endocrine glands functioning and their age-related disorders' development mechanisms: these glands include thymus, adrenal glands, thyroid and parathyroid glands, islets of Langerhans, neuro-glands of epiphysis and the hypothalamic-pituitary system;

  • The study of hormones functions in maintenance of homeostasis and the reasons for the changes in the concentration of secreted hormones with aging, in particular, melatonin, growth hormone, sex hormones;

  • Study of therapeutic ways to restore cells sensitivity to hormones; particularly insulin resistance therapy;

  • Study of the relationship between neuroendocrine system condition and hormonal homeostasis in age-related changes to psychological condition, in particular the study of the mechanisms of occurrence of senile depression associated with aging reduction in cognitive abilities, falls, physical activity and health;

  • Study of the effect of hormone replacement therapy on life expectancy and health status of the body;

  • Study of therapeutic approaches to the restoration of the functions of endocrine glands; in particular, the blocking chronic inflammation hypothalamic-pituitary, blocking aging-induced calcification of the pineal gland;

  • The role of systemic regulatory factors in the aging process, particularly in stress response and mechanisms for maintaining circadian rhythms;

  • The effect of stress on the occurrence of age-related pathologies, assessment of the level of stress of organism and functioning cells of various tissues and organs with hyperactivity of the hypothalamus-pituitary-adrenal axis;

  • The relationship between stress and carcinogenesis;

  • Identification of the role of circadian rhythms imbalance in aging and the formation of age-related pathologies;

  • Studying the system of regulatory mechanisms of aging using a model of uneven-aged parabiosis, and the identification of factors that stimulate aging or cause rejuvenation;

  • The study of regenerative mechanisms that occur during sleep;

  • Develop aging therapies based on the identified systemic regulatory factors;
Expected Outcome:
Endocrine gland rejuvenation therapies and targeted hormone receptor synthesis stimulators. Implementation of new approaches of systemic exposure to rejuvenation factors.
3.3
Immune system
  • The study of the causes of reduced resistance to viral and bacterial infections with age;

  • The study of the contribution of aging to the development of autoimmune diseases and the search for therapies to restore immune system function;

  • Studies of aging of the Central organs of the immune system (bone marrow and thymus), as well as aging of the spleen, lymph nodes, and certain types of immune cells, delocalized throughout the body;

  • The study of the mechanisms of aging of hematopoietic stem cells, their elimination and age-related dysfunction; in particular, reducing the share of production of lymphoid cells, reduction of B-cells and naive T-cells;

  • The study of the influence of aging on the migration ability of hematopoietic stem cells and their reinitiation of hematopoiesis;

  • The study of the causes of monoclonal hematopoiesis in the elderly;

  • Search of rejuvenation therapies of hematopoietic stem cells, studying the mechanisms of cultivation of hematopoietic stem cells in vitro without loss of stem properties and administration of autologous stem cells without the use of chemotherapeutic preconditioning;

  • The study of the thymus involution causes and the search for therapies aimed at reinitiation of Timorese and the increase in the proportion of cortex and medulla of thymus;

  • The development of therapies that increase the efficiency of cellular and humoral immunity in the elderly;

  • The study of the influence of aging on the immune system's ability to inhibit growth of tumor cells and the search for therapies that restore antitumor protection;

  • The study of age-dependent regulation of inflammatory processes, and the search for therapies that prevent chronic inflammation of various organs and tissues;

  • The study of inflammatory cytokines and proinflammatory proteins (like C-reactive protein and tumor necrosis factors) as biomarkers of human health and elements of cellular mechanisms that regulate cytokine production stability;
Expected Outcome:
Tools for restoring the antipathogenic and regulatory potential of the immune system. Therapies that block chronic inflammation and the pathologies caused by it.
3.4
Human peripheral systems
  • A wide range of studies aimed at studying specific features of aging of the respiratory, cardiovascular, digestive, genitourinary, musculoskeletal, sensory and integumentary systems. Research directions should help create therapies to the specific pathology of individual organs and tissues of different systems, caused by aging, in particular;

  • For the respiratory system associated with aging atrophy of the lungs, idiopathic pulmonary fibrosis, dystrophy of the upper respiratory tract and a decrease in alveolar surface;

  • Cardiovascular system: ageing-related remodeling of the heart and blood vessels, in particular, atrophy of the heart muscle, calcification and profibrotic changes, loss of elasticity, development of atherosclerotic processes, prothrombotic changes in the blood, raising blood pressure;

  • For the digestive system: associated with aging nutritional and metabolic diseases, degeneration of the gastrointestinal tract, fatty changes in the liver, chronic passive congestion of the liver;

  • For the genitourinary system associated with the aging hypertensive kidney disease, renal degeneration and atrophy, progressive hyperactivity of the bladder, decreased sexual desire, erectile dysfunction, prostatic hyperplasia and hypothyroidism testicles in men, menopause and related metabolic disorders in women;

  • For the musculoskeletal system associated with aging fragility, reduced bone mass, osteoporosis, rheumatoid arthritis, osteomalacia, mitochondrial myopathy, muscle weakness;

  • For sensor systems: ageing-related degeneration of eyes macular degeneration and posterior pole, reducing the size of the pupil, the rear compartment of the vitreous, reducing the quality and quantity of production of rheum, degeneration of the ear and mastoid process disorders of the vestibular system, alleviation of the sense of smell;

  • For the integumentary system associated with aging degeneration and atrophy of the skin, loss of skin elasticity, loss of hair on the male type, graying;
Expected Outcome:
Preventive therapies aimed at specific pathways of aging of individual peripheral organs.
3.5
Human microbiome
  • The study of species diversity of symbiotic bacteria of man and the age characteristics of their changes;

  • Studies of the mechanisms of interaction microbicides bacteria and cells of the body;

  • The study of signaling molecules produced by the microbiome of the gut and the study of their contribution to the induction processes of chronic inflammation, obesity, and the occurrence of age-related pathologies;

  • Study of the microbiome of centenarians;

  • Study of the effect of different diets on the change microbiota composition of the intestine;

  • Development of methods of changing the composition of the intestinal microbiota and colonization in the intestine of new strains of symbio-bacteria;

  • Study of the effect of probiotic supplements on health characteristics and to check their potential geroprotective properties;

  • Creation of model systems that are genetically modified symbiotic organisms would regulate the lifetime of a host organism, highlighting geroprotective and regulatory substances, in particular, in response to a change in the physiological state of a host organism;

  • The study of the contribution of the microbiome to the development of age-related diseases, including atherosclerosis, autoimmune and neurodegenerative diseases, and study the possibility of changing the composition of the microbiota as a therapeutic effect;

  • The development of approaches for using bacteria as delivery vehicles of therapeutic molecules, including for the treatment of genetic structures and interfering RNA;
Expected Outcome:
Identification of microbiome factors affecting longevity. Microbiome management tools.
4
Population studies of aging and rejuvenation
  • The analysis of the dynamics of mortality from age-related causes in different countries and populations;

  • Studies identifying population longevity factors, including environmental and genetic factors;

  • Study of development of various age-related diseases with particular lifestyles, including diet, activity, kind of work;

  • A comparative study of the impact of therapies of various age-related diseases in representatives of different populations;

  • Study on genetic characteristics of centenarians;

  • The study of factors that increase the lifespan of different populations;

  • Observational study of influence of biologically active additives and pharmacological drugs to the incidence of age-related diseases and mortality, as well as changes in biomarkers;
Expected Outcome:
Identification of population factors of longevity. Identification of significantly inhibiting aging elements of lifestyle, environmental conditions and diet.
5
Systemic approach: databases and mathematical models
These are pathological processes, simultaneously affecting many parts of the body and leading to the appearance of signs of aging as well as the cumulative interaction of these processes, leading to exponential rates of accumulation of errors and mortality during aging. The study of systemic mechanisms of rejuvenation uses knowledge about the system mechanisms of aging and is aimed at the simultaneous suppression of many of the individual mechanisms of aging.

The application of this approach requires a significant increase in the knowledge base about the course of biological processes in general and the development of new bioinformatics and automated approaches to analysis and modeling of biological processes. Through the creation of systematic approaches to rejuvenation, the roadmap supports projects in the following areas:
5.1
Databases
Creation of biological and pharmaceutical databases and atlases. Systematized data can be based on "omics" biology and contain collections of genomes, transcriptomes, proteomes, metabolomes of various tissues and organs of people depending on age, health status, lifestyle, history of diseases and characteristics of human biomarkers.

Projects can be focused on the systematization of data on the course of intracellular processes, in particular, on protein-protein interactions, on the composition of small molecules in the cell cytoplasm, on the lipid composition of mitochondrial membranes, on post-transcriptional modifications and intercellular processes, in particular on the characteristics of signaling molecules cells of various tissues.

Projects can be aimed at creating cell atlases that reflect differences in the number and functional states of different cell types, assessed, in particular, by surface membrane markers or characteristics of intracellular components, in normal and pathological conditions. Projects can focus on creating databases and computer programs to systematize knowledge about the changes in the content of components of various tissues, such as blood, under various physiological conditions and diseases, which in turn should lead to the creation and improvement of panels of biomarkers.

Important areas of research are the creation and systematization of blood biomarkers and data from "omics" biology obtained as a result of human exposure to various pharmaceutical agents; as well as the creation of databases of known genes, small molecules or proteins of various tissues and cells involved in aging and longevity.

Expected Outcome:
Development of a sufficient number of databases and the accumulation of sufficient volume of data for predictive conclusions and insights regarding aging biology.
5.2
Analysis and modeling of biomedical processes
  • Building of interaction networks based on omics and big biomedical data. Analysis of organisms aging as the dynamics of a complex network system;

  • Development of computer algorithms that extract and analyze biological data from scientific articles, clinical trials and databases;

  • Development of software for the prediction of the protein structure, amino acid sequences and structures of the ligands interacting with the receptors;

  • Development of bioinformatics tools for the analysis and optimization of "omics" data, in particular, transcription profiles, proteomes or metabolomes to facilitate the use of this information in studies, formulation of clinical recommendations and creation of new therapeutic approaches;

  • Simulation modeling for prediction of therapeutic molecules (including DNA-based and RNA-based therapeutic molecules) properties;

  • Building of aging models with the use of network theory and statistical physics to determine aging biomarkers and targets that can change the character of the aging process;

  • Simulation modeling for development of targeted therapy, including drug delivery based on viruses and exosomes in various organs, tissues, and interactions with different types of cells and receptors;

  • Solving medical problems, in particular machine learning algorithms for the analysis of x-ray images and CT scans, histological sections, and neurophysiological characteristics;

  • Methods for visualization of medical parameters of a patient, and the formulation of individual recommendations. In particular, the development of a screening system and analysis of biomarkers and of individual data, such as medical history, used drugs, genetic characteristics and lifestyle;

  • Probability determination of various age-related diseases. Creation of biological aging clocks, depending on the dynamics of biomarkers change and the available data on genetic and physiological characteristics of an individual;

  • Meta-analyses and systematic reviews on clinical and biological studies of molecular mechanisms of aging and the study of the characteristics of aging of individual tissues, organs and body systems and the search for mechanisms of rejuvenation;
Expected Outcome:
Comprehensive characterization of the aging process, allowing us to identify key targets and select the most effective therapies against them.
6
Prevention of age-related diseases—the main causes of human death
The Roadmap supports the development and implementation of new approaches to preventive therapy and treatment of age-related diseases, which are based on knowledge of the molecular mechanisms of aging and characteristics of aging of individual tissues, organs and systems of the body. Such therapeutic approaches in the case study in the preclinical stage should be based on the recommendations described in claim, which will reveal the effectiveness of therapy for a disease that has formed against the background of aging processes, and the geroprotective potential of therapy to increase the body's lifespan and block aging pathways.

As part of a program to increase human life expectancy, it is proposed to conduct clinical trials of geroprotectors and pharmacological agents that block aging pathways and activate the path of rejuvenation of the body, as therapies for certain age-related diseases, as well as preventive therapies for people at high risk of developing age-related diseases.

The Roadmap supports research on the identification of early markers that characterize the onset of age-related diseases, as well as the identification of early symptoms, the disappearance of which suggests the success of early therapy.

It is proposed to support studies of pharmacological substances approved as drugs in order to expand the spectrum of their use as geroprotective drugs that block the pathway of human aging.

Since aging is a complex process with various mechanisms, the Roadmap defines as an absolute priority the development of integrated therapies that include active substances that can block various aging pathways.

Expected Outcome:
Preventive therapies based on the analysis of aging biomarkers and preventing the formation of age-dependent pathologies due to targeted suppression of aging mechanisms.
7
Technological methods of rejuvenation and preservation of life
Roadmap proposes to maintain the technical research and development of instruments and devices that have full or partial replacement of biological functions of the organism in case of pathologies, as well as expanding and enhancing the ability of both patients and healthy people. Such research and development include, in particular:

  • Creation of artificial organs such as heart, kidney, liver, etc., miniaturization and improvement of existing devices, replacement organs, up to the size that allows the device to be placed inside the patient's body without discomfort in connection with the use of the device;

  • Developing wearable gadgets to track various biomarkers and characteristics of the human body, in particular the contents of various metabolites and hormones in blood, a change in the activity of the eye muscles and other physiological parameters;

  • Development of wearable devices, allowing carrying out pharmacological and physiological effects on the human body, including, depending on its current status;

  • Creation of a new generation of bioreactors for culturing stem cells without losing stem properties and the directional differentiation of cells, tissue and organs, including those requiring vascularization for transplant purposes;

  • Creation of devices for accelerated regeneration of wounds, injuries and burns received by the person, using advances in molecular and cell biology;

  • Creation of devices that support the viability of the human brain in case of damage of the peripheral systems;

  • Development and creation of devices for non-damaging cryopreservation and thawing of large biological objects which are treated as separate organs, such as the brain and whole organisms;
Expected Outcome:
Devices and gadgets capable of duplicating the functions of human organs.
8
The formation of the anti-aging clinical practice
It is proposed to support the design and development of a methodological base, standards and protocols aimed at introducing therapeutic approaches to anti-aging as an independent clinical practice. In this regard, the Roadmap, in particular, supports medical and legal developments:

  • Regulations allowing clinical trials in people of different ages to prevent the development of the aging phenotype and related age-related diseases;

  • Validation procedures for biomarkers of aging, which would reflect a change in life expectancy of a person and the likelihood of developing age-dependent diseases, and which could be used as intermediate points of results in conducting clinical trials of aging therapies;

The development of programs, computer and mobile applications is supported:

  • Allowing to automate the processes routinely performed by medical workers during clinical trials;

  • Increasing the efficiency of obtaining data during experiments and clinical trials;

  • Helping users follow medical advice, increasing motivation and compliance with clinical advice;

  • Helping users to systematize data received from gadgets and wearable sensors, to become a participant in experiments and research;

  • The development of methodological recommendations and standards for the provision of preventive care for representatives of the medical community is supported on the basis of well-known data on the effects of geroprotectors, the effects of diets and lifestyle on the course of aging processes;
Expected Outcome:
Creation of conditions for accelerating and reducing the cost of clinical trials of aging therapies. Preparation of therapies for implementation into clinical practice.
Our roadmap already systematizes all the main directions in the fight against aging (although we plan to clarify the content as much as possible). But the main goal of this document is to implement at least existing content as a common work plan for the scientific community and to initiate mega-projects in the field.
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