Classify an aging body to help an aging population

On November 1, in the journal Science, an appeal was made by scientists, researchers of aging, to the World Health Organization that it was necessary not only to look at aging, but to somehow classify it from a medical point of view. Simply put, they suggest aging to be recognized as a disease, diagnosed at various stages and treated. This is a politically important article, so we completely translated it and publish it. Pay attention to the amazing list of places of work of scientists, it is given at the end.



The article has a pretty good look at the medical aspects of aging. However, the fact that the article contains a significant emphasis on senolithic interventions and it attaches great importance to the role of senescent cells in aging did not escape our attention. It seems to us that this aspect requires extensive discussion. So the article itself:



All over the world, citizens live for long periods, prone to diseases associated with aging and multimorbidity. Given the unmet clinical, medical, labor, and economic needs of an aging population, we need interventions and programs that repair tissues and organs and prevent and eliminate aging-related injuries, illnesses, and senile asthenia (1).



In an attempt to solve these problems, the World Health Organization (WHO) called for comprehensive public health measures within the framework of the international legal framework based on human rights law (1).



However, for conducting clinical trials, it is necessary to diagnose the disease and prescribe treatment; an appropriate disease classification code adopted at the national level in the WHO International Classification of Diseases (ICD) is required.



Such classifications and steps are fundamental to health management and the interaction between government organizations and intergovernmental bodies. We describe a systematic and comprehensive approach to classifying and staging the stages of diseases associated with aging at the level of organs and tissues in order to provide appropriate interventions and clinical management, systems, resources and infrastructure.



Through the ICD, WHO oversees the international approval of classifications and disease stages, which are subsequently adopted by government and regulatory authorities at the national level for use in epidemiological, clinical and managerial contexts.



Information to represent the classification is structured to describe the periods, severity and pathology of the disease, components such as etiology, manifestation, treatment and diagnosis.



Aging of the body, aging of certain tissues and age-related injuries, diseases and decrepitude are currently classified and defined in the framework of the ICD, but in an unsystematic and incomprehensible way, including classification codes for skin aging, geriatrics, age-related cognitive decline (Code R54: Senility) and old age (Code MG2A: Old age) in addition to aging-related diseases such as cancer, cardiovascular disease and dementia.



Under this system, a patient may have a disease classified in one organ that is not classified in another organ, with the possibility of unaccounted for drug exposure in distal organs.



Due to the lack of classifications and stages, a developing pathology may not be recorded and treated. Medicines that prevent or reverse this pathology may not be prescribed to the patient. Current practices include incomplete and inaccurate approaches and the classification of patients as “at risk of disease”, do not include a preliminary classification of diseases and advanced approaches to classify pathologies.



Our goal is to expand and, if necessary, replace these approaches. Arguments that the lack of classification of the stages of organ aging at the moment does not allow the patient to be fully treated can provide legal justification for action. Governments and WHO are required to amend current provisions so that classification systems are systematic and comprehensive.



In our opinion, a systematic and comprehensive classification and determination of the stages of aging and diseases associated with aging at the systemic, organ, tissue and metabolic levels are easily achieved by synthesizing existing knowledge bases (2–10).



Aging of tissues and organs is determined similarly to aging of the body at the level of tissues and organs and includes pathological and pathogenic signs of aging of organs and cell aging, including decreased organ functions, decreased organ volume through cell loss, stem cell dysfunction, telomere shortening associated with cellular aging, secretory phenotype (SASP), inflammation, the burden of nuclear and mitochondrial mutations, protein aggregation, decreased genomic stability, epigenetic dysregulation, aging of the extracellular matrix and end products of glycation, steatosis and polyploidization (2–10).



Aging at the level of tissues and organs, which may include replicative cellular aging, has pathological and pathogenic characteristics (2–10). Although replicative cell aging can have a protective effect on oncogenesis, we argue that replicative cell aging can be pathogenic (2–4, 8, 9), targeting certain tissues and changing the pathological state of aging of tissues and organs can be used in the treatment of concomitant conditions and in any preventive and recovery approaches.



Circulating DNA can be traced back to tissue of origin (11), which may include biomarkers specific to organ and tissue for severity-related diseases and syndromes.



Senescent cell load and secretory factors associated with aging have also been evaluated previously for plasma proteins (9), in addition to human studies, with the removal of senescent cells using senolitics, demonstrating an improvement in overall physical condition (10).



Comparative biology demonstrates that cell and body aging vary depending on the type of cells and species, while some cell lines are biologically immortal, and some organisms are negligible aging, while maintaining their regenerative abilities and resistance to cancer (12, 13).



Potential benefits of such a classification system include:



(i) improving the understanding of the biology and pathology of tissues and organs, including accelerated aging of organs and tissues from progeroid disorders, metabolic diseases and external causes such as chemotherapy and radiotherapy, by improving diagnostic criteria, developing requirements, and conducting new clinical research criteria ;



(ii) developing and searching from existing medicines based on more accurately described diseases and stages, including improving the accuracy and completeness of indications, staging, as well as increasing the availability and completeness of functional end points;



(iii) the development of drugs according to new standards;



(iv) preclinical trial models consistent with the proposed classifications and stages;



(v) clinical trials with stratification and selection of patients associated with indications, multi-indications, multi-stage indications, combined regimens, multimodal therapy, improved endpoints and differential responses;



(vi) a personalized medicine strategy;



(vii) early diagnosis, early prevention and rehabilitation;



(viii) general medical statistics



(ix) medical records and IIAs with decision-making systems;



(x) the potential for intervention in advanced advanced stages and comorbid conditions;



(xi) mitigate age-related risk factors in prescribing and surgery;



(xii) preventive, rehabilitative and rehabilitative approaches and treatment planning;



(xiii) patient outcomes;



(xiv) public health statistics, policies and resources



We propose that classification systems and stages of aging of organs and tissues and related diseases be created as WHO ICD disease codes with corresponding common expansion codes, as they relate to aging, atrophic, pathologically remodeled, calcified and otherwise metabolically dysfunctional tissue.



This should include subclassifications for each subtype of tissue and disease and appropriate expansion codes to determine the stage and severity of near-zero tissue aging, atrophy, pathological remodeling, calcification and metabolic dysfunction.



Codes should be classified according to etiology and pathology, with subclassification of tissues and cells to account for differences in the rates of aging at the level of tissues, organs and organisms; the presence of damage during development and throughout life; and to develop a chronological age-independent structure of the pathology of organs and tissues with associated phenotypes and biomarkers.



A complete set of classifications - ICD-Aging-related (ICD-A) or otherwise ICD-Senescent (ICD-S) - should be used for aging, atrophic, pathologically remodeled, calcified and metabolically dysfunctional tissue for each organ and gland.



As with codes related to cancer classifications, we offer Senescent,

"Senescent Secretory" (Aging-related secretory phenotype), "Atrophic" (Atrophic),

"Calcified" and

“Uncertain whether Senescent or“ Effectively Zero Senescence. ”” (Uncertain whether it is senescent or “Effectively zero cell aging”).



We suggest that the codes of aging, atrophy, pathological remodeling, calcification and metabolic dysfunction with cell-specific subclassification of each organ and tissue, comparable with the ICD-O (oncology) classifications, will work in accordance with existing age-related disease codes, such as dementia, cancer and cardiovascular diseases and other systemic, metabolic and infectious codes to provide a comprehensive and systematic classification of diseases.



Hyperproliferative tissues must be appropriately encoded in such a structure. Any such classifications related to tissue aging that have been developed on an ad hoc basis, such as skin aging, should be formatted and combined with the proposed comprehensive and systematic classification and structure outlined here, including the classification of aging related codes as an etiology code and causality (14) (WHO ICD classification presented by SRGC and BLB is provided in supplementary materials).



The 0-V staging system for aging tissue and the 0-X severity scale for atrophy, remodeling, calcification and metabolic dysfunction associated with aging, in our opinion, is the most suitable, while “0” means almost zero tissue aging and zero pathological atrophy, remodeling, calcification, or metabolic dysfunction.



A staging system for aging tissue comparable to the classification of malignant tumors TNM (TNM) may be useful for the inflammatory and pathological secretory phenotype of aging tissue (SASP).



We propose the development of a classification of aging tissue for determining the sensitivity, secretory phenotype of aging tissue, pathological atrophy, remodeling and calcification (SSeARC).



The rationale for proposing a scale for the severity of stages and the pathogenic system of stages of aging of organs and tissues is based on oncological classifications, in which cells that avoid the pathological phenotype of cell aging become malignant with progressive and distal tissue effects. These cells have both TNM classification and systems with gradations from 0 to IV.



Specific markers are assumed to differ depending on the tissue, organ, and location in the body, as well as on the corresponding scales and severity. The staged system could classify sensitizing tissue by the actual absence of pathology of aging of organs and tissues, as well as by appearance, features and diagnostic criteria.



Stage I may include cells that are close to aging, with minimal pathological change;



stage II may include the presence of senescent cells with minimal pathological effect;



stage III may include the presence of senescent cells and extracellular matrix cross-linking (CNG) with an initial stage of pathology;



stage IV may include the presence of senescent cells and cross-links with the onset of an age-related disease;



Stage V may include signs of organ disease, tissue, and replicative aging, which can be fatal.



Characterization of the pathology of atrophic tissue and pathological remodeling and associated threshold levels may include histopathological and functional studies in combination with data from epidemiological studies and personalized medicine with classification of diseases of tissues and organs, including the corresponding structural, functional and clinical criteria.



We envisage that atrophic, pathological remodeling, calcification, systemic and metabolic dysfunction associated with aging classifications should be classified and organized in a similar way.



Diagnostic criteria may include a series of non-invasive and minimally invasive tests and include functional imaging; biopsy biomarkers; and biomarker panels with histopathology and omix tests as necessary (7, 9, 10, 15).



The classification of pathology, appearance, features and diagnostic criteria will include the similarity between organs and tissues associated with the fundamental processes of tissue aging and damage to organs and tissues and signs specific to organs and tissues.



Clinical biomarkers should be designed to classify tissue aging by quality of classification and stages suitable for clinical practice.



To illustrate the proposed classification and staging system, a 55-year-old European male patient with a general medical examination may have a number of multimorbidity including muscle atrophy III, and stage II muscle aging; IV stage of vascular aging calculated through arterial stiffness, measured by pulse wave velocity; and type III atherosclerosis, diagnosed by magnetic resonance imaging and blood analysis.



Clinical recommendations include the following: recommendations for treatment with one or more senolytic interventions that affect the aging of blood vessels or muscles and atherosclerotic plaque, taking into account the differentiation of the stages of damage characteristic of a particular organ, and the regimen of exercises aimed at slowing down aging and associated muscle atrophy and atherosclerosis, while preventing the progression of all stages of aging.



Sarcopenia should be included in a systematic and integrated manner along with aging, atrophy, remodeling and calcification of each tissue, gland and organ.



We affirm that tissue atrophy and remodeling have pathological effects and these effects can be seen in the pineal gland, heart (cardiac muscle atrophy), as well as involution and remodeling of the thymus.



We propose that a systematic and comprehensive structure encompasses all tissues, organs and glands of all functional scales, including the heart and vascular network, nervous system, glia, pineal gland and blood-brain barrier.



Aging, atrophy, remodeling, and calcification with respect to glands, lymph nodes, and bone marrow should be considered in addition to any relevant blood cell populations associated with immunosensing and tissues that function as barriers or are associated with filtration and microbial load.



Metabolic diseases should be properly classified for clinical trials and treatment, including diseases that accelerate the aging of organs and tissues, as well as for patients with aging tissues and organs, as well as with concomitant pathological and infectious diseases that affect several tissues and bodies combined.



“Threatened by age-related diseases” should be considered for all, without exception, signs related to aging, for the items listed here, as well as for improving treatment approaches for people at risk of disease and predisposed to diseases.



A common scoring system should be developed for each organ and for patients who combine aging of organs and tissues, pathological remodeling, metabolic damage, atrophy and classification of diseases associated with aging, for a combined assessment of damage and aging of the organ and to calculate the general status of the patient .



There are numerous problems that must be overcome for the comprehensive characterization of the disease, including the development of subtypes, stages, molecular mechanisms, and biomarkers.



However, diseases such as tumors have been classified as neoplasms and are defined as benign or malignant, prior to any genetic characterization of them.



Skin aging is already classified in the ICD and is carried out in the absence of a complete understanding of the molecular causes of organ aging. Limitations on the comprehensive molecular characterization of the disease may exist in relation to (i) classifications of diseases associated with molecular metabolism, (ii) severity of disease based solely on molecular mechanisms and biomarkers, and (iii) development of molecular biomarkers in connection with the WHO and ICD classifications and diagnostic criteria.



The United Nations and WHO should support efforts within the framework of the WHO policy on healthy aging. WHO, the International Agency for Research on Cancer (IARC) and other relevant groups should develop such classifications and systems for staging aging of organs and tissues, including the main pathology, appearance, features and diagnostic criteria.



Given the global importance of an aging society, governments and intergovernmental bodies should be involved in developing and supporting appropriate classifications and aligning them with agreed health policies and resources.



Governments should consider submitting such a proposal to the World Health Assembly for ratification in order to repeat the successes of the ICD-I and IARC in terms of organs and tissues.



We argue that a WHO body commensurate with IARC must be created to develop classifications and stages of aging, or else the IARC will be empowered to include organ and tissue aging and related diseases in addition to cancer.



The requirements for changing policies and connecting resources to develop a classification of aging organs and tissues include the same considerations as in the classifications and stages of oncology.



As an analogue of the classifications and staging systems of the WHO ICD, appropriate preclinical models should be developed, including the development of analogues of the WHO ICD classifications and stages for the characterization of disease pathology and drug development specific for the body, organs and tissues.



A comprehensive and systematic classification and staging of aging of organs and tissues through pathological modeling, atrophy, calcification and metabolic changes associated with aging is an urgent and unmet need.



The proposed classification and staging frameworks are intended to be used independently or in combination with existing classification codes in a complementary manner in the diagnosis, prevention and treatment of a disease.



The proposed approach will complement existing codes of diseases and syndromes that are already recognized to improve patient outcomes and increase the effectiveness of general patient care by filling in gaps in international healthcare management.



We invite governments and the World Health Organization to cooperate, as well as members of the scientific and medical community, to contribute to these efforts, including through feedback, consensus development, and the development and use of the proposed classification, formulation and disease criteria.









Translated by Eugene Malyshev.