Aging Fits the Disease Criteria of the International Classification of Diseases.

The disease criteria used by the World Health Organization (WHO) were applied to human biological aging in order to assess whether aging can be classified as a disease. These criteria were developed for the 11th revision of the International Classification of Diseases (ICD) and included disease diagnostics, mechanisms, course and outcomes, known interventions, and linkage to genetic and environmental factors. RESULTS: Biological aging can be diagnosed with frailty indices, functional, blood-based biomarkers. A number of major causal mechanisms of human aging involved in various organs have been described, such as inflammation, replicative cellular senescence, immune senescence, proteostasis failures, mitochondrial dysfunctions, fibrotic propensity, hormonal aging, body composition changes, etc. We identified a number of clinically proven interventions, as well as genetic and environmental factors of aging. Therefore, aging fits the ICD-11 criteria and can be considered a disease. Our proposal was submitted to the ICD-11 Joint Task force, and this led to the inclusion of the extension code for "Ageing-related" (XT9T) into the "Causality" section of the ICD-11. This might lead to greater focus on biological aging in global health policy and might provide for more opportunities for the new therapy developers.

Blood Biochemistry Analysis to Detect Smoking Status and Quantify Accelerated Aging in Smokers.

There is an association between smoking and cancer, cardiovascular disease and all-cause mortality. However, currently, there are no affordable and informative tests for assessing the effects of smoking on the rate of biological aging. In this study we demonstrate for the first time that smoking status can be predicted using blood biochemistry and cell count results andthe recent advances in artificial intelligence (AI). By employing age-prediction models developed using supervised deep learning techniques, we found that smokers exhibited higher aging rates than nonsmokers, regardless of their cholesterol ratios and fasting glucose levels. We further used those models to quantify the acceleration of biological aging due to tobacco use. Female smokers were predicted to be twice as old as their chronological age compared to nonsmokers, whereas male smokers were predicted to be one and a half times as old as their chronological age compared to nonsmokers. Our findings suggest that deep learning analysis of routine blood tests could complement or even replace the current error-prone method of self-reporting of smoking status and could be expanded to assess the effect of other lifestyle and environmental factors on aging.

The effects of donor age on organ transplants: A review and implications for aging research.

Despite the considerable amount of data available on the effect of donor age upon the outcomes of organ transplantation, these still represent an underutilized resource in aging research. In this review, we have compiled relevant studies that analyze the effect of donor age in graft and patient survival following liver, kidney, pancreas, heart, lung and cornea transplantation, with the aim of deriving insights into possible differential aging rates between the different organs. Overall, older donor age is associated with worse outcomes for all the organs studied. Nonetheless, the donor age from which the negative effects upon graft or patient survival starts to be significant varies between organs. In kidney transplantation, this age is within the third decade of life while the data for heart transplantation suggest a significant effect starting from donors over age 40. This threshold was less defined in liver transplantation where it ranges between 30 and 50 years. The results for the pancreas are also suggestive of a detrimental effect starting at a donor age of around 40, although these are mainly derived from simultaneous pancreas-kidney transplantation data. In lung transplantation, a clear effect was only seen for donors over 65, with negative effects of donor age upon transplantation outcomes likely beginning after age 50. Corneal transplants appear to be less affected by donor age as the majority of studies were unable to find any effect of donor age during the first few years posttransplantation. Overall, patterns of the effect of donor age in patient and graft survival were observed for several organ types and placed in the context of knowledge on aging.

Machine Learning on Human Muscle Transcriptomic Data for Biomarker Discovery and Tissue-Specific Drug Target Identification.

For the past several decades, research in understanding the molecular basis of human muscle aging has progressed significantly. However, the development of accessible tissue-specific biomarkers of human muscle aging that may be measured to evaluate the effectiveness of therapeutic interventions is still a major challenge. Here we present a method for tracking age-related changes of human skeletal muscle. We analyzed publicly available gene expression profiles of young and old tissue from healthy donors. Differential gene expression and pathway analysis were performed to compare signatures of young and old muscle tissue and to preprocess the resulting data for a set of machine learning algorithms. Our study confirms the established mechanisms of human skeletal muscle aging, including dysregulation of cytosolic Ca2+ homeostasis, PPAR signaling and neurotransmitter recycling along with IGFR and PI3K-Akt-mTOR signaling. Applying several supervised machine learning techniques, including neural networks, we built a panel of tissue-specific biomarkers of aging. Our predictive model achieved 0.91 Pearson correlation with respect to the actual age values of the muscle tissue samples, and a mean absolute error of 6.19 years on the test set. The performance of models was also evaluated on gene expression samples of the skeletal muscles from the Gene expression Genotype-Tissue Expression (GTEx) project. The best model achieved the accuracy of 0.80 with respect to the actual age bin prediction on the external validation set. Furthermore, we demonstrated that aging biomarkers can be used to identify new molecular targets for tissue-specific anti-aging therapies.

Population Specific Biomarkers of Human Aging: A Big Data Study Using South Korean, Canadian, and Eastern European Patient Populations.

Accurate and physiologically meaningful biomarkers for human aging are key to assessing antiaging therapies. Given ethnic differences in health, diet, lifestyle, behavior, environmental exposures, and even average rate of biological aging, it stands to reason that aging clocks trained on datasets obtained from specific ethnic populations are more likely to account for these potential confounding factors, resulting in an enhanced capacity to predict chronological age and quantify biological age. Here, we present a deep learning-based hematological aging clock modeled using the large combined dataset of Canadian, South Korean, and Eastern European population blood samples that show increased predictive accuracy in individual populations compared to population specific hematologic aging clocks. The performance of models was also evaluated on publicly available samples of the American population from the National Health and Nutrition Examination Survey (NHANES). In addition, we explored the association between age predicted by both population specific and combined hematological clocks and all-cause mortality. Overall, this study suggests (a) the population specificity of aging patterns and (b) hematologic clocks predicts all-cause mortality. The proposed models were added to the freely-available Aging.AI system expanding the range of tools for analysis of human aging.

Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization.

While many efforts have been made to pave the way toward human space colonization, little consideration has been given to the methods of protecting spacefarers against harsh cosmic and local radioactive environments and the high costs associated with protection from the deleterious physiological effects of exposure to high-Linear energy transfer (high-LET) radiation. Herein, we lay the foundations of a roadmap toward enhancing human radioresistance for the purposes of deep space colonization and exploration. We outline future research directions toward the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, and methods of slowing metabolic activity while preserving cognitive function. We conclude by presenting the known associations between radioresistance and longevity, and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well.

Towards natural mimetics of metformin and rapamycin.

Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.