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Aliper, A.

Publications and source records attributed to Aliper, A..

10 recordsLinked to original sources

The End of Aging Clocks: Training Foundation Models to Reason in Aging and Longevity

The aging clock paradigm has yielded dozens of specialist models that can estimate chronological age or mortality from virtually any biodata type. Yet each such model operates within a fixed modality, relies on a predetermined feature set, and produces limited biological interpretation. Here, we report Longevity-LLM v0.1, a Qwen3-14B model fine-tuned through supervised and reinforcement learning regimes on DNA methylation, proteomics, clinical biomarker, and RNA expression data. Longevity-LLM achieves high ranks in the recently announced Longevity Bench, including such tasks as cancer survival and RNA- or proteome-based age prediction. After reinforcement fine-tuning, the model achieved a 4.34-year MAE in epigenetic age prediction, surpassing the Horvath multi-tissue clock. In addition to age prediction, Longevity-LLM can carry out numerous other tasks, including proteomic profile generation, for which it significantly outperforms all frontier LLMs. These results demonstrate that a single modestly sized LLM can match or replace purpose-built aging clocks across data modalities. This work constitutes an interim report from the initial sprint of our Multi-Modal AI Gym for Science (MMAI), an initiative dedicated to building foundation models for drug discovery and aging research.

bioinformatics↗

Integrating AI and causal genetics to prioritize therapeutic targets for aging and age-related diseases

Aging is increasingly viewed as a pathologic process and a principal driver of diverse age-related diseases (ARDs). Framing aging as a disease offers an opportunity to identify therapeutic targets capable of modifying multiple chronic disorders simultaneously. Here, we developed an AI-driven target discovery framework that integrates large-scale multi-omic datasets to prioritise therapeutic targets shared between aging and 12 ARDs across four major disease areas: neurological, inflammatory, metabolic, and fibrotic disorders. We identified 29 high-confidence and 16 previously unrecognized aging-associated targets implicated across selected disease areas, together with convergent pathway perturbations characterized by robust upregulation of interferon and inflammatory signaling, alongside coordinated downregulation of MYC-driven proliferative programs, consistent with heightened inflammatory activation and reduced anabolic activity during aging. Hallmarks of aging assessment revealed chronic inflammation as the most enriched hallmark across aging and ARDs. Mendelian randomization provided genetic causal support for IL6, IL6R, NLRP3, NOS2, TLR4, and GLP1R in aging-related traits and multiple ARDs, highlighting potential opportunities for drug repurposing. Co-localization analysis further demonstrated a shared genetic signal at the IL6R locus between gene expression levels and parental survival. Together, our findings outline a scalable AI-guided multi-omic framework for identifying causal and repurposable therapeutic targets for aging and ARDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/705676v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@b94af7org.highwire.dtl.DTLVardef@e89e80org.highwire.dtl.DTLVardef@1fde804org.highwire.dtl.DTLVardef@8b817b_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

Longevity Bench: Are SotA LLMs ready for aging research?

Aging is a core biological process observed in most species and tissues, which is studied with a vast array of technologies. We argue that the abilities of AI systems to emulate aging and to accurately interpret biodata in its context are the key criteria to judge an LLMs utility in biomedical research. Here, we present LongevityBench -- a collection of tasks designed to assess whether foundation models grasp the fundamental principles of aging biology and can use low-level biodata to arrive at phenotype-level conclusions. The benchmark covers a variety of prediction targets including human time-to-death, mutations effect on lifespan, and age-dependent omics patterns. It spans all common biodata types used in longevity research: transcriptomes, DNA methylation profiles, proteomes, genomes, clinical blood tests and biometrics, as well as natural language annotations. After ranking state-of-the-art foundation models using LongevityBench, we highlight their weaknesses and outline procedures to maximize their utility in aging research and life sciences.

bioinformatics↗

Advancing Target Discovery Through Disease-Specific Integration of Multi-Modal Target Identification Models and Comprehensive Target Benchmarking System

Target identification is crucial for drug development. AI-driven approaches leveraging multi-omics and computational modeling can accelerate this process. However, integrating multi-modal data for disease-specific target identification and predicting translational potential remains challenging. Moreover, the absence of a systematic evaluation framework for model performance limits confidence in target reliability. We present a unified platform combining machine learning-based target identification with comprehensive benchmarking. As a testbed, we developed Target Identification Pro (TargetPro), a disease-specific model spanning 38 diseases across oncology, metabolic, immune, fibrotic, and neurological categories. TargetPro shows strong predictive performance for clinical-stage targets and reveals disease-specific patterns, underscoring the need for tailored target detection models. We next created Target Identification Benchmark (TargetBench 1.0) to rigorously assess target identification systems, including large language models, based on their ability to recover established targets and find high-quality novel candidates. This integrated approach offers a streamlined strategy to evaluate target discovery models, ultimately improving drug development efficiency.

bioinformatics↗

DORA AI Scientist: Multi-agent Virtual Research Team for Scientific Exploration Discovery and Automated Report Generation

Modern goal-oriented scientific research process involves hierarchical teams of researchers of diverse backgrounds performing generalist and domain-specific tasks. Many of these tasks include hypothesis generation, literature review, data collection, cleanup, processing and analysis, experimental design, virtual and physical experiments, research report and academic paper writing, reference management, bibliography and quality control. Most of these tasks can be performed automatically or in a co-pilot mode by the generative reinforcement learning systems. In this paper, we introduce a versatile multi-agent scientific exploration and draft outline research assistant (DORA), which provides multiple templates and workflows for automated or semi-automated research studies and report generation. Under user guidance, it employs hierarchical teams of AI agents based on the plug-and-play generalist and domain-specific large language models (LLMs) exploiting a variety of specialized research tools and open data repositories and generates high-quality research outputs publication drafts with maximally-accurate references. DORA is designed to minimize the time and effort required for manuscript preparation, thereby enabling researchers to devote more attention to high-value discovery tasks. The system is constantly evolving with user feedback with regular feature and resource updates. The platform is available at https://dora.insilico.com.

bioinformatics↗

AI-Driven Toolset for IPF and Aging Research Associates Lung Fibrosis with Accelerated Aging

Idiopathic pulmonary fibrosis (IPF) is a condition predominantly affecting the elderly and leading to a decline in lung function. Our study investigates the aging-related mechanisms in IPF using artificial intelligence (AI) approaches. We developed a pathway-aware proteomic aging clock using UK Biobank data and applied it alongside a specialized version of Precious3GPT (ipf-P3GPT) to demonstrate an AI-driven mode of IPF research. The aging clock shows great performance in cross-validation (R2=0.84) and its utility is validated in an independent dataset to show that severe cases of COVID-19 are associated with an increased aging rate. Computational analysis using ipf-P3GPT revealed distinct but overlapping molecular signatures between aging and IPF, suggesting that IPF represents a dysregulation rather than mere acceleration of normal aging processes. Our findings establish novel connections between aging biology and IPF pathogenesis while demonstrating the potential of AI-guided approaches in therapeutic development for age-related diseases.

bioinformatics↗

Precious3GPT: Multimodal Multi-Species Multi-Omics Multi-Tissue Transformer for Aging Research and Drug Discovery

We present a multimodal multi-species multi-omics multi-tissue transformer for aging research and drug discovery capable of performing multiple tasks such as age prediction across species, target discovery, tissue, sex, and disease sample classification, drug sensitivity prediction, replication of omics response and prediction of biological and phenotypic response to compound treatment. This model combines textual, tabular, and knowledge graph-derived representations of biological experiments to provide insights into molecular-level biological processes. We demonstrate that P3GPT has developed an intuition for the interactions between compounds, pathologies, and gene regulation in the context of multiple species and tissues. In these areas, it outperforms existing LLMs and we highlight its utility in diverse case studies. P3GPT is a general model that may be used as a target identification tool, aging clock, digital laboratory, and scientific assistant. The model is intended as a community resource available open source as well as via a Discord server.

bioinformatics↗

Testing for batch effect through age predictors

Transcriptome profiling has been shown really useful in the understanding of the aging process. To date, transcriptomic data is the second most abundant omics data type following genomics. To deconvolute the relationship between transcriptomic changes and aging one needs to conduct an analysis on the comprehensive dataset. At the same time, biological aging clocks constructed for clinical use needs to robustly predict new data without any further retraining. In this paper, we develop a transcriptomic deep-learned age predictor. Deep neural networks (DNN) are trained and tested on more than 6 000 blood gene expression samples from 17 datasets. We apply methods based on output derivatives of DNN to rank input genes by their importance in age prediction and reduce the dimensional of the data. We also show that batch effect in transcriptome datasets of healthy humans is indeed significant, but the existing normalization techniques, while removing technical variation quite effectively, also remove age-associated changes. So robust methods of age prediction are needed.

bioinformatics↗

Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/507780_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1ad6feaorg.highwire.dtl.DTLVardef@18e72a9org.highwire.dtl.DTLVardef@109f18aorg.highwire.dtl.DTLVardef@1d0c9b7_HPS_FORMAT_FIGEXP M_FIG C_FIG AbstractThe human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Previous analyses of gut microflora revealed associations between specific microbes and host health and disease status, genotype and diet. Here, we developed a method of predicting biological age of the host based on the microbiological profiles of gut microbiota using a curated dataset of 1,165 healthy individuals (3,663 microbiome samples). Our predictive model, a human microbiome clock, has an architecture of a deep neural network and achieves the accuracy of 3.94 years mean absolute error in cross-validation. The performance of the deep microbiome clock was also evaluated on several additional populations. We further introduce a platform for biological interpretation of individual microbial features used in age models, which relies on permutation feature importance and accumulated local effects. This approach has allowed us to define two lists of 95 intestinal biomarkers of human aging. We further show that this list can be reduced to 39 taxa that convey the most information on their hosts aging. Overall, we show that (a) microbiological profiles can be used to predict human age; and (b) microbial features selected by models are age-related.

bioinformatics↗

Integrated deep learned transcriptomic and structure-based predictor of clinical trials outcomes

Despite many recent advances in systems biology and a marked increase in the availability of high-throughput biological data, the productivity of research and development in the pharmaceutical industry is on the decline. This is primarily due to clinical trial failure rates reaching up to 95% in oncology and other disease areas. We have developed a comprehensive analytical and computational pipeline utilizing deep learning techniques and novel systems biology analytical tools to predict the outcomes of phase I/II clinical trials. The pipeline predicts the side effects of a drug using deep neural networks and estimates drug-induced pathway activation. It then uses the predicted side effect probabilities and pathway activation scores as an input to train a classifier which predicts clinical trial outcomes. This classifier was trained on 577 transcriptomic datasets and has achieved a cross-validated accuracy of 0.83. When compared to a direct gene-based classifier, our multi-stage approach dramatically improves the accuracy of the predictions. The classifier was applied to a set of compounds currently present in the pipelines of several major pharmaceutical companies to highlight potential risks in their portfolios and estimate the fraction of clinical trials that were likely to fail in phase I and II.

bioinformatics↗