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Article ; Online: Unsupervised learning of aging principles from longitudinal data.

Avchaciov, Konstantin / Antoch, Marina P / Andrianova, Ekaterina L / Tarkhov, Andrei E / Menshikov, Leonid I / Burmistrova, Olga / Gudkov, Andrei V / Fedichev, Peter O

Nature communications

2022 Volume 13, Issue 1, Page(s) 6529

Abstract: Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large ... ...

Abstract	Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements. Assuming that aging results from a dynamic instability of the organism state, we designed a deep artificial neural network, including auto-encoder and auto-regression (AR) components. The AR model tied the dynamics of physiological state with the stochastic evolution of a single variable, the "dynamic frailty indicator" (dFI). In a subset of blood tests from the Mouse Phenome Database, dFI increased exponentially and predicted the remaining lifespan. The observation of the limiting dFI was consistent with the late-life mortality deceleration. dFI changed along with hallmarks of aging, including frailty index, molecular markers of inflammation, senescent cell accumulation, and responded to life-shortening (high-fat diet) and life-extending (rapamycin) treatments.
MeSH term(s)	Mice ; Animals ; Frailty ; Unsupervised Machine Learning ; Aging/physiology ; Longevity ; Neural Networks, Computer
Language	English
Publishing date	2022-11-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-34051-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit

Timothy V. Pyrkov / Konstantin Avchaciov / Andrei E. Tarkhov / Leonid I. Menshikov / Andrei V. Gudkov / Peter O. Fedichev

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 10

Abstract: Aging is associated with an increased risk of chronic diseases and functional decline. Here, the authors investigate the fluctuations of physiological indices along aging trajectories and observed a characteristic decrease in the organism state recovery ... ...

Abstract	Aging is associated with an increased risk of chronic diseases and functional decline. Here, the authors investigate the fluctuations of physiological indices along aging trajectories and observed a characteristic decrease in the organism state recovery rate.
Keywords	Science ; Q
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit.

Pyrkov, Timothy V / Avchaciov, Konstantin / Tarkhov, Andrei E / Menshikov, Leonid I / Gudkov, Andrei V / Fedichev, Peter O

Nature communications

2021 Volume 12, Issue 1, Page(s) 2765

Abstract: We investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics laboratory. To simplify the analysis, we used a log-linear ... ...

Abstract	We investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics laboratory. To simplify the analysis, we used a log-linear mortality estimate from the CBC variables as a single quantitative measure of the aging process, henceforth referred to as dynamic organism state indicator (DOSI). We observed, that the age-dependent population DOSI distribution broadening could be explained by a progressive loss of physiological resilience measured by the DOSI auto-correlation time. Extrapolation of this trend suggested that DOSI recovery time and variance would simultaneously diverge at a critical point of 120 - 150 years of age corresponding to a complete loss of resilience. The observation was immediately confirmed by the independent analysis of correlation properties of intraday physical activity levels fluctuations collected by wearable devices. We conclude that the criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress factors and signifies a fundamental or absolute limit of human lifespan.
MeSH term(s)	Adaptation, Physiological/physiology ; Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Aging/psychology ; Biomarkers/blood ; Blood Cell Count/methods ; Female ; Health Status ; Humans ; Longevity/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Resilience, Psychological ; Young Adult
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-05-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23014-1
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Article ; Online: Cell-Based Methods for the Identification of Myc-Inhibitory Small Molecules.

Burkhart, Catherine A / Haber, Michelle / Norris, Murray D / Gudkov, Andrei V / Nikiforov, Mikhail A

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2318, Page(s) 337–346

Abstract: Oncoproteins encoded by dominant oncogenes have long been considered as targets for chemotherapeutic intervention. However, oncogenic transcription factors have often been dismissed as "undruggable." Members of the Myc family of transcription factors ... ...

Abstract	Oncoproteins encoded by dominant oncogenes have long been considered as targets for chemotherapeutic intervention. However, oncogenic transcription factors have often been dismissed as "undruggable." Members of the Myc family of transcription factors have been identified as promising targets for cancer chemotherapy in multiple publications reporting the requirement of Myc proteins for maintenance of almost every type of tumor. Here, we describe cell-based approaches to identify c-Myc small molecule inhibitors by screening complex libraries of diverse small molecules based on Myc functionality and specificity.
MeSH term(s)	Cell Line, Tumor ; Drug Screening Assays, Antitumor/methods ; Genes, myc/drug effects ; Genes, myc/genetics ; Genes, myc/physiology ; Humans ; Oncogene Proteins/drug effects ; Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-myc/antagonists & inhibitors ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Small Molecule Libraries/pharmacology ; Transcription Factors/drug effects ; Transcription Factors/metabolism
Chemical Substances	Oncogene Proteins ; Proto-Oncogene Proteins c-myc ; Small Molecule Libraries ; Transcription Factors
Language	English
Publishing date	2021-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1476-1_19
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Article ; Online: Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease.

Miller, Ian / Totrov, Max / Korotchkina, Lioubov / Kazyulkin, Denis N / Gudkov, Andrei V / Korolev, Sergey

Nucleic acids research

2021 Volume 49, Issue 19, Page(s) 11350–11366

Abstract: Long interspersed nuclear element-1 (L1) is an autonomous non-LTR retrotransposon comprising ∼20% of the human genome. L1 self-propagation causes genomic instability and is strongly associated with aging, cancer and other diseases. The endonuclease ... ...

Abstract	Long interspersed nuclear element-1 (L1) is an autonomous non-LTR retrotransposon comprising ∼20% of the human genome. L1 self-propagation causes genomic instability and is strongly associated with aging, cancer and other diseases. The endonuclease domain of L1's ORFp2 protein (L1-EN) initiates de novo L1 integration by nicking the consensus sequence 5'-TTTTT/AA-3'. In contrast, related nucleases including structurally conserved apurinic/apyrimidinic endonuclease 1 (APE1) are non-sequence specific. To investigate mechanisms underlying sequence recognition and catalysis by L1-EN, we solved crystal structures of L1-EN complexed with DNA substrates. This showed that conformational properties of the preferred sequence drive L1-EN's sequence-specificity and catalysis. Unlike APE1, L1-EN does not bend the DNA helix, but rather causes 'compression' near the cleavage site. This provides multiple advantages for L1-EN's role in retrotransposition including facilitating use of the nicked poly-T DNA strand as a primer for reverse transcription. We also observed two alternative conformations of the scissile bond phosphate, which allowed us to model distinct conformations for a nucleophilic attack and a transition state that are likely applicable to the entire family of nucleases. This work adds to our mechanistic understanding of L1-EN and related nucleases and should facilitate development of L1-EN inhibitors as potential anticancer and antiaging therapeutics.
MeSH term(s)	Base Sequence ; Binding Sites ; Cloning, Molecular ; Crystallography, X-Ray ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Cleavage ; DNA-(Apurinic or Apyrimidinic Site) Lyase/chemistry ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Deoxyribonuclease I/chemistry ; Deoxyribonuclease I/genetics ; Deoxyribonuclease I/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Genome, Human ; Genomic Instability ; Humans ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Substrate Specificity ; Thermodynamics
Chemical Substances	Recombinant Proteins ; DNA (9007-49-2) ; Deoxyribonuclease I (EC 3.1.21.1) ; LINE-1 endonuclease, human (EC 3.1.21.1) ; APEX1 protein, human (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18)
Language	English
Publishing date	2021-09-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkab826
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Article ; Online: p53 and the Carcinogenicity of Chronic Inflammation.

Gudkov, Andrei V / Komarova, Elena A

Cold Spring Harbor perspectives in medicine

2016 Volume 6, Issue 11

Abstract: Chronic inflammation is a major cancer predisposition factor. Constitutive activation of the inflammation-driving NF-κB pathway commonly observed in cancer or developed in normal tissues because of persistent infections or endogenous tissue irritating ... ...

Abstract	Chronic inflammation is a major cancer predisposition factor. Constitutive activation of the inflammation-driving NF-κB pathway commonly observed in cancer or developed in normal tissues because of persistent infections or endogenous tissue irritating factors, including products of secretion by senescent cells accumulating with age, markedly represses p53 functions. In its turn, p53 acts as a suppressor of inflammation helping to keep it within safe limits. The antagonistic relationship between p53 and NF-κB is controlled by multiple mechanisms and reflects cardinal differences in organismal responses to intrinsic and extrinsic cell stresses driven by these two transcription factors, respectively. This provides an opportunity for developing drugs to treat diseases associated with inappropriate activity of either p53 or NF-κB through targeting the opposing pathway. Several drug candidates of this kind are currently in clinical testing. These include anticancer small molecules capable of simultaneous suppression of p53 and activation of NF-κB and NF-κB-activating biologics that counteract p53-mediated pathologies associated with systemic genotoxic stresses such as acute radiation syndrome and side effects of cancer treatment.
MeSH term(s)	Cellular Senescence ; DNA Damage ; Genetic Predisposition to Disease ; Humans ; Inflammation/complications ; Inflammation/genetics ; NF-kappa B/metabolism ; Neoplasms/etiology ; Neoplasms/genetics ; Neoplasms/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	NF-kappa B ; Tumor Suppressor Protein p53
Language	English
Publishing date	2016-11-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a026161
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Article ; Online: Unsupervised learning of aging principles from longitudinal data

Konstantin Avchaciov / Marina P. Antoch / Ekaterina L. Andrianova / Andrei E. Tarkhov / Leonid I. Menshikov / Olga Burmistrova / Andrei V. Gudkov / Peter O. Fedichev

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 14

Abstract: Biomarkers of age and frailty may aid in understanding the aging process, predicting lifespan or health span and in assessing the effects of anti-aging interventions. Here, the authors show that combining physics-based models and deep learning may ... ...

Abstract	Biomarkers of age and frailty may aid in understanding the aging process, predicting lifespan or health span and in assessing the effects of anti-aging interventions. Here, the authors show that combining physics-based models and deep learning may enhance understanding of aging from big biomedical data, observe effects of anti-aging interventions in laboratory animals, and discover signatures of longevity.
Keywords	Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A Prototype Method for the Detection and Recognition of Pigments in the Environment Based on Optical Property Simulation.

Pishchalnikov, Roman Y / Chesalin, Denis D / Kurkov, Vasiliy A / Shkirina, Uliana A / Laptinskaya, Polina K / Novikov, Vasiliy S / Kuznetsov, Sergey M / Razjivin, Andrei P / Moskovskiy, Maksim N / Dorokhov, Alexey S / Izmailov, Andrey Yu / Gudkov, Sergey V

Plants (Basel, Switzerland)

2023 Volume 12, Issue 24

Abstract: The possibility of pigment detection and recognition in different environments such as solvents or proteins is a challenging, and at the same time demanding, task. It may be needed in very different situations: from the nondestructive in situ ... ...

Abstract	The possibility of pigment detection and recognition in different environments such as solvents or proteins is a challenging, and at the same time demanding, task. It may be needed in very different situations: from the nondestructive in situ identification of pigments in paintings to the early detection of fungal infection in major agro-industrial crops and products. So, we propose a prototype method, the key feature of which is a procedure analyzing the lineshape of a spectrum. The shape of the absorption spectrum corresponding to this transition strongly depends on the immediate environment of a pigment and can serve as a marker to detect the presence of a particular pigment molecule in a sample. Considering carotenoids as an object of study, we demonstrate that the combined operation of the differential evolution algorithm and semiclassical quantum modeling of the optical response based on a generalized spectral density (the number of vibronic modes is arbitrary) allows us to distinguish quantum models of the pigment for different solvents. Moreover, it is determined that to predict the optical properties of monomeric pigments in protein, it is necessary to create a database containing, for each pigment, in addition to the absorption spectra measured in a predefined set of solvents, the parameters of the quantum model found using differential evolution.
Language	English
Publishing date	2023-12-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704341-1
ISSN	2223-7747
ISSN	2223-7747
DOI	10.3390/plants12244178
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Article ; Online: Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans.

Cancer research communications

2023 Volume 3, Issue 11, Page(s) 2256–2267

Abstract: Long interspersed nuclear element-1 (LINE-1 or L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues by the mechanisms involving p53 but is frequently derepressed in ... ...

Abstract	Long interspersed nuclear element-1 (LINE-1 or L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues by the mechanisms involving p53 but is frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. In this study, we established an immunoassay to detect circulating autoantibodies against L1 proteins in human blood. Using this assay in >2,800 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers than in healthy individuals. Remarkably, elevated levels of anti-ORF1p-reactive IgG were observed in patients with cancer with disease stages 1 and 2, indicating that the immune response to L1 antigens can occur in the early phases of carcinogenesis. We concluded that the antibody response against L1 antigens could contribute to the diagnosis and determination of immunoreactivity of tumors among cancer types that frequently escape early detection. Significance: The discovery of autoantibodies against antigens encoded by L1 retrotransposons in patients with five poorly curable cancer types has potential implications for the detection of an ongoing carcinogenic process and tumor immunoreactivity.
MeSH term(s)	Humans ; Retroelements ; Long Interspersed Nucleotide Elements/genetics ; Neoplasms/genetics ; Autoantibodies/genetics ; Immunoglobulin G/genetics
Chemical Substances	Retroelements ; Autoantibodies ; Immunoglobulin G
Language	English
Publishing date	2023-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-23-0289
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Article ; Online: A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications.

Mett, Vadim / Kurnasov, Oleg V / Bespalov, Ivan A / Molodtsov, Ivan / Brackett, Craig M / Burdelya, Lyudmila G / Purmal, Andrei A / Gleiberman, Anatoli S / Toshkov, Ilia A / Burkhart, Catherine A / Kogan, Yakov N / Andrianova, Ekaterina L / Gudkov, Andrei V / Osterman, Andrei L

Communications biology

2021 Volume 4, Issue 1, Page(s) 466

Abstract: The Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid ... ...

Abstract	The Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid neutralizing immune response, presumably due to immune memory from prior exposure to flagellated enterobacteria. To enable multi-dose applications, we used structure-guided reengineering to develop a next-generation, substantially deimmunized entolimod variant, GP532. GP532 induces TLR5-dependent NF-κB activation like entolimod but is smaller and has mutations eliminating an inflammasome-activating domain and key B- and T-cell epitopes. GP532 is resistant to human entolimod-neutralizing antibodies and shows reduced de novo immunogenicity. GP532 also has improved bioavailability, a stronger effect on key cytokine biomarkers, and a longer-lasting effect on NF-κB. Like entolimod, GP532 demonstrated potent prophylactic and therapeutic efficacy in mouse models of radiation-induced death and tissue damage. These results establish GP532 as an optimized TLR5 agonist suitable for multi-dose therapies and for patients with high titers of preexisting flagellin-neutralizing antibodies.
MeSH term(s)	Cell Line, Tumor ; HEK293 Cells ; Humans ; Peptides/pharmacology ; Signal Transduction ; Toll-Like Receptor 5/agonists
Chemical Substances	CBLB502 ; Peptides ; TLR5 protein, human ; Toll-Like Receptor 5
Language	English
Publishing date	2021-04-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-01978-6
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