The Ratio of the Genome Two Functional Parts Activity as the Prime Cause of Aging

Salnikov, Lev; Baramiya, Mamuka G.

doi:10.3389/fragi.2020.608076

Cited by 10 publications

(12 citation statements)

References 16 publications

(20 reference statements)

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“…We share the viewpoint that in the case of a multicultural organism, aging is always accompanied by a decrease in the resources required by its cells for repair and tissue regeneration [15,16,17, 18]. The reasons for such a decrease in resources are well explained in our theoretical model of the functional division of the metazoan genome [19,20]. We argue that the genome of all cells of the organism contains two functionally independent parts.…”

Section: Introductionmentioning

confidence: 78%

DNA methylation meta-analysis confirms the division of the genome into two functional groups

Salnikov¹,

Goldberg

Sukumaran

et al. 2022

Preprint

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Based on a meta-analysis of human genome methylation data, we tested a theoretical model in which aging is explained by the redistribution of limited resources in cells between two main tasks of the organism: its self-sustenance based on the function of the housekeeping gene group (HG) and functional differentiation, provided by the (IntG) integrative gene group. A meta-analysis of methylation of 100 genes, 50 in the HG group and 50 in IntG, showed significant differences ( p<0.0001) between our groups in the level of absolute methylation values of genes bodies and its promoters. We showed a reliable decrease of absolute methylation values in IntG with rising age in contrast to HG, where this level remained constant. The one-sided decrease in methylation in the IntG group is indirectly confirmed by the dispersion data analysis, which also decreased in the genes of this group. The imbalance between HG and IntG in methylation levels suggests that this IntG-shift is a side effect of the ontogenesis grownup program and the main cause of aging. The theoretical model of functional genome division also suggests the leading role of slow dividing and post mitotic cells in triggering and implementing the aging process.

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Section: Introductionmentioning

confidence: 78%

DNA methylation meta-analysis confirms the division of the genome into two functional groups

Salnikov¹,

Goldberg

Sukumaran

et al. 2022

Preprint

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“…There is reason to believe that Homo sapiens have not yet reached the pinnacle of evolution. Therefore, completing here our series of publications (Baramiya, 1988;Baramiya, 2000;Baramiya, 2018;Salnikov and Baramiya, 2020) on the theoretical substantiation of a new section of developmental biology, we propose to call it Developmental Biogerontology. financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.…”

Section: Discussionmentioning

confidence: 97%

“…In other words, the phenomenon of genes pleiotropy can always be described by the transition from symbiotic relations at the beginning of development, to parasitic ones at the end. It is this transition that occurs in multicellular organisms when their organismic organization passes from the necessary symbiotic relationships to parasitic ones ( Salnikov and Baramiya, 2020 ). The resources required for improved integrative/organismal functions are taken away from the core autonomous functions of cells, represented by the THG portion of the genome.…”

Section: Ontogenesis and Its “Cost”mentioning

confidence: 99%

“…As a result, there is a preserved but epigenetically blocked pathway for continuous and full quantitative and qualitative self-renewal of tissues, organs and functions. In other words, we have paid for reach the top of the current stage of development with inevitable involution, aging, aging associated diseases and mortality ( Salnikov and Baramiya, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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From Autonomy to Integration, From Integration to Dynamically Balanced Integrated Co-existence: Non-aging as the Third Stage of Development

Salnikov¹,

Baramiya

2021

Front. Aging

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Reversible senescence at the cellular level emerged together with tissue specialization in Metazoans. However, this reversibility (ability to permanently rejuvenate) through recapitulation of early stages of development, was originally a part of ontogenesis, since the pressure of integrativeness was not dominant. The complication of specialization in phylogenesis narrowed this “freedom of maneuver”, gradually “truncating” remorphogenesis to local epimorphosis and further up to the complete disappearance of remorphogenesis from the ontogenesis repertoire. This evolutionary trend transformed cellular senescence into organismal aging and any recapitulation of autonomy into carcinogenesis. The crown of specialization, Homo sapiens, completed this post-unicellular stage of development, while in the genome all the potential for the next stage of development, which can be called the stage of balanced coexistence of autonomous and integrative dominants within a single whole. Here, completing the substantiation of the new section of developmental biology, we propose to call it Developmental Biogerontology.

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“…The aging process is affected by a number of interconnected genetic, epigenetic, metabolic, and environmental factors; however, their exact degree of contribution is unclear as there is no universally accepted theory of aging (Salnikov and Baramiya, 2020) within which their contribution can be put into context. Several molecular mechanisms such as telomere shortening and cellular senescence, defective autophagy, and DNA damage have been shown to play a critical role in driving aging and related diseases (López-Otín et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing

2021

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Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).

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The Ratio of the Genome Two Functional Parts Activity as the Prime Cause of Aging

Cited by 10 publications

References 16 publications

DNA methylation meta-analysis confirms the division of the genome into two functional groups

DNA methylation meta-analysis confirms the division of the genome into two functional groups

From Autonomy to Integration, From Integration to Dynamically Balanced Integrated Co-existence: Non-aging as the Third Stage of Development

Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing

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