The RNA-Seq data analysis shows how the ontogenesis defines aging.

This paper presents a global statistical analysis of the RNA-Seq results of the entire Mus musculus genome. We explain aging by a gradual redistribution of limited resources between two major tasks of the organism: its self-sustenance based on the function of the housekeeping gene group (HG) and functional differentiation provided by the integrative gene group (IntG). All known disorders associated with aging are the result of a deficiency in the repair processes provided by the cellular infrastructure. Understanding exactly how this deficiency arises is our primary goal. Analysis of RNA production data of 35,630 genes, from which 5,101 were identified as HG genes, showed that RNA production levels in the HG and IntG genes had statistically significant differences (p-value <0.0001) throughout the entire observation period. In the reproductive period of life, which has the lowest actual mortality risk for Mus musculus, changes in the age dynamics of RNA production occur. The statistically significant dynamics of the decrease of RNA production in the HG group in contrast to the IntG group was determined (p-value = 0.0045). The trend toward significant shift in the HG/IntG ratio occurs after the end of the reproductive period, coinciding with the beginning of the mortality rate increase in Mus musculus indirectly supports our hypothesis. The results demonstrate a different orientation of the impact of ontogenesis regulatory mechanisms on the groups of genes representing cell infrastructures and their organismal functions, making the chosen direction promising for further research and understanding the mechanisms of aging.

Aging is a Side Effect of the Ontogenesis Program of Multicellular Organisms.

The review presents a brief outline of the current state of the main theoretical approaches to the aging problem. The works of authors, supporting the theory of "accumulation of errors" and theories stating the presence of a hypothetical "aging program" in all multicellular organisms are reviewed. The role of apoptosis and its connection with phenoptosis, as well as the theory of "hyperfunction" are analyzed. Our own approach to this problem is presented, in which aging is explained by the redistribution of limited resources between the two main aims of the organism: its self-sufficiency, based on the function of the housekeeping genes (HG) group, and functional specialization, provided by the integrative genes (IntG) group. Agreeing with the inseparable connection between aging and the ontogenesis program, the main role in the aging mechanisms is assigned to the redistribution of resources from the HG self-sufficiency genes to the IntGs necessary for the operation of all specialized functions of the organism as a whole. The growing imbalance between HGs and IntGs with age, suggests that switching of cellular resources in favor of IntGs is a side effect of ontogenesis program implementation and the main reason for aging, inherent in the nature of genome functioning under conditions of highly integrated multicellularity. The hypothesis of functional subdivision of the genome also points to the leading role of slow-dividing and postmitotic cells, as the most sensitive to reduction of repair levels, for triggering and realization of the aging process.

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

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.

From cancer to rejuvenation: incomplete regeneration as the missing link (part II: rejuvenation circle).

In the first part of our study, we substantiated that the embryonic reontogenesis and malignant growth (disintegrating growth) pathways are the same, but occur at different stages of ontogenesis, this mechanism is carried out in opposite directions. Cancer has been shown to be epigenetic-blocked redifferentiation and unfinished somatic embryogenesis. We formulated that only this approach of aging elimination has real prospects for a future that is fraught with cancer, as we will be able to convert this risk into a rejuvenation process through the continuous cycling of cell dedifferentiation-differentiation processes (permanent remorphogenesis). Here, we continue to develop the idea of looped ontogenesis and formulate the concept of the rejuvenation circle.

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

The metazoan genome composes of sets of housekeeping genes (HG) for fundamental cellular autonomous processes and integrative genes (IntG) that provide integrative functions and form the body as an integrated whole. The main paradigm for multicellularity development which has been improved in evolution, is the submission of the cellular autonomy to the interests of the integrated whole. Permanent increase of the "functional tax" of IntG-genome (IntG-shift) and epigenetic restriction of autonomy in phylogenesis/ontogenesis is the essence and root cause of aging, inherent in the very nature of highly integrated multicellularity. The regulation of the balance shift toward HG can be managed to eliminate aging and avoid carcinogenesis, which is only due to the irreversibility of this shift. Here we propose the criterion for measuring the functional and biological age of cells and the body as a whole for assessing the effectiveness of any type of palliative geroprotective or radical anti-aging intervention.