A brief assessment of the current state of the use of Hallmarks of aging is given in the article. It is noted that the biological clock based on registration of DNA methylation process is only a statistical indicator and has no direct connection to the known mechanisms of aging, reflecting only the fact of genome regulation during ontogenesis. In other words, the process of genome methylation is not the leading program, but rather it fixes the result of the main program of ontogenesis. The same problems are inherent to aging markers based on registration of changes in RNA synthesis levels in different genes. In our opinion, the Hallmarks of aging should primarily be connected with or directly reflect the most fundamental bases and processes which are universal for any organisms. When analyzing the data on Hallmarks of aging, the greatest attention is paid to the late stages of ontogenesis. We believe that the main period of development is the stage of ontogenesis intended for physical growth and reaching sexual maturity. This is the period when the ontogenetic regulatory network of the organism stops its growth by the time it reaches reproductive period, triggering the cascade of processes leading to aging. The article briefly describes and shows the perspectives for using the “infrastructural hypothesis” for understanding the role of ontogenesis program in aging processes. From our point of view, the indicators we use in our “infrastructural” hypothesis are not only biologically justified but also prospective as Hallmarks of aging.
This paper presents a brief review of the main Hallmarks of aging we have today and the results obtained using them. To this day, the methods of measuring biological age have been well developed. A number of “biological clocks” indicating individual biological age have been created. Although we can see the arrows indicating age on such clocks, the mechanism that drives them is still hidden from us. The main question is still the connection of Hallmarks of aging with the mechanisms of aging and ontogenesis. The main question for gerontology - what is the cause of aging - is still a mystery, making it difficult to assess the Hallmarks of aging used in this phenomenon.
Currently, two main types of biomarkers are used to study aging and assess age. These are epigenetic markers, represented by the expression of gene methylation and various coordinated gene production clusters. Their parameters correlate well with age both in experimental animals and humans . Consideration of the main Hallmarks of aging is useful as a unifying perspective, but how useful it is as an explanatory paradigm remains a question. The importance of Hallmarks of aging for understanding the underlying causes of aging in the way that a scientific paradigm or unifying theory should do remains a question .
DNA methylation, which affects chromatin state and gene expression, is one of the most studied genomic regulatory processes today [3,4]. The peculiarities of the regulatory function of methylation continue to be studied, but there is no doubt about the connection of this process with ontogenetic development and aging [5,6]. The works linking methylation to biological age in Mammalia are the most widespread in this direction [7-10]. The undoubted connection between methylation and aging processes provides an opportunity for experimental verification of various approaches to this problem. Data on the correlation between the methylation profile and biological age are also widely used as an efficiency criterion in works aimed at rejuvenation of organismal cells . When assessing the large number of works devoted to genome methylation, the main conclusion is that this process is multidirectional.
Epigenetic regulation relates both to the genes themselves and the histone proteins that regulate their accessibility; its level behaves differently in different genes - it increases in some genes and decreases in others. Data on genome methylation can show biological age accurately enough, but as a statistical indicator it has no direct connection to the known mechanisms of aging, reflecting only the fact of genome regulation during ontogenesis. Here we should note the work in which the authors make an attempt to link
the methylation level with thermodynamic processes reflecting
the fundamental basis of the organism’s functioning .
In one of our works  we analyzed the appearance of
coordinated variance changes with age, indirectly indicating
an external influence on methylation indices, possibly related
to the action of the ontogenesis program. We can conclude
that many modern studies devoted to the analysis of genome
methylation have never provided a clear answer to the question
of the functional role of the methylation process itself [14-17].
It is possible that the process of genome methylation does not
programs, but rather fixes the result of the ontogenesis program.
The works on age-related changes in the transcriptome analyzed
the changes that occur with RNA production during life. A gradual
decrease in production during life was found, accompanied by
multidirectional changes in RNA production levels in individual
gene groups [18-20].
Summarizing the currently available data on age-associated
reduction in gene expression, it can be argued that it contributes
to a progressive decline in cellular functions. Understanding
the mechanisms governing transcriptome aging is essential
for determining the underlying aging mechanisms [21-30].
Simultaneous changes in methylation and RNA production
reflect the work of the ontogenesis program, associated with
differentiation and development of cell functions in the organism.
Here again we see more multidirectional changes, but not
aging per se. As already mentioned, the connection between
the processes of aging and ontogenesis is obvious, but two
approaches should be distinguished here. Many authors proceed
from the assumption that aging, as well as organism development,
is controlled by the ontogenesis program. In our opinion, the
presence of a separate program aimed at the development of
organism aging is not evolutionarily reasonable and has not been
experimentally confirmed. We take a different approach, from the
point of view of which ontogenesis is the program for successful
reaching maturity, and aging is a reasonable, from the species’
point of view, side effect [31,32].
There are two stages in the ontogenetic program. The first
stage during embryogenesis involves the sequential inclusion of
genes necessary for cell differentiation and organism formation.
The second stage beginning in the postnatal period is for physical
growth and reaching sexual maturity. It is during this period that
the ontogenetic regulatory network of the organism stops its
growth by the time it reaches reproductive period, triggering the
cascade of processes leading to aging. It is necessary to distinguish
the main cause of aging and the mechanisms that trigger it. For
this purpose, we use the “infrastructural hypothesis” that we
have outlined in previous works [33,34]. We explain aging by the
gradual redistribution of a limited amount of resources between
two main tasks of the organism: its self-sustenance based on
the function of the housekeeping gene (HG) group, the atlas of
which is presented in the work of the authors group  and the
functional differentiation provided by the integrative gene group
(IntG) that constitutes most of the remaining genes.
We argue that an insufficient level of repair is the main cause
of aging. Understanding exactly how this deficiency arises is our
main goal. Our confirmation of the differences in RNA production
in the studied functional groups of the genome suggests that
there is a global mechanism of ontogenesis that affects the
activity of these groups and, most importantly, their correlation.
As was shown in our recent work , the implementation of
the ontogenesis program naturally leads to an imbalance of
activity between HG and IntG groups. In turn, such imbalance
leads to insufficient provision of cellular functions with their
infrastructure represented in the genome by the HG functional
group and, as a result, to aging of the organism. This indicates
that the positive ontogenetic regulation in the beginning is aimed
at ensuring development and reproduction, and provided by
the increased level of HG production subsequently disappears,
inevitably leading to aging. Thus, the main conclusion of this work
is the fact of asymmetric effect of ontogenetic regulators on the
cellular infrastructure represented by the HG functional group in
the genome. Determining the specific regulatory factors of this
event is the main goal of our future work.
When studying aging, most researchers focus on age-related
changes occurring in the organism at a later age. During this period
various studied parameters reach their maximum differences
from their normal values. Research focusing on changes occurring
in the second half of ontogenesis are limited to the consequences
of aging processes, ignoring their causes. Besides this, the data
on aging trait dynamics in experimental animals at a later age
have one more disadvantage. The animals participating in these
experiments are sort of long-livers, with certain genetic features
allowing them to reach the age limit for the species. Thus, the
experimental groups have their own natural selection, which
significantly changes the overall picture of the obtained results. In
our opinion, this fact should not only be taken into account in the
experimental work, but it should be studied separately.
To conclude, it should be noted once again that Hallmarks of
aging indicators should primarily be connected with or directly
reflect the most fundamental bases and processes, universal for
any organisms. From our point of view the indicators we use in our
“infrastructural” hypothesis are not only biologically grounded
but also prospective signs of aging from the point of view of their