By Alexey Olovnikov, PhD
[Published with permission of Dr. Olovnikov in search of support for his work and cooperation]
The essence of the chronographic aging theory, the possibility of its verification and consequences
The chronographic theory of aging (Olovnikov A.M. Chronographic theory of development, aging, and origin of cancer: Role of chronomeres and printomeres. Curr Aging Sci. 2015; 8 (1): 76-88) is based on the assumption of a consistent loss by brain’s neurons of their special extra-chromosomal DNA amplificates. They are copies of some regulatory sites of chromosomal DNA. Chromosomal originals of these copies remain virtually intact until the end of the organism’s life. Gradually losing these amplificates from neurons, a body, owing to this process, evaluates the course of endogenous time throughout life. Amplificates in neurons of a brain are designated as chronomeres. Similar amplificates are also present in other, non-neuronal cells, where they are referred to as printomeres. All these amplificates are the double-stranded DNA molecules. They are relatively small perichromosomal copies of their chromosomal originals. The length of chronomeres may be from a few hundred to thousands of nucleotides. Different chronomeres have distinct sequences depending on the specificity of those neurons in which they are located. Each chronomere is aligned “side by side” with its chromosomal original, that is next to it, though extrachromosomally. In other words, each chronomere is represented by an independent separate DNA molecule. Chronomere is fixed on a body of its chromosome like a fish-sticking on shark – in the sense that chronomere uses the chromosome as a physical support. Retention of chronomere on the support is assisted with auxiliary heterochromatin’s proteins. The nucleotide sequence of the chronomere and its chromosomal original (the corresponding regulatory sequence of chromosomal DNA ) are identical. Therefore, chronomere sequences during the routine DNA sequencing remain unnoticed.
Chronomeres and printomeres are involved in maintaince of cellular differentiation, i.e. these perichromosomal organelles participate in the control of cell specificity. But in the brain’s neurons, chronomeres are responsible also for an another specific function: they are part of the life-long clock of a body. In neurons that differ in specificity, chronomeres respectively have distinct DNA sequences. Corresponding neurons, when they sequentially lose their chronomeres, are able to inform the body about its current physiological age: in this manner the neurons do change the properties of innervated body’s targets, i.e. body’s corresponding systems, organs, tissues and cells. That is why the numerous physiological and even anatomical characteristics gradually change in any person over time. Due to the loss of chronomeres by neurons, the body “knows” when, for example, it is the time to implement the puberty, when it is time for menopause or andropause, etc. Chronomere-related lifelong clock, or neuronal chronograph, performs its “ticking” already in the embryo, thus participating in the formation and then in the physiological maturation of the organism. But continuing to “tick” after maturation of his host, chronograph is eventually leading a host to the grave. The smaller the number of chronomeres left in the brain of an old person, the less, ceteris paribus, time is left to live for this human being.
Potential therapeutic uses of chronomeres: In the future, when it will be possible to regenerate chronomeres in an old brain (using as templates their chromosomal originals, which unlike chronomeres do not disappear from neurons), the doctors will be able to literally “twist off the clock back”, i.e. to directly rejuvenate the person. Another alternative is potentially not ruled out also – by slowing the losses of chronomeres it will be possible to get virtually a complete control over the pace of aging. To get such possibilities, it is necessary to perform enough hard work. The first crucial step is to find these amplificates. Only then the search for pharmacological and other means, which allow to control the process of aging, may become possible.
Linear DNA of chronomere has free ends, they are designated as the acromeres, to distinguish them from the telomeres that protect the free ends of the chromosomal DNA. Like telomeres, acromeres should protect its linear chronomeric DNA at its ends from exonucleases. By their nucleotide sequences, acromeres with high probability should have the vertebrate-like telomere repeats. In humans, the acromeres also may have TTAGGG repeats, but the number of such repeates in each acromere are probably much less compared with the long telomeres in the same neurons.
What should be done to identify chronomeres?
One can treat the samples of neuronal nuclear DNA with terminal transferase to add, for example, poly-T to all 3’ ends of DNA. Since the two DNA strands in a linear DNA molecule are antiparallel, the both poly-T tails in any sought-for amplificate (in a chronomere, as well as in a printomere) will be in an inverted orientation in regard to each other. The identification of such structures in the samples of neuronal chromosomes (using all proper controls to exclude occasional DNA breaks) will show the presence and even the locations of the sought-for chronomeres on the surface of chromosomal DNA in neurons.
Next steps – sequencing of identified chronomeres and preparing of catalogues of chronomeres for humans and laboratory animals. Following this, it will be possible to look for ways to regenerate chronomeres – restoring the aged neurons in vitro and then in the aged brains of animals. Also it will be possible to use some viral vectors armed with chronomeric sequences as an alternative way of neuronal rejuvenation.
A proved absence of the predicted perichromosomal amplificates in neurons would be a complete and unconditional refutation of the chronographic theory of aging. On the contrary, detection of chronomeres will be a pivotal event that will open the straight path to a future victory over numerous age-related pathologies and aging itself.
The key predictions of my former theory concerning cell aging, namely telomere theory, were: i) shortening of telomeres in dividing cells, ii) the existence of a special variant of DNA polymerase (a telomerase in current terminology), which should compensate telomere shortening, and iii) the prediction that this enzyme should be found in cancer cells and in sex cells. All these predictions of mine were confirmed – a quarter of a century later after their publication. The founder of Geron Corporation, Dr. M. West, has noted that this Corporation was organized taking into account the ideas of my telomere theory. The material on this subject can be found, for example, on these websites: http://www.michaelwest.org/Telomeres-as-the-Clock-of-Aging-and-Immortalization.htm ; https://web.archive.org/web/20161026194847/http://www.evidencebasedcryonics.org/2008/10/12/biotimes-quest-to-defeat-aging/ “Dr. West became so convinced of Olovnikov’s theory that he formed a company called Geron to investigate it further. As reported by Life Extension Magazine: “Forty million dollars later,” West recalls, “the gamble paid off.” West’s group had in fact produced Olovnikov’s mysterious enzyme…”
The aging of a body, though it is composed of cells, cannot be explained, however, only through the senescence of individual cells. Chronographic theory refers now to the higher levels of regulation, explaining both cellular aging and, more importantly, the organismal aging. It is not difficult to foresee that a new direction suggested by my chronographic theory of aging also will attract in the future the worldwide attention of scientific institutions and companies. Is it necessary to waste again another decades?
Alexey M. Olovnikov,