Towards Harnessing Growth to Create Rejuvenation

A recent pair of open access papers offer an interesting viewpoint on embryonic development, aging, cancer, and possible approaches to rejuvenation in this era of biotechnology. I'm not sure that I agree with more than half of it, but it does make for a good read, even given that the language is somewhat obtuse in places. Tissue growth is the unifying process, wherein: (a) embryonic development is the epitome of regulated, successful, beneficial growth; (b) aging suppresses and damages the shackled processes of growth that are turned to tissue maintenance; (c) cancer is unfettered and uncontrolled growth; and (d) the research community might achieve rejuvenation by finding a way to harness the vigor of cancer and embryonic development in a controlled way. This is of course an ambitious goal, we most likely stand a long way from it, and there are forms of molecular damage, such as accumulation of metabolic waste in long-lived cells of the central nervous system, that can't be addressed by growth.

Nonetheless, it seems a valid topic for discussion given the present interest in applying reprogramming technologies to living animals (and perhaps people not too many years from now). Reprogramming in this context is the process of turning normal cells into induced pluripotent stem cells, essentially mimicking embryonic stem cells in their behavior. This reverses epigenetic marks of aging and other changes, such as loss of mitochondrial function. Unexpectedly, delivering the Yamanaka factors into mice produces benefits to health, not disruption of tissue function as cells are converted into inappropriate types and behaviors, and not a comprehensive unleashing of cancer, as one might expect to happen. A number of groups are now working on ways to reprogram or partially and temporarily reprogram cells in order to produce rejuvenation in animal models.

From cancer to rejuvenation: incomplete regeneration as the missing link (Part I: the same origin, different outcomes)

There are two major problems: the eradication of cancer and aging. For radical rejuvenation, gerontologists attempt to activate signaling pathways for rejuvenation/pluripotency. Quite often, such attempts result in the formation of tumors. This happens because the only way is to radically rejuvenate and this normally, without special intervention, leads to cancer. At the same time, oncologists are trying to suppress all these signaling pathways of rejuvenation, based on the idea that tumor cells are the enemies and that they should be eliminated by all available means. In short, this strategy can be called a killing strategy (both through direct action and creating conditions unfavorable for cell growth and proliferation). This currently applied killing strategy does not restore tissue and function deficiency but rather exacerbates it. That is why, after some clinical success, this strategy leads to a recurrence of cancer and the formation of cell clones that are resistant to therapy.

In pregnancy, it is the immune privilege of the fetus that ensures the unidirectionality of the vector totipotency to differentiation, or integrating growth (IG). IG is defined here as the submission of potency of single cells composing an organism to the development program and functions of the whole organism. However, in the adult organism, in the absence of immune privilege, this recapitulation is transformed into cancer, or disintegrating growth (DG).

Cancer cells are normal cells with a blocked entry to the normal growth path and redifferentiation, and the last feature is the only marker of malignant growth. It is this blocking and nonlimited execution of a developmental program in reverse order that is the cause of the disintegrative character of its growth or, in other words, the cause that transforms rejuvenation into DG - not the expression of the so-called oncogenes. Oncogene expression does not affect the normal morphogenetic potential of cells. Oncogenes, as genes that cause cancer, do not exist at all. They are normal genes, due to which organisms are developed and due to which they can potentially reach immortality. All properties that are associated with cancer, except blocked redifferentiation, are features of the embryonic pathway recapitulation and self-renewal, and they are inherent for cells at different stages of ontogenesis.

The transformation of normal cells into tumor cells is an adaptive response to a failure in self-restoration and repair capabilities. Due to the rebirth process, complete tissue renewal leading to the elimination of senescence occurs similarly to embryonic tissue development. We propose to use this potential of transformed cells to eliminate senescence. This will make it possible to direct the process of transformation toward an integrated growth path, to prevent the clinical phenomenon of malignancy and to use the potential of transformed cells to initialize the self-renewal program and program of unlimited life for the whole organism.

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

Aging is a process and a consequence of processes brought about by steadily increasing restriction of the self-renewal ability, limiting life expectancy, and leading to an increase in the probability of death and, inevitable death resulting from the fading of functions, failure of the regulatory mechanisms, occurrence of endogenous disorders and increased susceptibility to exogenous factors. In our opinion, one of the fundamental (systemic) flaws of gerontology is the idea of the existence of a special aging program and the search for the cause of aging, which states that if removed, aging can be eliminated. However, there is only one general program, a program of growth and development (ontogenesis), of which aging is an integral part. The essence of this program is the stabilization of multicellular integrity by submitting the purposes of the constituent parts (cells) to the purposes of the whole (tissues, organs and the body in entirety), through the epigenetic restriction of cell potencies in favor of perfecting (complicating) tissue specialization, for what we pay for with aging, all types of endogenous pathology and, as a result, mortality.

From this, it follows that the 'cause' of aging is not some special mechanism but a program/order, which can be overridden only by implementing another program, a program, of permanent, unlimited, quantitative and qualitative full restoration of structures, functions and functional interconnections. In other words, the linear unidirectionality of ontogenesis, fatally leading to aging and death, can only be overcome with permanent reontogenesis, through the looping of this linearity. This does not require an application of any force against nature, because similar processes were invented by nature itself and because they work in practically immortal multicellular organisms, such as Hydra vulgaris. It is important to note that Hydra does not have cancer as a pathological process. In other words, a periodic return or 'rollback' to the blast state does not cause cancer (disintegrating growth, DG) in those types of immortal organisms.

During ontogenesis, cells such as neurons or myocardiocytes become postmitotic, thus playing an integrative role in the functioning of an organism. The beginning of the ontogenetic program of development includes its own control of division in relation to cells until its complete stop in postmitotic cells, making them one of the main targets for aging processes. To increase the regenerative possibilities of an organism, it is necessary to make postmitotic cells 'build themselves anew'. The main biological ways to accomplish this is full-scale reprogramming that brings cells back to the early stages of pluripotency. It must be emphasized that what later becomes cancer is initially started as spontaneous reprogramming and the goal is to prevent the transformation of this process into carcinogenesis and direct it as rejuvenation. By creating similar conditions in the body, we can apply safe systemic-induced reprogramming in vivo, without fear of resulting in cancer.

Comments

Sounds like a conversation between Dr. Terrel and Roy from "Blade Runner".

Posted by: Thomas Schaefer at October 12th, 2020 11:57 PM

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