This paper, published earlier in the year, is a reaffirmation of the consensus position that aging is caused by the accumulation of cell and tissue damage, made at a time in which programmed aging theories are becoming more popular. Initiatives such as those of and other groups, in which cells are at least partially reprogrammed towards a pluripotent state in living animals, have spurred greater interest in the characteristic epigenetic changes that take place with aging. That reversing those epigenetic changes produces rejuvenation by many measures is interesting and promising, but it isn’t clear that it can be taken as evidence that epigenetic programs of change are at the root of aging. We might look instead at the evidence for detrimental epigenetic change in cells throughout the body to be an unfortunate consequence of the processes of DNA double strand break repair, for example. If confirmed, that puts age-related epigenetic change firmly in the category of damage, not a program that exists independently of damage as a root cause of aging.

Aging is an irreversible process, and most organisms can never escape the diversity and accumulation of damage that their own functions generate. To reduce damage, species with a simple organization may opt to discard some damage with a part of the cytoplasm, but this mechanism needs to be investigated in more complex species. Interventions such as parabiosis may partially restore aged organ functions through transfusion of young blood to an old organism. This may be considered as a damage dilution process, where the old blood is diluted by the less damaged young blood. It was shown that, following hematopoietic stem cell transfer, the blood of the recipient follows the epigenomic age of the donor, suggesting a possibility to consistently generate younger blood than the actual age of the organism, if the source of hematopoietic stem cells is a young donor. It is important to emphasize that the transition to a younger age, based on one or more tissues being younger than the rest and younger than the chronological age, does not necessarily mean a longer lifespan for the subject, particularly if the lifespan is limited by a particular dysfunction or disorder that causes death.

Although somatic aging appears at first sight irreversible, we cannot bypass the fact that it is successfully reset to zero from generation to generation, suggesting that, during germline development, embryonic development, or some other phases of life there is a process that rewinds the aging clock. Somatic cell nuclear transfer shows that this rewinding process can be also induced in differentiated cell nuclei. These mechanisms of dilution or repair of damage are currently unclear, although evidence suggests that they may involve a combination of cell division, cell selection, epigenetic remodeling, and global activation of genes, especially those genes for controlling DNA damage. These mechanisms allow cells to dilute even the scarcest molecular species such as functionally abnormal RNA, proteins, harmful metabolites, and those that would not be sensed by a cell. Thus, a combination of cell growth, selection, and proliferation dilutes mild damage, in addition to the removal of damage through specialized detoxification, repair, excretion, preemption, and other approaches. These mechanisms together allow the cells to keep the damage in control.

It should be noted that division and dilution are not necessarily related in the context of proliferation of differentiated somatic cells, as, unlike germ cells or stem cells, these cells may undergo senescence or tumor transformation when proliferating in culture. This suggests that there is a particular relationship between cell division and damage dilution, whose mechanism is not yet understood. We think that this relationship is reflected, for instance, in the differences between early embryonic and aged cells, partially due to their different differentiation states. The former may stay in quiescent stage to avoid further damage or proliferate to select the cells with less damage. Compared to adult cells, embryonic cells specifically experience two waves of global demethylation and re-methylation, establishing the same DNA methylation pattern for every generation. These differences suggest a possibility that certain embryonic cells and somatic cells have different modes and rate of damage accumulation and dilution through proliferation. From the damage perspective, the proliferation of cells with more specialized functions bears higher damage, as more specialized molecules are produced, allowing more side-products to be generated. Furthermore, adult stem cells may overcome the proliferation limit when exposed to a mixed pro-stemness signal. This shows that the combined effect of niche pathways that promote the stemness of the adult stem cells may act similarly to reprogramming. Thus, the difference in the damage accumulation between somatic cells and stem cells may lie, at least in part, in the cell matrix environment in which cells reside. Moreover, the environment may undergo a transition to sacrifice stemness for specific biological functions.

To visualize this stage-shifting concept, we advance a weight-scale metaphor, which we call a “stemness-function” model. We designate the two states as “pro-stemness” and “pro-function” based on the balance between damage production and its removal by proliferation and apoptosis. During early life, organisms remain in a “pro-stemness” state, encouraging cells to proliferate and grow so that the damage is unchecked and does not cause cell cycle arrest. In that state, although stem cells exhibit a limited intrinsic immune function, the function to recognize “self” and “nonself” is not yet fully developed, allowing a lower level of inflammation and an increased potential for regeneration. In contrast, in somatic cells, the damage generation can be sensed easier, triggering the reactions such as the DNA damage repair process, growth arrest, apoptosis, and immune responses. Therefore, organisms must undergo a transition from the “pro-stemness” to “pro-function” states, wherein differentiation and specification of cells are supported. Following this transition, the cells enhance their function in reproduction, damage sensing and apoptosis pathway, complete the immune function, and increase fitness by generating specific biological products related to their functions, while adult stem cells at this stage undergo gradual exhaustion. At this stage, damage accumulation is spontaneous while damage dilution via proliferation is not supported in most cell types. During the process of fertilization or before/after it, this damage gets thoroughly checked, cleared and diluted by the transition to the “pro-stemness” state.

What perturbations might then be expected to delay or reverse aging? If a mild “pro-function” feature is induced in the cells with the “pro-stemness” state, it may extend lifespan as we learn from mild overexpression of certain tumor suppressors. Similarly, the weakened immune system upon rapamycin treatment provides an example that the opposite may also work. On the other hand, if a specific function (supported by a certain gene) that shifts the system toward the “pro-function” state is introduced, it may lead to death or premature aging, caused by a sudden increase in function and damage. This might be the case when tumor-suppressor Tp53 is overexpressed in mice, and the animals show a significantly shorter lifespan. It should be noted, however, that similar cases of Tp53 overexpression in mouse models show an indistinguishable lifespan. Nevertheless, considering that cancer-related deaths are more common in lab mice than in humans and that these risks are limited in these cancer-resistant mouse models, there is still a possibility that the overexpression accelerates aging. Conversely, if a “pro-stemness” signal introduced to cells in the “pro-function” state, it may also cause deleterious effects, resulting in cell death or aberrant immortality. For instance, forcing cell proliferation by expressing oncogenes in fibroblasts promotes tumor transformation.