Reversal of Hepatocyte Senescence

Researchers are doing far too many things with cells for any one person to know about every single study, or even every category of study. In the past twenty years the doors have opened and the costs dropped to the point at which any laboratory can support numerous separate and adventurous voyages of discovery into cell behavior and biology. Cells are stretched, sliced, grown, transplanted this way and that, genetically engineered, exposed to substances, and so on and so forth, and thousands of these studies are ongoing at any given time.

In among all of this exploration, we should not be surprised to find that some researchers uncover ways to reverse aspects of cellular aging. It is important to remember that cell aging is a different thing altogether from the aging of an organism made up of cells. One affects the other, but it isn't a direct relationship by any means. Cells respond to their circumstances and there is plenty of evidence to suggest that if given the right stimulus some types of cell can remake themselves to a large degree, stripping out damage and unwanted waste to become pristine. We know that this happens somewhere in the sequence of events that leads to embryonic development: parents are old, children are young. We also know that bacteria, hydra, and similar entities can perform much the same operation under some circumstances. This is certainly not something you'd want taking place in your nervous system, however, and the fact that we have complex brains and nervous systems may be a consequence of the fact that our cells don't habitually carry out this sort of dramatic cleansing process, unlike those of some species of lower organism.

There are other less drastic examples, however, such as those associated with the state of cellular senescence in which a cell ceases to divide but doesn't destroy itself. Cells in old tissues become senescent in greater numbers, due to some combination of greater levels of cellular damage and a response to signaling proteins present in the cellular environment. This is most likely an adaptation of an embryonic development process to the suppression of cancer risk in later life. However, it is of decidedly mixed results: less cancer, yes, but senescent cells are generally badly behaved in ways that harm tissue integrity and organ function. We would like to get rid of them as the accumulation of senescent cells is in fact one of the causes of degenerative aging. Removal of these cells by means of targeted destruction seems to be beneficial in those studies attempted to date.

What if we could reverse cellular senescence, however? It is a little early to claim that this is a plausible goal, or that it would cause fewer problems than it solved, but there is some research taking place along these lines. In connection with all of this, the paper linked below outlines the discovery of cells acting to reverse their senescent status in response to circumstances as they are manipulated in a system for growing liver cells known as hepatocytes. This involves the use of genetically engineered immune deficient mice as hosts for transplanted human hepatocyte cells, and one characteristic of this system is that as the human cells grow in number they can be serially transplanted between mice to increase the rate of growth so as to obtain a usefully large amount of cells in a usefully short period of time. It is worth remembering that the research community is not yet at the point of being able to arbitrarily grow every type of cell at the drop of the hat: many lines of research still require complex systems involving laboratory animals in order to investigate cells in a life-like environment. This will change in the years ahead, but it is what it is for now.

Using this system of serial transplants of human hepatocytes between mice, these researchers noticed that the cells responded to transplantation by reversing their senescent status:

Reversal of hepatocyte senescence after continuous in vivo cell proliferation

A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether the continuously proliferating hepatocytes could avoid or reverse senescence has not been fully not elucidated yet. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16ink4a-pRB pathways.

Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase deficient (Fah-/-) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations.

We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The re-activation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver, suggesting that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy.

You might consider this result in the context of other studies that have shown renewal of stem cell activity when stem cells are moved from old individuals to young individuals, or simply have the protein levels present in an old environment replaced by those of a younger environment. It is a data point and a starting position for further research into whether or not it is useful to attempt to reprogram cells in the body by altering levels of signaling proteins. The initial signs are promising, but there is ever the concern that waking these cells will raise the risk of cancer, or cause other disruptions that may outweigh the benefits.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.