Can Delivery of New Cells to Tissue Slow or Reverse the Accumulation of Senescent Cells?

Cellular senescence is a reaction to internal damage and the surrounding circumstances a cell finds itself in. A senescent cell ceases dividing and adopts a range of behaviors that provide a mix of benefits and harm. It provides some resistance against cancer, as a senescent cell is harder to turn cancerous and the immune system tends to destroy senescent cells. On the other hand senescent cells emit signals that harm surrounding tissue integrity and raise the odds of other nearby cells also becoming senescent - which is probably desirable from the point of view of suppressing cancer, but it also harms health, and to a certain degree cancers adapt to this situation and thrive because of it. Cellular senescence is an evolutionary struggle in mid-throes: senescence is a mechanism that has its origin in embryonic development, then repurposed to resist cancer, and now cancers in turn strive to turn it to their advantage.

From our point of view as individuals, cellular senescence is a now a net loss. We will deal with cancer through new technology: medicine is on track to achieve a first pass at that goal within a few decades. But cellular senescence is a root cause of aging. Senescent cells accumulate over time, degrading health and contributing to the downward spiral of degeneration and frailty. Studies in mice have provided evidence to reinforce theory on this point: targeted removal of senescent cells provides extension of healthy life span, at least in animals engineered to have more than the usual number of senescent cells. Work is presently underway to demonstrate the same in normal mice.

I noticed a recent paper today which provides another example of a means to address an artificial increase in the numbers of senescent cells. Rats were treated with a carcinogenic substance that increases the number of senescent cells in the liver, a model for generating cancers for study, and then provided with an infusion of fresh liver cells - just plain cells, not stem cells. That prevented or reversed the induced increase in cellular senescence.

Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease.

Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). [One] group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group.

Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes.

This is pretty interesting. Is the case that delivery of large numbers of ordinary adult cells into tissue could cull senescent cells, or remove their senescent state, or greatly slow their accumulation? One has to be skeptical, however, given that this is not taking place in old mice, and it is an artificial process of induced senescence rather than the results of aging. Further, the liver is somewhat unusual among organs in mammals, capable of far more regeneration than other complex tissues. Ordinary liver cells may be more versatile and restorative than other types of cell.

The authors present an interesting set of ideas on cellular senescence further down in this paper:

An intriguing interpretation of cell senescence postulates that this unique phenotype emerges when a cell integrates two types of signals: one that reads for growth and one that imposes a block in the replicative cycle. For example, DNA damaging agents do not induce senescence in quiescent cells; however, they do so if the presence of persistent DNA damage and cell cycle arrest is coupled with growth promoting stimuli. Under these conditions, cells switch on the senescence program and express markers related to both cell cycle block and growth stimulation.

The researchers believe that an examination of changes in gene expression profiles in the rats in this study support this view. The changes visible after exposure to the carcinogen were reversed by delivery of new liver cells, which went on to repopulate the liver and - presumably - change the environment such that senescent cells were either removed, restored to non-senescent states, or not created.

The current consensus on what to do about senescent cells and their effect on long-term health focuses on building means of targeted destruction, in the same way as cancer cells are nowadays being targeted based on their distinctive chemistry. Numerous research groups are working on the components of future treatments to clear out senescent cells, although it must be said that there is very little funding for this in comparison to other areas of research. Sadly this is the story for much of the science most relevant to extending healthy human life.

In comparison, reversing senescence in situ is thought to be hard, or at least harder. Certainly far less is known about how to go about it. This study, even though a reversal of an artificial situation, is a starting point. I'd very much like to see someone try the straightforward cell delivery approach in the same way in old rats. Perhaps it will work, or perhaps the new cells will be overwhelmed and their benefits largely disabled by the old cellular environment they are introduced into. Either way, it seems something that should be tried based on the results here.


But if the immune system rids of senescent cells (linked to aging), wouldn't there be some at least tiny benefit with aging with a very strong immune system vs a weak one? Do we see differences here?

Posted by: wendy at January 29th, 2014 2:55 PM
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