The rate of aging may be evolutionarily determined as a balancing act between maintenance of regenerative capacity and prevention of cancer (see our earlier article, Devil’s bargain: Tradeoffs between stem cell maintenance and tumor suppression). The idea is that the same mechanisms that stop our cells from proliferating out of control might also prevent them from dividing in order to repair damage.

Like all theories of aging, this one has its advocates (of which I am one) and its detractors (whom I’m certainly willing to hear out). Today I wanted to share two recent review-type articles (one of them is a book chapter) that address the issue.

On the “pro” side is an article by Christian Beauséjour, who’s worked in the field of cellular senescence for quite some time. He reviews evidence that senescence, which evolved as a tumor suppressor function, may contribute to age-related decline in the hematopoetic stem cell (HSC) compartment. From a recent volume of the Handbook of Experimental Pharmacology:

Bone marrow-derived cells: the influence of aging and cellular senescence.

During the course of an entire lifespan, tissue repair and regeneration is made possible by the presence of adult stem cells. Stem cell expansion, maintenance, and differentiation must be tightly controlled to assure longevity. Hematopoietic stem cells (HSC) are greatly solicited given the daily high blood cell turnover. Moreover, several bone marrow-derived cells including HSC, mesenchymal stromal cells (MSC), and endothelial progenitor cells (EPC) also significantly contribute to peripheral tissue repair and regeneration, including tumor formation. Therefore, factors influencing bone marrow-derived cell proliferation and functions are likely to have a broad impact. Aging has been identified as one of these factors. One hypothesis is that aging directly affects stem cells as a consequence of exhaustive proliferation. Alternatively, it is also possible that aging indirectly affects stem cells by acting on their microenvironment. Cellular senescence is believed to have evolved as a tumor suppressor mechanism capable of arresting growth to reduce risk of malignancy. In opposition to apoptosis, senescent cells accumulate in tissues. Recent evidence suggests their accumulation contributes to the phenotype of aging. Senescence can be activated by both telomere-dependent and telomere-independent pathways. Genetic alteration, genome-wide DNA damage, and oxidative stress are inducers of senescence and have recently been identified as occurring in bone marrow-derived cells. Below is a review of the link between cellular senescence, aging, and bone marrow-derived cells, and the possible consequences aging may have on bone marrow transplantation procedures and emerging marrow-derived cell-based therapies.

In the other corner we have a review from Aranda-Anzaldo and Dent, who propose that the evolutionary history of p53 makes it unlikely that it’s even an important tumor suppressor gene in short-lived species like the mouse, much less an antagonistically pleiotropic gerontogene (for definition and discussion of those concepts, see our earlier article Conditioned for aging):

Reassessing the role of p53 in cancer and ageing from an evolutionary perspective

The gene p53 has been fashioned as the guardian of the genome and as prototype of the tumour suppressor gene (TSG) whose function must be inactivated in order for tumours to develop. The ubiquitous expression of truncated p53 protein isoforms, results in “premature ageing” of laboratory mouse strains engineered for expressing such isoforms. These facts have been construed in the argument that p53 evolved in order to protect organisms with renewable tissues from developing cancer yet, because p53 is also an inducer of cellular senescence or apoptosis after extensive DNA damage, it becomes a limiting factor for tissue renewal by depleting tissues from stem/precursor cells thus leading to whole-organism ageing. From that point of view p53 displays antagonist pleiotropy contributing to the establishment of degenerative diseases and ageing. Therefore, tumour suppression becomes a balancing act between cancer prevention and ageing. Nevertheless, here we present current evidence showing that the aforementioned argument is rather inconsistent and unwarranted on evolutionary grounds. The evolutionary perspective indicates that p53 evolved so as to play a subtle but very important role during development while its role as a TSG is only important in animals that are protected from most sources of extrinsic mortality, thus suggesting that p53 was primarily selected for its developmental role and not as a TSG. Therefore no real antagonist pleiotropy can be attached to p53 functions and their relationship with whole-organism ageing might be a laboratory artefact.

Strong words indeed, especially at the end.

The paper itself is quite dense, and I admit that I haven’t had a chance to sift through it carefully, so for now I’m just going to present the paper and invite others to read it with me.

Beauséjour’s position is much more in the “mainstream” of recent conference discussions, and it happens to be more or less how I think about these issues, but I’m looking forward to carefully evaluating the other side of the debate. I’d be especially interested to know how other biogerontologists weigh the arguments on both sides.