Fight Aging!

Everything is connected to everything else: our biochemistry is a web of tightly interacting processes, systems and feedback loops. You can't consider any one process in isolation of the whole if you'd like to learn more about how we work. This level of interaction is one reason why it is likely easier to learn to repair damage to our metabolism - the damage that causes aging - than to significantly change our metabolic systems to generate damage more slowly, and thus age more slowly.

With that in mind, I thought I'd point out a selection of papers that illustrate some of the more obvious linkages between stem cells, cancer, DNA damage, telomeres and aging - all a big ball of intricately knotted string. As cells - especially stem cells - become damaged, multiple sentinal processes try to destroy or place them into a quiescent state in order to avoid the runaway replication and mutation of cancer. But removing cells from active service reduces the effectiveness of the body, and is one cause of aging. This is an evolutionary balance of multiple competing and co-operating processes, degeneration with age on the one hand and avoidance of cancer on the other.

DNA repair in stem cell maintenance and conversion to cancer stem cells:

Genomic stability is essential for cell and organism longevity. Without genomic stability, replication errors and external stress as well as direct forms of DNA damage can induce mutations, which decrease cell survival, cause altered gene expression, and can lead to cellular transformation. All represent the antithesis of maintenance of normal stem cell function. We argue here that genomic stability is essential for stem cell maintenance and longevity. This concept is supported by human diseases associated with premature aging and animal models of DNA damage repair abnormalities all of which lead to abnormalities of stem cell survival.

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Thus one origin of the cancer stem cell phenotype is the inability to maintain genomic stability among the stem cell population leading to mutational alterations and transformation. Capturing stem cells at this transition point represents an exciting field of discovery possibly leading to early detection and therapeutic interventions.

Two faces of p53: aging and tumor suppression:

The p53 tumor suppressor protein, often termed guardian of the genome, integrates diverse physiological signals in mammalian cells. In response to stress signals, perhaps the best studied of which is the response to DNA damage, p53 becomes functionally active and triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence). Both apoptosis and cellular senescence are potent tumor suppressor mechanisms that irreversibly prevent damaged cells from undergoing neoplastic transformation.

However, both processes can also deplete renewable tissues of proliferation-competent progenitor or stem cells. Such depletion, in turn, can compromise the structure and function of tissues, which is a hallmark of aging. Moreover, whereas apoptotic cells are by definition eliminated from tissues, senescent cells can persist, acquire altered functions, and thus alter tissue microenvironments in ways that can promote both cancer and aging phenotypes. Recent evidence suggests that increased p53 activity can, at least under some circumstances, promote organismal aging.

Telomeres, senescence, and hematopoietic stem cells:

The replicative lifespan of normal somatic cells is restricted by the erosion of telomeres, which are protective caps at the ends of linear chromosomes. The loss of telomeres induces antiproliferative signals that eventually lead to cellular senescence. The enzyme complex telomerase can maintain telomeres, but its expression is confined to highly proliferative cells such as stem cells and tumor cells.

The immense regenerative capacity of the hematopoietic system is provided by a distinct type of adult stem cell: hematopoietic stem cells (HSCs). Although blood cells have to be produced continuously throughout life, the HSC pool seems not to be spared by aging processes. Indeed, limited expression of telomerase is not sufficient to prevent telomere shortening in these cells, which is thought ultimately to limit their proliferative capacity.