Reviewing What is Known of the Aging of Stem Cells

One of the important contributions to the aging process is a progressive reduction in stem cell activity. The majority of tissues in the body are in a constant process of turnover. The somatic cells making up the bulk of all tissues reach the Hayflick limit on replication and self-destruct, and are replaced by new cells generated by tissue-specific stem cell populations. With age, these stem cells spend ever more time quiescent, and thus the supply of new somatic cells declines, causing tissues and organs to deteriorate and ultimately fail. This loss of stem cell support is thought to have evolved as part of a balance between risk of death by cancer versus risk of death through failing tissues. As cells become more damaged with age, the risk of cancer with cell activity increases. Lower levels of stem cell activity dampen that risk somewhat, at the cost of a slower decline into frailty and disease. Still, restoration of youthful stem cell activity is one necessary component of any future toolkit of rejuvenation therapies. To the degree that this raises cancer risk, that is an additional challenge to overcome along the way, not a reason to stand back and do nothing.

Aging is an unavoidable physiological consequence of the living animals. Mammalian aging is mediated by the complex cellular and organismal processes, driven by diverse acquired and genetic factors. Aging is among the greatest known risk factors for most human diseases, and of roughly 150,000 people who die each day across the globe, about two thirds die from age-related causes. In the modern era, one of the emerging fields in medicine is stem cell research, as stem cells have the remarkable potential for use to treat a wide range of diseases. Stem cells are undifferentiated pluripotent cells that can give rise to all tissue types and serve as a sort of internal repair system. Until the recent advance in development of induced pluripotent stem cells (iPSCs), scientists primarily worked with two kinds of pluripotent stem cells from animals and humans: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and non-embryonic "somatic" or "adult" stem cells, which are found in various tissues.

Although stem cell science promises to offer revolutionary new ways of treating diseases, it is identified that aging affects the ability of stem (and progenitor) cells to function properly, which ultimately can lead to cell death (apoptosis), senescence (loss of a cell's power of division and growth), or loss of regenerative potential. Aging may also shift gene functions, as reported for some genes, such as p53 and mammalian target of rapamycin (mTOR), which are beneficial in early life, but becomes detrimental later in life. In this regard, a novel theory, namely the "stem cell theory of aging", has been formulated, and it assumes that inability of various types of pluripotent stem cells to continue to replenish the tissues of an organism with sufficient numbers of appropriate functional differentiated cell types capable of maintaining that tissue's (or organ's) original function is in large part responsible for the aging process.

In addition, aging also compromises the therapeutic potentials of stem cells, including cells isolated from aged individuals or cells that had been cultured in vitro. Nevertheless, in either case, understanding the molecular mechanism involved in aging and deterioration of stem cell function is crucial in developing effective new therapies for aging- as well as stem cell malfunction-related diseases. In fact, given the importance of the aging-associated diseases, scientists have developed a keen interest in understanding the aging process as well as attempting to define the role of dysfunctional stem cells in the aging process.

From the various advances in stem cell research, it is clear that we grow old partly because our stem cells grow old with us. The functions of aged stem cells become impaired as the result of cell-intrinsic pathways and surrounding environmental changes. With the sharp rise in the aging-associated diseases, the need for effective regenerative medicine strategies for the aged is more important than ever. Fortunately, rapid advances in stem cell and regenerative medicine technologies continue to provide us with a better understanding of the diseases that allows us to develop more effective therapies and diagnostic technologies to better treat aged patients.



I can understand how stem cells evolved, as you say Reason, to reduce the cancer risk of having all cells able to replicate without limit, but I'm not so sure we can explain stem cell failure with age the same way - after all evolution is blind and only cares about passing on genes, not what happens in post-reproductive life. So it seems more likely to me that stem cell quiescence is accidental and caused by something else external - one of the other forms of damage perhaps.

This also makes sense when you consider that iPSCs have been shown to have telomeres, epigenetic markers and replicative potential all restored to a pristine state.

Posted by: Mark at March 23rd, 2017 9:38 AM

@Mark: In humans one might argue the grandmother effect and the evolutionarily recent lengthening of human life span in comparison to other close primate relatives, but you can't do that in many other species.

Posted by: Reason at March 23rd, 2017 9:54 AM

Not sure I can go along with the grandmother hypothesis, as you say it's implausible in most other species, but I suppose extending the length of reproductive life also extends total lifespan as well, and evolution will do this once predation and non-age related disease rate falls low enough. Its a stretch to extend that to stem cells quiescence though, as you have to get pretty damn old for that to matter, right?

Posted by: Mark at March 23rd, 2017 10:24 AM

@Deleo: Next post. I would have noted it yesterday, but the paper wasn't available at that time.

Posted by: Reason at March 23rd, 2017 5:02 PM

@Deleo: They don't mention SENS anywhere ¬¬

Posted by: Antonio at March 23rd, 2017 5:34 PM

Evolution would favor genetic variation because a species is competing for survival against other species, not just it's prey. The Greenland shark appears to have removed itself from the evolutionary arms race and achieved longevity.

Posted by: Tj Green at March 25th, 2017 8:41 AM

Tj Green: Genomes and are a trait individuals, and they are individuals who get selected or die. So evolution doesn't care about what is good for a species, only for a individual. Thus it doesn't select for genetic variation for the wealth of the species against other species.

Posted by: Antonio at March 25th, 2017 10:39 AM
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