There is a mature literature on evolution and aging intended to explain how, despite selection for the morphological, metabolic, physiological, and behavioral prerequisites for survival and procreation, with the passage of time bodies deteriorate ultimately resulting in death. The focus of such explanations is typically on concepts such as age-related variation in the potency of selection and the related notion of antagonistic pleiotropy (Fabian and Flatt, 2011), by which suggests that genes able to promote survival and reproductive success in youth may increase loss of function with age. These concepts address selection on intact organisms. In contrast, a recent article in Science (Goodell and Rando, 2015) contains an article addressing the role of selection directly on somatic cells and in particular tissue-specific stem cells.
The authors first point out that since humans, like animals on farms or in zoos, rarely face mortality due to predation, starvation, or exposure to the elements, they tend to live substantially longer than would otherwise be the case and well beyond the peak reproductive years that are subject to maximal selection. They term this state of affairs “protected aging.” As a consequence, the human genome would not be expected to be optimized by organismal selection for maintaining the maximum functions of tissues and organs into these later stages of life. buy zovirax generic name
Goodell and Rando then call attention to the fact tissues are typically generated from tissue-specific stem cells. While it has become commonplace to state that all of the somatic cells in the body are genetically identical, the reality is more complex. Even putting aside mature B and T lymphocytes, which have unique genomic contents due to the rearrangement of genes encoding antigen-specific receptors and associated genomic deletions, there is a relentless process of mutation in stem cells. According to the authors, genomic deep sequencing studies have demonstrated that, for example, as many as ten mutations per year accumulate in hematopoietic stem cells (HSC). At advanced ages, each HSC can harbor on the order of 700-800 mutations. levaquin over the counter
This magnitude of genomic alteration means that the population of stem cells in the bone marrow, and apparently in other tissues, is actually genetically diverse thereby laying the groundwork for clonal competition. A somatic cell equivalent of antagonistic pleiotropy, involving different levels of organization instead of different stages of life, then comes into play. Some mutations that favor the proliferation of a stem cell may simultaneously reduce the production of differentiated progeny cells or the functions of those cells. So, a genetic variant that is beneficial for a stem cell, in terms of proliferation, may negatively affect the organism as a whole. Another possibility is that the mutation(s) favoring a particular stem cell in proliferative competition with other stem cells in the same tissue may be neutral or even beneficial for the functioning of differentiated progeny cells in that tissue, but one or more other mutations coincidentally found in that same highly competitive stem cell significantly decrease the functioning of the cells descended from it. In either case, over the long run, this process can, and has been shown for bone marrow and skin, to lead to fewer active stem cell clones as the most proliferative clones overwhelm the less proliferative. Eventually the great majority of differentiated tissue cells derived from these few stem cell clones could manifest reduced functional capacities. Further studies will be needed to confirm this scenario. Lasix over the counter
The remainder of the article focuses on how changes in patterns of covalent modifications of histones or DNA, so-called epigenetic marks, and environmental stimuli may influence stem cells and thereby the pace of decline in tissue function. Regarding epigenetic changes in stem cells that may influence aging, DNA methylation, which usually decreases the extent of gene transcription, in HSCs from older individuals, as compared to younger individuals, tended to be decreased for genes that contribute to self-renewal and increased for genes that are involved in differentiation of stem cell progeny. This pattern suggests the possibility that with age bone marrow stem cell self-renewal increases while differentiation and the associated and critical functions of mature blood cells decline. Such epigenetic alterations can modify stem cell phenotypes, like the somatic mutations discussed above, so that stem cells producing less functional progeny cells nevertheless increase relative to other stem cells and ultimately cause a physiological decline at the organismal level.
With respect to environmental influences on stem cells, the authors cite studies based on so-called heterochronic transplantation demonstrating that stem cells from young mice transplanted into aged mice exhibited functional decline, and stem cells from old mice transplanted into young mice exhibited functional profiles more like stem cells from young mice. Other investigations have added support for the notion that factors found in blood, such as cytokines that can participate in inflammatory responses, accelerate the aging of cells and tissues. C1q, a component of the complement system and a soluble molecule found in blood, along with beta2-microglobulin, a dissociable component of class I major histocompatibility complex molecules, have also been found to promote aging of, respectively, muscle and neural stem cells.
Goodell and Rando note that these ideas regarding the evolution of tissue-specific stem cell populations have support from both experimental and theoretical studies. They additionally point out that mathematical models suggest that even without selection, persistent competition over an extended time interval among stem cells in a given tissue would lead the population to evolve towards a single dominant clone on the basis of the equivalent of genetic drift.
I expect that the evolution of stem cell populations in various tissues will come to be seen as an additional important factor contributing to aging along with other mechanisms such as non-enzymatic glycosylation of proteins leading to crosslinks (Sell and Monnier, 2012), telomere shortening (Blackburn et al., 2015), metabolic changes (Verdin, 2015), and, possibly, microbiome diversity (O’Toole and Jeffery, 2015). The evolution and medicine community should come to accept that evolution influences aging through multi-level selection.
References
Fabian, D. & Flatt, T. (2011) The Evolution of Aging. Nature Education Knowledge 3(10):9.
Goodell MA, Rando TA. Stem cells and healthy aging. Science. 2015 Dec 4;350(6265):1199-204. doi: 10.1126/science.aab3388. Review. PubMed PMID: 26785478.
Sell DR, Monnier VM. Molecular basis of arterial stiffening: role of glycation – a mini-review. Gerontology. 2012;58(3):227-37. doi: 10.1159/000334668. Epub 2012 Jan 4. Review. PubMed PMID: 22222677.
Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science. 2015 Dec 4;350(6265):1193-8. doi: 10.1126/science.aab3389. Review. PubMed PMID: 26785477.
Verdin E. NAD⁺ in aging, metabolism, and neurodegeneration. Science. 2015 Dec 4;350(6265):1208-13. doi: 10.1126/science.aac4854. Review. PubMed PMID: 26785480.
O’Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015 Dec 4;350(6265):1214-5. doi: 10.1126/science.aac8469. Review. PubMed PMID: 26785481.
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GERM LINE STEM-CELLS, NAD+, and GRANDMA
Thank you Dr. Greenspan for another fine article. Three comments.
1. While your article deals primarily with somatic cells, we should not forget that similar “clonal competition” arguments apply to germ-line stem cell populations (Shinde et al. 2013). You will recall that the Arnheim laboratory, with a testis sector sampling “jackpot” approach pioneered by Bateson and Punnett decades earlier, used the argument to explain why achondroplastic dwarfs tend to be among the last born children in a family.
2. The switch from one physiological state (stem cells) to another (differentiation and proliferation) can be compared with the switch from a “resting” physiological state to a differentiative one, as with ‘resting’ (G0 phase) lymphocytes that enter the cell cycle (G1 phase). You mention Verdin (2015) who pointed to the maintainance of NAD+ levels by the enzyme NAMPT. The corresponding gene was identified by differential expression cDNA cloning as one of those activated very early in the transition of human lymphocytes from the G0 to the G1 phase of the cell cycle. In the 1980s we named it G0S9 and placed a partial sequence in GenBank. Thus, genes that affect NAD+ could be critically involved in stem-cell transitions.
3. It is not entirely true that, “the human genome would not be expected to be optimized by organismal selection for maintaining the maximum functions of tissues and organs into these later stages of life.” Grandparental input into the care of the young has added an extra dimension to this.
Shinde DN et al. (2013) New evidence for positive selection helps explain the paternal age effect observed in chondroplasia. Human Mol Genet 22: 4117-4126.
Thank you Dr. Forsdyke for another thoughtful and informative comment. Below, I reply point-by-point.
1. Although I wanted to focus on and draw attention to the role of somatic cells in health and aging in this particular post, I appreciate your noting the existence of selection among germ cells and the potential of clonal competition among sperm progenitors to cause disease. The article by Shinde et al. provides an extremely interesting example.
2. Thanks for pointing out the possible connection between age-related changes in NAD+ metabolism and stem cell function.
3. I did not mean to imply that there is no post-reproductive selection, as I have accepted for some time the potential contributions of grandparents to the reproductive success of children and grandchildren. However, I do expect that selection on that basis might be less potent than it is for adults of reproductive age. If this question has not been directly addressed, perhaps it would represent a worthy basis for additional investigation whether via observational or theoretical approaches.