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.
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.
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.
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.
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.