Calorie Restriction Leads to More Very Small Embryonic-Like Stem Cells in Long-Lived Mice
Very small embryonic-like stem cells (VSELs) are supposed by some researchers to be a population of pluripotent stem cells that support adult tissues throughout life. Pluripotency, the capability to generate most or all of the cell types in the body, makes these stem cells potentially very useful in research and applications of regenerative medicine, where low-cost, reliable sources of large numbers of patient-matched cells for any tissue type are much in demand. The fewer steps along the way to obtaining that supply the better, so the prospect of obtaining pluripotent cells directly from a patient is attractive: that might eliminate the need to generate induced pluripotent stem cells or use some other reprogramming method.
Unfortunately there is some debate over whether VSELs exist at all, or at least in the form proposed by the various groups publishing papers on the topic. VSELs are not the only type of pluripotent stem cell thought to exist in adult tissue, and there are various other names given by various other research groups chasing much the same phenomenon. Independent replication of their work has been patchy however. This may all turn out to be a matter of cells choosing to alter their characteristics in response to circumstances at the end of the day, or the fact that it can sometimes take a few years for techniques in a new field to solidify and standardize. Given the amount of published work on putative pluripotent cells of various sorts in adult tissues I would be surprised to see it all come to nothing in the end, but there are clearly unexplained factors that make it difficult for the community to come to a consensus on this matter.
Here, for example, a research group are far enough down the road of working with VSELs to be comparing the details of their presence with and without calorie restriction in a long-lived mouse breed:
One of the proposed means of increasing life span is caloric restriction (CR). In support of this notion, it has been demonstrated that CR without malnutrition is an effective means to decelerate the aging process, increase median and maximum lifespan, as well as delay reproductive senescence in a variety of species, including mice.We recently reported that life span in experimental murine strains (e.g., Laron and Ames dwarf mice) correlates with the number of very small embryonic-like stem cells (VSELs) residing in adult tissues. Specifically, long-living murine strains with low levels of insulin-like growth factor 1 (IGF-1) circulating in peripheral blood (PB) display higher numbers of VSELs in bone marrow (BM) than age-matched normal control animals. The higher numbers of BM-residing VSELs in these animals also correlated with higher numbers of hematopoietic stem progenitor cells (HSPCs) in BM.
We envision that VSELs, which express several markers of pluripotency, are a population of early-development stem cells that, due to epigenetic changes in certain paternally imprinted genes involved in insulin/insulin-like growth factor signaling (IIS), are kept as a quiescent population of cells in adult tissues. Importantly, the epigenetic mechanism that attenuates VSELs responsiveness to IIS has a positive effect on maintaining their number in adult tissues. However, VSELS have the potential to become specified into more-differentiated tissue-committed stem cells (TCSCs) after reversing expression of imprinted genes to the somatic type. We also believe that VSELs most likely overlap with other types of early-development pluri/multipotent stem cells (e.g., spore-like stem cells, multipotent adult stem cells, or multipotent adult progenitor cells) in adult tissues described by other investigators.
Interestingly, a population of small cells corresponding to BM-purified VSELs has also been described in murine ovaries and testes. These ovary- and testis-residing VSELs have been postulated to be precursors of gametes both in mice and humans. We observed that long-living Laron dwarf mice, which we have demonstrated to have higher numbers of VSELs in BM, have the period of active ovulogenesis prolonged to an advanced age, and Laron dwarf mice older than 2 years can become pregnant and deliver healthy offspring.
Based on these observations and the well-known facts that CR lowers IGF-1 levels in PB and has a beneficial effect on life span in mice, we became interested in the effect of CR on the number of murine VSELs and HSPCs as well as on the morphology of ovaries and testes. In our studies, 4-week-old female and male mice were subject to CR by permitting feeding ad libitum (AL) only on alternate days for a period of 9 months.
Our data indicate that mice under CR have a higher number of BM- and spleen-residing as well as PB-circulating VSELs than control mice fed AL. CR also correlated with a higher number of HSPCs in hematopoietic tissues as well as with an increase in the number of primordial and primary follicles in ovaries. At the same time, however, no significant changes were observed in the testes of mice on CR. Thus, our data explain the positive effect of CR on longevity in mice by a novel early development stem cell related mechanism.