Neurogenesis is the creation and integration of new neurons into neural circuits, necessary for learning, and for the maintenance of functional brain tissue. Neural stem cells are responsible for providing a supply of new neurons, but, as is the case for stem cells throughout the body, their activity declines with age. Loss of neurogenesis is one important contributing factor in the aging of the brain. Considered at the high level, a progressive loss of stem cell activity may be an evolved response to rising levels of cell and tissue damage and dysfunction, reducing the risk of death by cancer at the cost of a slow decline into death by loss of tissue function. At the low level, scientists are digging in to the specific mechanisms involved in age-related stem cell dysfunction. Today's research materials are an example of this sort of research program, focused on neural stem cells in this case.
All stem cells produce daughter somatic cells via replication in order to maintain the tissues that they support. Stem cells practice asymmetric cell division as one of several necessary strategies needed to maintain the pace of replication over a lifetime. They unload accumulated metabolic waste and damaged components onto each new daughter somatic cell in order to keep the level of damage in the stem cell low. Researchers here identified that lamin B1 is important in ensuring this asymmetry in neural stem cells, but levels decline with age. They used a gene therapy approach to increase lamin B1 expression, thereby improving neural stem cell function and the supply of new neurons in mice.
A new study shows how the formation of new neurons is impaired with advancing age. Protein structures in the nuclei of neural stem cells make sure that harmful proteins accumulating over time are unevenly distributed onto the two daughter cells during cell division. This seems to be an important part of the cells' ability to proliferate over a long time in order to maintain the supply of neurons. With advancing age, however, the amounts of nucleic proteins change, resulting in defective distribution of harmful proteins between the two daughter cells. This results in a decrease in the numbers of newly generated neurons in the brains of older mice.
The central element in this process is a nuclear protein called lamin B1, the levels of which decrease as people age. When the researchers increased lamin B1 levels in experiments in aging mice, stem cell division improved and the number of new neurons grew. The research is part of several ongoing projects aiming to reactivate aging stem cells. The ability to regenerate damaged tissue generally declines with age, thus affecting almost all types of stem cells in the body. These latest findings are an important step towards exploring age-dependent changes in the behavior of stem cells. "We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer's. Even if this may still be many years in the future."
Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here, we show that the nuclear lamina protein lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus.