Now that senescent cells are widely acknowledged as a cause of aging and age-related disease, and now that a large industry is forming to find ways to destroy or otherwise render harmless these cells, a great deal more investigative work into the biochemistry of senescence is taking place than was the case in earlier years. While destruction is very straightforward, and certainly easier to engineer at the present time, a sizable faction of scientists are interested in finding ways to turn off the harmful signals secreted by senescent cells. It is this signaling, the senescence-associated secretory phenotype (SASP), that causes all of the damage: chronic inflammation; destructive remodeling of the surrounding tissue structure; encouraging nearby cells to also become senescent; and so forth.
Because the SASP is complicated and poorly mapped, and no doubt depends on the operation of scores of interacting mechanisms inside a cell, and few of those mechanisms are particularly well mapped in this context, it seems to me that investigating ways to modulate the SASP is more of an academic exercise than a road to therapies at the present time. It cannot possibly compare in efficiency to destroying senescent cells. The only reason to avoid destroying these cells would be the discovery of essential senescent populations, such as neurons in the brain that are both senescent and carrying out vital functions, perhaps. So far that hasn't been the case: old mice do just fine when given senolytic therapies to destroy senescent cells throughout the body, including the brain.
Nonetheless, we might ask whether or not there are master regulators of the SASP yet to be discovered. If so, their existence might make SASP suppression a more viable proposition in the future. The open access research results below may represent a step in that direction. The researchers have found what looks like a fairly important point of control for the SASP, or at least a point of dependency, and that suggests the possibility of a master regulator, even if the exact mechanism examined here turns out to be infeasible as the basis for a point of intervention (which seems quite likely to be the case at first glance).
Some of the damaging cell effects linked to ageing could be prevented by manipulating tiny parts of cells, a study shows. Scientists have shed light on how the harm caused by senescence - a vital cell process that plays a key role in diseases of ageing - could be controlled or even stopped. Researchers say the findings could have relevance for age-related diseases, although they caution that further research is needed.
During senescence, cells stop dividing. This can be beneficial in assisting wound-healing and preventing excessive growth. Some aspects of senescence are also harmful and can lead to tissue damage and the deterioration of cell health as seen in diseases of older age. Researchers focused on a chain of harmful processes triggered by senescence, known as the senescence-associated secretory phenotype (SASP). The SASP is a cascade of chemical signals that can promote damage to cells through inflammation. The researchers showed that manipulating a cell's nuclear pores - gateways through which molecules enter the heart of the cell - prevented triggering of the SASP. Findings also show that DNA had to be reorganised in space within in the cell nucleus in order for the SASP to be triggered.
Three-dimensional (3D) genome organization is governed by a combination of polymer biophysics and biochemical interactions, including local chromatin compaction, long-range chromatin interactions, and interactions with nuclear structures. One such structure is the nuclear lamina (NL), which coats the inner nuclear membrane and is composed of lamins and membrane-associated proteins, such as Lamin B receptor (LBR). Large blocks of heterochromatin are associated with the nuclear periphery, and mapping genome interactions with laminB1 identifies more than 1000 lamina-associated domains (LADs).
One situation in which there is a dramatic reorganization of heterochromatin is in oncogene-induced senescence (OIS) - a cell cycle arrest program triggered by oncogenic signaling. OIS cells undergo striking chromatin reorganization with loss of heterochromatin and constitutive LADs from the nuclear periphery and the appearance of internal senescence-associated heterochromatin foci (SAHFs). SAHFs are not observed in nontransformed replicating cells.
The nuclear envelope is perforated by nuclear pores that control transport between the cytoplasm and nucleus. The nuclear pore complex (NPC) is a large transmembrane complex consisting of ∼30 proteins called nucleoporin. The nuclear area underneath nuclear pores is devoid of heterochromatin. The nucleoporin TPR has been shown to be responsible for heterochromatin exclusion zones at the NPC.
The composition and density of the NPC change during differentiation and tumorigenesis. We therefore hypothesized that the NPC could contribute to global chromatin organization and that, specifically, heterochromatin organization could result from a balance of forces attracting heterochromatin to the NL and forces repelling it away from the NPC. In support of this hypothesis, we show here that nuclear pore density increases during OIS and that this increase is necessary for heterochromatin reorganization into SAHFs. We identified TPR as a key player in this reorganization. Furthermore, we demonstrated the functional consequences of heterochromatin reorganization in OIS for the programmed activation of inflammatory cytokine gene expression: the senescence-associated secretory phenotype (SASP).