The understanding that senescent cells existed and were important in human health and aging started sometime around the discovery and subsequent exploration of the Hayflick limit to cellular replication, in the 1960s. By the time that the SENS rejuvenation research proposals were first formalized, more than three decades later, a little after the turn of the century, the research community had a much better understanding of cellular senescence as a phenomenon, as well as a good deal of indirect evidence to show that (a) senescent cells accumulated with age, and (b) their presence contributed to age-related disease and dysfunction. That weight of evidence is why senescent cell clearance was included in the SENS proposals for rejuvenation therapies from the outset. In recent years, more direct evidence has been established, demonstrations of extended life and improved health in mice resulting from the targeted destruction of senescent cells. A range of methodologies are available to achieve this goal, and many of them are presently heading in the direction of clinical availability. Senescent cell clearance will likely be the first broadly available, actual, real rejuvenation treatment - a way to turn back one narrow part of the aging process.
Senescent cells cause harm through what is known as the senescence-associated secretory phenotype (SASP), the secretion of signals that spur inflammation, tissue modeling, and alterations in cellular behavior. Even a small number of senescent cells, say 1% of the cells in an organ, can alter tissue structure and the behavior of normal cells to a great enough degree to produce disease symptoms. Since there are so few senescent cells, however, their destruction is a feasible project: if removal can be accomplished in a selective manner, it will not greatly harm an organ. Some researchers are more interested in altering SASP, however, trying to minimize or block the damaging factors while leaving senescent cells present. This seems to me to be an inferior approach, one that will require a lot more work, and which is far less developed and understood than efforts to destroy these cells at the present time. The SASP is a very complex set of signals and molecules, and if a research group spends years working on removing one item from that mix, what then of all the others? Further, a SASP suppression therapy is something that would have to be taken as medicine on a continuing basis, whereas destruction of senescent cells can happen as a single treatment as needed, say once every few years.
Setting aside debates over methodologies and treatments, it is certainly the case that initial results from clearance of senescent cells have invigorated the field, pulling in greater funding and effort. It wasn't so many years ago that the few research groups involved in this work were struggling to raise any meaningful funding for studies in mice. Now, however, we're going to be seeing a whole lot more work in the years ahead on the characterization of senescent cells, improved methods of detection and targeting, and better understanding how and where these unwanted cells are contributing to specific age-related conditions. The research results linked below fall into the latter category: the researchers improve the understanding of the way in which diabetes produces blindness by showing that cellular senescence is a bridging mechanism in the retina. The metabolic alterations of diabetes produce a loss of oxygenation in the retina, which in turn produces greater numbers of senescent cells, and the SASP from those cells then causes disarray in retinal structure: inflammation and pathological growth of blood vessels that destroys the machinery of sight. It is an interesting point to consider that a range of diseases, age-related and otherwise, may provoke greater cellular senescence as a part of the progression of pathology, even though cellular senescence is not one of the main root causes of these condition. In this and similar ways all of the fundamental forms of cell and tissue damage that cause aging are linked together, feeding from one another, making up a web of interacting forms of damage and consequences.
Diabetic retinopathy is the most prominent complication of diabetes and the leading cause of blindness in working age individuals. The ability to control and cure this disease has been limited so far. But a study sheds new understanding on the mechanisms of the disease as it uncovered a program of accelerated aging of the neurons, blood vessels and immune cells of the retina in areas where blood vessels had been damaged. Researchers found that cells of the retina that are cut off from their main source of oxygen and nutrients during disease are resilient and do not die. Instead, they enter a state of cellular senescence where they are dormant yet start producing a series of factors that contribute the blinding disease.
The exciting work lead to the successful mapping and identification of the molecules that are activated during this process of premature aging. Interfering with the early cellular aging process occurring in mouse models of retinopathy with currently available and novel drugs resulted in improved regeneration of blood vessels within the retina and reduced retinal damage. "Currently available treatments for diabetic retinopathy are either invasive or present adverse side effects when used for long term regimens. Our study does not identify a cure, but by mapping out the events that lead to premature senescence in retinopathy, we are now able to consider novel therapeutic interventions to slow down the disease process and preserve vision."
Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP).
We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.