In just a few short years, the study of cellular senescence has grown enormously. It has become an area of intense interest and funding in comparison to its prior status as a thin sideline of cancer research and a yet another of the backwaters of aging research. Sadly, aging research considered as a whole is still a neglected, poorly funded field of medical science in comparison to its importance to all of our futures, but this will hopefully change soon. The 2011 demonstration of a slowing of degeneration in an accelerated aging lineage of mice via removal of senescent cells opened a great many eyes. A growing number of studies since then have shown reversal of many specific aspects of aging through clearance of senescent cells, and the potential for removal of senescent cells to form the basis for the effective treatment of many age-related diseases. These studies are accompanied by varied approaches to the selective destruction of these unwanted, harmful cells in aged tissues, including several classes of drug compound, gene therapies, and antibody therapies. This is an important transition for the study of aging as a medical condition: the first legitimate, working rejuvenation therapies now exist in their earliest stages. They have become a reality. From here the field will only become ever more promising.
The July issue of EBioMedicine gathers together papers from recent months to focus on aging and metabolism. Prominent in this collection are papers on the biology of senescent cells, the contribution of senescent cells to aging, and methods of selectively destroying senescent cells. I pointed out a few of these when they were first published online earlier this year, but I think it worth looking through the collection as it is presented here. This is the future: the stream that will become a flood, a huge new industry of medicine. It is impossible to work in the medical life sciences without having heard something of this newly important area of research and development. Senolytic therapies capable of safely clearing a large fraction of the burden of senescent cells in old individuals may well do more for health in later life than all of the heralded advances of the past thirty years, statins and early stem cell therapies included. These are exciting times that we live in - and then, I would hope, not too many years from now, we'll be able to say all of this again as glucosepane cross-link breakers become a reality as well, another line of rejuvenation research that should be just as influential, at the very least for cardiovascular health.
The mounting challenges healthcare systems face with an aging population are largely due to increased prevalence of noncommunicable diseases (NCDs). In 2015, NCDs accounted for 70% of all deaths globally. 80% of NCD-related deaths are attributed to cardiovascular disease, cancer, respiratory diseases, and diabetes. In this issue find a series of articles discussing diverse aspects of geroscience - the relatively new field of understanding the biology of aging and age-related disease. At the core of geroscience research is the dogma that aging is not simply an immutable outcome of life, but that its biological underpinnings, once understood, can be manipulated to improve health. From the series of pieces presented in this issue, it becomes apparent that aging and age-related disease are intimately entangled with metabolic function, both at the molecular/cellular and organismal levels. The etiology of cardiovascular disease, cancer, lung, liver, and kidney dysfunction, and diabetes can be at least in part attributed to metabolic defects associated with increasing age.
Cellular senescence describes the phenomenon where somatic cells cease to divide, become resistant to apoptosis, and develop a senescence-associated secretory phenotype (SASP) that can have deleterious effects on surrounding tissues and throughout the body. One article discusses the role of mitochondrial dysfunction in cellular senescence and how breakdown of mitochondrial components (mitophagy) is likely involved in senescence and aging. How telomeres - irrespective of length, contrary to the previous notion that shortened telomeres were simply a readout of a cell's age - can both protect against and effect cellular senescence programs is discussed in another article. Translational approaches to targeting the biological basis of aging is a rapidly-developing field. A third article discusses targeting cellular senescence programs to improve fitness. Among these approaches are so-called senolytic agents, which selectively clear senescent cells and relieve the associated pathophysiology they confer.
So far, the best explanation for replicative senescence is the shortening of telomeres, regions composed of DNA repeats associated with proteins, found at the ends of chromosomes. In the 1990s, it was shown that telomere regions gradually shorten with cell division and that this correlates with the induction of cellular senescence. Importantly, it was demonstrated that ectopic expression of the enzyme telomerase, which is capable of elongating telomeres, counteracts telomere shortening driven by cell division and bypasses the senescence arrest. This experiment demonstrated that telomere length was the limiting factor in the senescence arrest and therefore played a causal role in the process. Since then, great advances have been made in the understanding of how telomeres are able to signal the senescence arrest. These mechanisms are of particular importance in the field of ageing, since cellular senescence, driven by telomere dysfunction, has been shown to be a causal driver of ageing and age-related pathology.
In recent years, important conceptual advances have been made in terms of our understanding of the role of senescent cells in vivo. It is now clear that the impact of senescence in vivo is not restricted to the loss of proliferative capacity. Apart from the cell-cycle arrest, senescent cells have been shown to experience dramatic changes in terms of gene expression, metabolism, epigenome and importantly, have been shown to have a distinct secretome profile, known as the Senescence-Associated Secretory Phenotype (SASP), which mediates the interactions between senescent and neighboring cells. The SASP includes pro-inflammatory cytokines as well as growth factors and extracellular matrix degrading proteins and is thought to have evolved as a way for senescent cells to communicate with the immune system (potentially to facilitate their own clearance), but also as an extracellular signal to promote the regeneration of tissues through the stimulation of nearby progenitor cells. Nonetheless, it has been shown that a "chronic" SASP is able to induce senescence in adjacent young cells, contributing to tissue dysfunction.
Recent data indicates that senescent cells play a variety of beneficial roles during processes such as embryonic development, tumor suppression, wound healing and tissue repair. On the other hand, senescent cells have been detected in multiple age-related diseases and in a variety of different tissues during ageing. The positive and negative effects of senescence in different physiological contexts may be a reflection of the ability of the immune system to effectively clear senescent cells. It has been speculated that an "acute" type of senescence plays generally beneficial roles in processes such as embryonic development and wound-healing, while a "chronic" type of senescence may contribute to ageing and age-related disease. The role of telomeres in the induction of these two types of senescence is still unclear. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres.
Cell senescence is increasingly recognized as a major contributor to the loss of health and fitness associated with aging. Senescent cells accumulate dysfunctional mitochondria; oxidative phosphorylation efficiency is decreased and reactive oxygen species production is increased. In this review we will discuss how the turnover of mitochondria (a term referred to as mitophagy) is perturbed in senescence contributing to mitochondrial accumulation and Senescence-Associated Mitochondrial Dysfunction (SAMD). We will further explore the subsequent cellular consequences; in particular SAMD appears to be necessary for at least part of the specific Senescence-Associated Secretory Phenotype (SASP) and may be responsible for tissue-level metabolic dysfunction that is associated with aging and obesity. Understanding the complex interplay between these major senescence-associated phenotypes will help to select and improve interventions that prolong healthy life in humans.
There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species, however, reducing the risk of results in mice failing to translate to humans. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans, perhaps given during periods of good health. If so, this would reduce risk of side-effects. Progression from the discovery of the first senolytics to being at the point of initiating proof-of-concept clinical trials has been remarkably fast. With sustained effort and a lot of luck, these agents could be transformative.