A Conservative Scientific View of Cellular Senescence and Aging

The evidence for cellular senescence to increase with age, and in doing so act as a root cause of aging, is extensive and compelling. It starts with decades of indirect evidence, increasing the research community understanding of how senescent cells behave and what the results of that behavior are at the small scale, and has led up to recent animal trials of senolytic treatments that selectively destroy senescent cells, demonstrated to produce extended life and reversal of specific, measurable aspects of aging. It is, however, still the case that from a very conservative scientific view, in which outright, direct proof of every aspect of a theory is desired, there are sizable gaps in the understanding of cellular senescence in aging. That will not stop the development of senolytic rejuvenation therapies, which can proceed on the practical basis of following the path that works, which is to say targeted removal of senescent cells, but it does make it possible to write papers on the sort noted here, in which those gaps are explored.

The present consensus view of senescence cells is that there are numerous distinct types of such cell, their senescent state caused either by stress, toxins, or reaching the Hayflick limit on cellular replication. All these classes of senescent cell behave in similar ways, and most destroy themselves quite quickly after becoming senescent, or are destroyed by the immune system. A few linger, however, and churn out a mix of signals that disrupt regenerative processes, spur inflammation, scramble important extracellular matrix structures, and alter the behavior of nearby cells for the worse. A small number of senescent cells, even just 1% by number in a tissue, can significantly damage organ function.

Nonetheless, a fair amount of this picture is not completely stitched together and beyond reasonable doubt, if the point of view is to be one of absolute proof, demanded end to end. There are self-contained studies showing benefits attained through clearing senescent cells, and of course the life span study from last year, but also question marks over how cellular senescence is assessed, what the common markers for senescence actually signify, and the degree to which senescence increases in various tissues over time. This is usual for any developing field of research. As a topic, like much of practical aging research, cellular senescence was poorly funded, near ignored for decades. Now that proofs have emerged of its importance, more researchers are interested and the funding is available to double back and fill in all the places that would benefit from more rigorous assessment. Again, that really doesn’t make much difference to the development of the first generation of rejuvenation therapies based on destruction of senescent cells; that is forging ahead as an exercise in engineering rather than science. Filling in the gaps in understanding will probably help to improve the quality of the second generation of such therapies, however.

Stress, cell senescence and organismal ageing

Because cells are the fundamental building blocks of humans and animals, it is clear that cellular changes contribute to the ageing process. A major open question, however, is the nature of those changes and how exactly they contribute to degeneration and disease in old age. In 1961, it was discovered that human cells can only divide a finite number of times in culture. The limited proliferative ability of human cells in vitro, known as replicative senescence (RS), has since become a major focus of research in biogerontology. In addition to RS, a number of factors can accelerate and/or trigger cell senescence, including various forms of stress like oxidative stress.

For a long time it was debated whether the discovery of cellular senescence had any physiological relevance or was merely an artefact of cells grown in relatively artificial culture conditions. It was proposed that senescence may represent ageing, however, recent data has revealed that this view is too simplistic, since senescence has been shown to play multiple important physiological roles, such as: tumour suppression, tissue repair and wound healing, embryonic development, and age-related degeneration. In addition, senescent cells have been detected in the context of many different age-related diseases, including atherosclerosis, lung disease, diabetes, and many others.

Given the multitude of functions of senescent cells, which can be of a positive or negative nature depending on the context, it has been argued that there may be different types of senescence rather than a universal phenotype. For instance, senescence during embryonic development occurs transiently, since senescent cells are rapidly removed by the immune system after executing their role, and is not associated with the activation of a DNA damage response (DDR). In contrast, during ageing, senescent cells are thought to be persistent, induced by random molecular damage and associated with the activation of a DDR. Recent work has demonstrated that senescent cells are able to attract (potentially via the secretion of chemokines) different immune cells. It is possible that persistence of senescent cells in tissues during ageing and age-related diseases is a consequence of the inability of the immune system to clear senescent cells – in view of the well reported decline of the immune system with age – however this has not yet been experimentally tested.

Do senescent cells accumulate with age? One of the main challenges to the study of senescence in vivo has been the absence of a universal marker that can unequivocally identify senescent cells. The most widely-used marker is the presence of senescence-associated β-galactosidase (SA-β-gal) activity. Both in vitro and in vivo, the percentage of cells positive for SA β-gal increases with, respectively, population doublings and age. However, there are major limitations to the use of this marker, since SA-β-Gal staining can also be detected in immortalized cells and quiescent cells. Also, it has been suggested that a major limitation of using SA β-gal staining in vivo is a false-positive signal from macrophages and other pro-inflammatory cells. In addition, since it requires fresh tissues, its detection is not straightforward technically and has more than often generated conflicting results.

Given the challenge of identifying a specific marker able to identify senescent cells, most researchers currently rely on a multiple marker approach. Indeed, several markers have been identified which are closely associated with cellular senescence, including absence of proliferation markers, changes in heterochromatin, telomere-associated DNA damage, expression of cyclin-dependent kinase inhibitors p21, p16, and senescence-associated distension of satellites (SADS). In a variety of mouse tissues, it is clear that most of these markers increase with age; however, given the fact that most of these markers are not exclusive for senescent cells, the exact frequency of senescent cells in older tissues is still unknown. Furthermore, given the limited availability of tissues, little is known about the accumulation of senescent cells with age in healthy humans.

Interestingly, many senescence markers have also been found in post-mitotic tissues such as neurons, adipocytes, and osteocytes, which goes against the dogma that senescence is restricted to proliferating cells. It is possible that with ageing, senescence-inducing pathways (which play roles in tumour suppression and during development) can be inadvertently switched on during ageing of post-mitotic cells. However, given that the primary characteristic of senescence is a permanent cell-cycle arrest, the consequences of the activation of these pathways in post-mitotic cells are still not understood.

While there is little evidence to suggest that cells running out of divisions are a major factor in ageing, it is possible that stress and various insults are contributors to senescence in vivo. Even a small fraction of senescent cells in organs may impair tissue renewal and homeostasis, decrease organ function, and contribute to the ageing phenotype, as shown by the studies genetically ablating senescent cells. While our knowledge about senescence in vivo has increased exponentially in the last decade, this is mostly through work using laboratory mice, which have known limitations. As such, one major challenge in the field is to determine levels of senescent cells in human tissues and whether they contribute to ageing and/or pathologies in humans. Furthermore, given the diverse functions of senescent cells in processes such as repair, wound healing, cancer, development and ageing, we still need to better characterize senescence in vivo in these different contexts. Finally, we still know very little about in vivo rates of occurrence and turnover of senescent cells. Therefore, in spite of recent advances in our understanding of senescence, many questions remain and these will be timely and important areas of research for years to come.

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