Can Cellular Senescence be Reversed in the Near Future, and is Reversal Desirable?

Cellular senescence is one of the causes of degenerative aging. Normal somatic cells in adults become senescent at the end of their replicative life span, when they reach the Hayflick limit on cell divisions, or in response to damage or a toxic environment. Most such cells self-destruct or are destroyed by the immune system, but some linger to cause problems, ever more of them over the years. A senescent cell generates a mix of signals known as the senescence-associated secretory phenotype (SASP) that promotes inflammation, damages surrounding tissue structures, and alters the behavior of nearby cells for the worse. Senescence isn't all bad, however: in limited doses, it helps to lower the risk of cancer by shutting down those cells most at risk. It also occurs during wound healing and embryonic development, and plays necessary roles in both of those processes. Nonetheless, cellular senescence helps to kill us as we age, and as more of these cells accumulate in tissues, their presence speeds the progression of many age-related diseases.

Researchers are taking two broad approaches to cellular senescence at the present time. The first is to build therapies that can selectively destroy senescent cells, following the SENS rejuvenation model of periodic removal of damage. If the number of senescent cells is managed so as to keep that count low, then they will not cause further harm. This has the advantage of being straightforward and requiring little further research to put into practice. A range of demonstrated treatments and potential treatments already exist - gene therapies, immunotherapies, senolytic drugs, and so forth - and companies such as Oisin Biotechnologies and UNITY Biotechnology are bringing some of these technologies to the clinic. The second approach is nowhere near as far along, and involves altering the behavior of senescent cells to make the SASP less harmful. There is a long way to go yet in order to produce a decent therapy on this front, and it isn't clear how much potential there is in the present avenues of investigation, or how much more research is required to make meaningful progress. Such a therapy wouldn't remove senescent cells, and therefore would have to be a continual rather than periodic treatment.

There is a third potential approach, however, which is to revert senescent cells back to a normal state of operation. In the ordinary course of events, senescence is thought to be an irreversible state, though there is a substantial grey area here, as nothing is black and white in biochemistry. There may well be different degrees and types of senescence, similar outcomes produced by different balances of the same varied collection of processes and triggers. I think it highly unlikely that the switch for senescence boils down to one controlling protein and one configuration. That said, cells are state machines and substantial reprogramming of that state has already been demonstrated, such as for induced pluripotency. Given sufficient understanding of the machinery and the signals involved, it should be possible to turn a senescent cell into a perfectly normal cell. There is the caveat that it will probably just turn right back again if the stimulus or damage that provoked the change in the first place is still around, however. Thus any practical approach to revert senescence is likely only useful if accompanied by other forms of repair or alteration, such as lengthening of telomeres to push the cell back from the Hayflick limit. It is an open question as to whether or not this sort of approach would cause further problems by putting damaged and older cells back into circulation, but to a certain extent that question is in the process of being answered by work on telomerase gene therapies and first generation stem cell therapies, both of which appear to produce that outcome to some degree. This is all highly speculative, however - there is a lot of work left to be accomplished to turn arguments and evidence into solid facts.

From my point of view none of this is really worth the effort for therapeutic development given that senescent cells can be destroyed to produce benefits, and anything other than destroying them is going to be much harder to achieve. It is of course useful from a pure science perspective; it adds to the map of metabolism and the way in which cellular biochemistry interacts with aging. With that in mind, the paper linked below is an example of researchers investigating some of the machinery that forms the switches and triggers that determine whether or not a cell adopts a senescent state. At this point the cutting edge of cellular biochemistry has moved well past simpler considerations of genes and proteins and is delving into the highly complex interactions that take place inside the processes of gene expression, wherein the genetic blueprint is converted into one or more proteins. This has numerous stages, and at every stage there is a dance of various regulatory molecules also produced from DNA. The closer that researchers look, the more there is to be mapped.

Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1

Cellular senescence is a state of indefinite growth arrest triggered by exposure of a cell to stress-causing stimuli. When the stress signal arises from successive rounds of replication causing gradual shortening of telomeres, which exposes telomeric DNA and triggers a DNA damage response, the ensuing program is named replicative senescence. When the stress signal comes from other sources of damage, such as oxidants, radiation, heat, activated oncogenes, or toxins, the ensuing program is named stress-induced senescence. Senescence is characterized by increased activity of the tumor suppressor TP53, higher levels of its transcriptional target p21/CDKN1 and the CDK inhibitor p16/INK4A, and activation of the p16 target retinoblastoma (pRB). Senescent cells have a complex impact on human physiology and pathology. Some effects of senescent cells are beneficial, such as tissue remodeling, wound repair, and growth suppression of potentially oncogenic cells. However, many effects of senescent cells are believed to be detrimental. Besides causing tissue dysfunction, senescent cells exhibit a senescence-associated secretory phenotype (SASP), whereby they produce and secrete inflammatory cytokines and chemokines, matrix metalloproteases, and growth and angiogenic factors. The accumulation of senescent cells has been associated with disease processes such as sarcopenia, arthritis, cancer, diabetes, and neurodegeneration.

MicroRNAs (miRNAs) are ∼22-nucleotide long noncoding (nc)RNAs that form part of the RNA-induced silencing complex (RISC), within which the RNA-binding protein (RBP) AGO2 binds microRNAs directly. MicroRNA-RISC complexes influence protein expression patterns through the interaction of the microRNA with subsets of mRNAs via partial complementarity, generally leading to reduced stability and/or reduced translation of the mRNA. By influencing protein expression patterns, microRNAs have been implicated in key cellular processes, including numerous pathways that control senescence. Indeed, many microRNAs show altered expression levels during senescence. A notable class of microRNAs implicated in growth arrest and senescence is the human let-7 family. Given that let-7 members are expressed from genomic regions that are deleted in tumors and that they suppress expression of oncogenes and proteins that enhance cell proliferation, the let-7 family has been implicated in tumor suppression. Conversely, let-7 members have been proposed to promote senescence, as their levels rise during cell senescence and let-7 suppresses the production of proteins that promote proliferation and inhibit senescence.

Circular RNAs (circRNAs) are ncRNAs that form covalently closed circles. Initially, they were considered byproducts of splicing, but recent work has revealed that a vast number of circRNAs exist in mammalian cells and that some of them are abundant and stable, suggesting that they may have regulatory functions in the cell. A substantial fraction of spliced transcripts gives rise to circRNAs, but the repertoire of transcripts from which circRNAs are derived is cell type-specific, supporting the notion that circRNA biogenesis and function may be highly regulated. CircRNAs are believed to influence several cellular processes. CircRNAs have been known for more than two decades but did not draw much attention until recently, when their high abundance was revealed by transcriptome-wide RNA-sequencing and several circRNAs have been characterized as inhibitors of microRNAs and thus regulators of gene expression.

Here, we used high-throughput RNA sequencing (RNA-Seq) to survey senescence-associated circRNAs (which we termed 'SAC-RNAs') differentially expressed in proliferating and in senescent human fibroblasts. Among the circRNAs selectively reduced in senescent cells, we focused on CircPVT1, as silencing CircPVT1 in proliferating cells triggered senescence. Although several microRNAs were predicted to bind CircPVT1, only let-7 was found enriched after pulldown of endogenous CircPVT1, suggesting that CircPVT1 might selectively modulate let-7 activity and hence expression of let-7-regulated mRNAs. Reporter analysis revealed that CircPVT1 decreased the cellular pool of available let-7, and antagonizing endogenous let-7 triggered cell proliferation. Importantly, silencing CircPVT1 promoted cell senescence and reversed the proliferative phenotype observed after let-7 function was impaired. Consequently, the levels of several proliferative proteins that prevent senescence, such as IGF2BP1, KRAS and HMGA2, encoded by let-7 target mRNAs, were reduced by silencing CircPVT1. Our findings indicate that the SAC-RNA CircPVT1, elevated in dividing cells and reduced in senescent cells, sequesters let-7 to enable a proliferative phenotype.

Comments

It would be more easy and safe to prolong the telomeres before the cella become senescent.

Posted by: Martin S. at December 14th, 2016 3:36 AM

I'm wondering what does happen with the "empty space" thats left when you destroy a senescent cell. Is it repopulated by a new cell or does it stay "empty"? If so, wouldnt it be a problem to accumulate more and more of "empty space" as we remove more and more senescent cells?

I'm not a researcher, so sorry if thats a stupid question (just sprang to my mind).

Gab

Posted by: Gab at December 14th, 2016 5:25 AM

@Gab: When the cell is dead/dying, it's eaten by a macrophage or another cell and that eater produces growth factors, that promote the replacement of the dead cell: https://en.wikipedia.org/wiki/Efferocytosis

Posted by: Antonio at December 14th, 2016 6:38 AM

Thank you for the info, Antonio. Good to know.

Posted by: Gab at December 14th, 2016 7:24 AM

Gudkov and others are also investigating senescent associated macrophages (SAMS) and believe these are the best target for senolytics. The macrophages clear up the junk and dead cells and modulation of macrophages can effect plaques and all kinds of things so I can see why they think this. Ultimately I think the most mileage is in repairing immunosenescence so that the body has a functionally young immune system capable of removing senescent cells as part of its normal operation. The obvious combo would be a round of senolytics followed up with rejuvenation/replacement of the immune system. We are currently testing rejuvenated macrophages to this end.

Posted by: Steve Hill at December 14th, 2016 7:47 AM

One concern is that the extracellular matrix may play a role in inducing fibroblast senescence. If so, ECM repair might also be quite important, e.g., see -
" Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix"
http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2010.00654.x/full

"Rejuvenation of chondrogenic potential in a young stem cell microenvironment"
https://www.researchgate.net/profile/Jingting_Li/publication/258034394_Rejuvenation_of_chondrogenic_potential_in_a_young_stem_cell_microenvironment/links/00463527272b1947c2000000.pdf

Posted by: Lou Pagnucco at December 14th, 2016 2:20 PM

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