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One extremely promising and emerging field of research is nano-biotechnology. Nano-biotechnology could potentially be an extremely powerful tool in our quest for a longer, healthier life.

Senescent cells are known to be essential in multiple aging processes. Getting rid of these problem cells is, therefore, something we could do to potentially increase our healthy lifespan, and nanoscale robots may help us do just this.

Detecting senescent cells

Senescent cells have different levels of gene expression and mitochondrial function, different epigenetics, and a different secretome profile. Therefore, they secrete specific molecules in specific quantities [1], and this is very important for detecting and targeting them.

The detection and targeting of these senescent cells is somewhat difficult and currently not very precise [1]. This is due to there being different types of senescent cells, including a non-chronic (non-damaging) type as well as changes in senescent cells that also occur in healthy cells. Currently, the most common way to detect senescent cells is by measuring SA-beta-gal activity. SA-beta-gal is an isoform of the beta-galactosidase enzyme (an enzyme normally responsible for the breakdown of sugars known as beta-galactosides). This isoform is widely expressed by senescent cells and is optimally active at pH 6.0, thus making it possible to detect these cells by assaying them for the presence of SA-beta-gal. However, this has major limitations, as SA-beta-gal can be expressed in non-senescent cells under certain conditions and is absent in some senescent cells [2]. Other markers for senescence, such as lipofuscin (pigment granules), have been used, but they also have limitations, such as not being exclusive to senescent cells. Regardless of the limitations, SA-beta-gal is a good marker for senescence until better markers are discovered. Once detected, we have to get to these cells, bind to them specifically, and kill them.

Nano-robots against senescent cells

A very promising way of doing this is by developing nano-scale robots that can travel through our bodies and bind to and destroy senescent cells when they detect them. The viability of this was clearly demonstrated by a team of Spanish researchers. The team developed a nanodevice that specifically delivers cargo to senescent cells and not to any other type of cells. The nanodevice has a substance which is “capped”, or covered, with galacto-oligosaccharide (GOS). Upon encountering senescent cells, this cap is cleaved by SA-beta-gal, releasing the cargo [3]. Several studies have demonstrated the feasibility of designing and producing nanoscale devices that contain multiple components [4, 5, 6, 7], such as components to detect and bind to specific sites, components that hold a drug, and a trigger that releases the drug only upon binding to the desired site.

Furthermore, in 2011, a team of scientists managed to create a nano-device that was guided to specific sites using magnetic resonance imaging (MRI) [8]. All this knowledge could possibly be combined and used in the future to manufacture precise, controllable nanorobots that would target and kill senescent cells, thus getting rid of one of the main causes of aging. So far, we have seen how we can detect senescent cells, get to them, and deliver a drug in order to eliminate them. However, what kind of drugs will we need to deliver in order to kill these cells?

How to kill senescent cells

There are currently two main approaches to get rid of senescent cells. One is to kill them with drugs, and the other is to get rid of them by using gene therapy. Drugs that specifically target and kill senescent cells are called senolytics.

Senescent cells, in theory, should commit apoptosis, since they become senescent as a result of damage and stress, and they do so in order to avoid becoming cancerous. Indeed, pro-apoptotic (or pro-suicidal) metabolic processes have been observed to be highly active in senescent cells. However, these cells do not commit suicide but stay alive and do not divide. Due to this, scientists hypothesize that there must be some mechanisms within the senescent cells that counteract their own suicidal tendencies. Indeed, research done on this detected proteins that were essential for senescent cell survival, and eliminating these proteins from senescent cells caused them to die. Therefore, these proteins and the pathways in which they are involved (senescent cell anti-apoptotic pathways, or SCAPs), as well as the genes that encode them, are good targets for senolytic drugs [9].

To date, several senolytic drugs have been developed. Research in this field is very active, more senolytic drugs are being developed, and more SCAPs will probably be identified in the future. However, there are many cell types, so there are many senescent cell types, and their SCAPs are different. Therefore, a single senolytic does not work on every senescent cell. This is where multicomponent nanorobots would come in handy. Indeed, there are several studies showing the feasibility of developing multicomponent, multifunctional nanorobots. In one study [4], molecules containing a hydrophobic (“water hating”) tail and a polar, hydrophilic (“water loving”) head group were designed. Due to the chemical properties of these molecules, when placed into a water-containing environment (such as the human body), they aggregate to form a spherical nanodevice called a micelle, which has its polar groups on its surface.

Such a polar group can be variable, and it can be changed and adapted to different purposes. For example, it can be adapted to be a molecule that recognizes senescent cells, or it can be adapted to be a molecule that interferes with a certain SCAP. Because these nanodevices are made up of many of these single molecules, different types of proteins can be attached to a single nanodevice. We could possibly, therefore, make a nanodevice that travels through the body, detects senescent cells, and targets different types of SCAPs; such a device would be useful against many (or all) senescent cell types.

P16-INK4a is a protein that is often associated with cellular senescence. Therefore, cells expressing this protein can be targeted, as a group of scientists demonstrated in 2016 [10]. Their approach was to deliver a gene to cells that express p16-INK4a, and this gene was under the control of the same machinery that transcribed the gene responsible for the p16-INK4a protein. This means that the inserted gene (called AP20187) would only be expressed in p16-INK4a expressing cells (i.e. senescent cells). AP20187 codes for apoptosis-inducing factors, thus causing senescent cells that express it to commit apoptosis, and this is indeed what happened in this study.

Because of their extremely small size and their ability to become multifunctional, nano-devices have great potential to become a very efficient way to deliver genes to cells, as they have recognition and delivery components on their surfaces as well as components that increase their solubility.

Proof of principle studies

So far, many of these studies were only done on mice, but they serve as proof of principle, and, hopefully, we will one day achieve the same results in humans. Researchers not only managed to significantly extend the life of mice, they also managed to rejuvenate old mice, as a team from the Netherlands showed in a 2017 paper [11]. They managed to target and kill senescent cells (and only senescent cells) in old mice that had damaged kidneys and were weak and losing hair. Upon treatment with the anti-senescent cell drug, the mice became more youthful, their hair started to grow back and to gain pigment, and their kidneys started functioning properly again. Furthermore, the mice started running on the wheel again and were more willing to explore their surroundings.

Studies done in the laboratory on human cells showed very promising results as well. In late 2017, a team from the University of Exeter managed to treat senescent cells with splicing factors (factors that ensure that genes are used properly and perform their desired functions) and make them divide and behave like youthful cells again [12]. This technique could possibly be used on the cells in our bodies.

Conclusion

There are other, similar results that give us great hope that life extension and rejuvenation technologies will become available to humans in the near future, potentially giving us the option of living significantly longer and healthier lives.

References

[1] Salmonowicz, H. and Passos, J. (2017). Detecting senescence: a new method for an old pigment. Aging Cell, 16(3), pp.432-434.

[2] Lee, B., Han, J., Im, J., Morrone, A., Johung, K., Goodwin, E., Kleijer, W., DiMaio, D. and Hwang, E. (2006). Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell, 5(2), pp.187-195.

[3] Agostini, A., Mondragón, L., Bernardos, A., Martínez-Máñez, R., Marcos, M., Sancenón, F., Soto, J., Costero, A., Manguan-García, C., Perona, R., Moreno-Torres, M., Aparicio-Sanchis, R. and Murguía, J. (2012). Targeted Cargo Delivery in Senescent Cells Using Capped Mesoporous Silica Nanoparticles. Angewandte Chemie, 124(42), pp.10708-10712.

[4] Peters, D., Kastantin, M., Kotamraju, V., Karmali, P., Gujraty, K., Tirrell, M. and Ruoslahti, E. (2009). Targeting atherosclerosis by using modular, multifunctional micelles. Proceedings of the National Academy of Sciences, 106(24), pp.9815-9819.

[5] Ignatyev, M. (2010). Necessary and sufficient conditions of nanorobot synthesis. Doklady Mathematics, 82(1), pp.671-675.

[6] Leary, S., Liu, C. and Apuzzo, M. (2006). Toward the Emergence of Nanoneurosurgery: Part III—Nanomedicine: Targeted Nanotherapy, Nanosurgery, and Progress Toward the Realization of Nanoneurosurgery. Neurosurgery, 58(6), pp.1009-1026.

[7] Wong, J., Mohseni, R., Hamidieh, A., MacLaren, R., Habib, N. and Seifalian, A. (2017). Will Nanotechnology Bring New Hope for Gene Delivery?. Trends in Biotechnology, 35(5), pp.434-451.

[8] Vartholomeos, P., Fruchard, M., Ferreira, A. and Mavroidis, C. (2011). MRI-Guided Nanorobotic Systems for Therapeutic and Diagnostic Applications. Annual Review of Biomedical Engineering, 13(1), pp.157-184.

[9] Kirkland, J., Tchkonia, T., Zhu, Y., Niedernhofer, L. and Robbins, P. (2017). The Clinical Potential of Senolytic Drugs. Journal of the American Geriatrics Society, 65(10), pp.2297-2301.

[10] Baker, D., Childs, B., Durik, M., Wijers, M., Sieben, C., Zhong, J., A. Saltness, R., Jeganathan, K., Verzosa, G., Pezeshki, A., Khazaie, K., Miller, J. and van Deursen, J. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), pp.184-189.

[11] Baar, M., Brandt, R., Putavet, D., Klein, J., Derks, K., Bourgeois, B., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D., van der Pluijm, I., Essers, J., van Cappellen, W., van IJcken, W., Houtsmuller, A., Pothof, J., de Bruin, R., Madl, T., Hoeijmakers, J., Campisi, J. and de Keizer, P. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, 169(1), pp.132-147.e16.

[12] Latorre, E., Birar, V., Sheerin, A., Jeynes, J., Hooper, A., Dawe, H., Melzer, D., Cox, L., Faragher, R., Ostler, E. and Harries, L. (2017). Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biology, 18(1).

About the author
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Vlad Cadar

As of June 2018, Vlad is about to graduate from the University of Manchester, where he studied for a biochemistry degree. Starting in September 2018, Vlad plans on beginning a master's degree in Molecular Genetics and Biotechnology at the University of Leiden in the Netherlands. He is extremely passionate about rejuvenation biotechnology, and after his studies, he intends to do research in this field. In the last year of his biochemistry degree, he completed a science communication project, and throughout his collegiate studies, he has written several well-received review articles.
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