Senescent Cells & Aging

In truth, I had planned on writing about something else this week, but then I got distracted. What happened was, my attention (which at its optimum functions somewhere between a fruit fly and a goldfish) got diverted when I came across a few articles discussing the results of this study: "The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.". (You can download the full text PDF for free)


The articles responsible for piquing my interest: (Not so much for the prospect of prolonging our lifespan per say, rather for that of improving the quality of our lives as we age.)

• New class of drugs dramatically increases healthy lifespan, mouse study suggests March 9, 2015 ScienceDaily

• Senolytics: Scientists identify new drug that slows the ageing process and could dramatically increase our life expectancy  March 10, 2015 The Independent

• Why Old Age May Soon Look Very Different: Senolytics, A New Class of Drugs, Slows Aging Process March 11, 2015 MedicalDaily

SOME BACKGROUND INFORMATION

SENESCENCE, defined simply, is the halting of cell growth. [11]

SCENESCENT CELLS are thus cells with halted cell growth; the artful dodgers of programmed cell death (apoptosis). [11]

SENOLYTICS are a group of drugs that target and kill senescent cells in our bodies. [11]

Cellular Senescence

Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt a phenotype: [1] 

(upper) Primary mouse embryonic fibroblast cells (MEFs) before senescence. Spindle-shaped. 

(lower) MEFs became senescent after passages. Cells grow larger, flatten shape and express senescence-associated β-galactosidase (blue areas), a marker of cellular senescence. 

“Our cells have built-in programming that sometimes veers them far away from their normal fate. … Pushing these cells to undergo such transformations is favored by evolution because it meets short-term needs, and having a few of these abnormal cells in the body is nearly harmless. But the number of these cells in our tissues gradually rises over time, until by our fifth decade or so they begin to reach levels that are harmful to normal tissue function.” [2]

There are many mechanisms through which senescence is induced in our bodies; though all forms of cellular senescence seem to share common signaling pathways involving tumor suppressor protein p53. [3] 

P53 is a topic all on its own, but in brief: 

Upon DNA damage or other stresses, various pathways
will lead to the dissociation of the p53 and mdm2 complex.
Once activated, p53 will induce a cell cycle arrest to allow
either repair and survival of the cell or apoptosis to discard
the damaged cell. [4]

• Senescence can also play a role in wound response, preventing cells “from overstepping their bounds and generating an overgrowth of fibrous connective tissue.” [2]

Human chromosomes (grey) 

capped by telomeres (white) [5]

Replicative senescence can occur when the telomeric ends of DNA become too short. (An inevitability of the aging process.) [3]

"A telomere is a region of repetitive  nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighbouring chromosomes." [5]

The problem with the accumulation of these senescent cells in our bodies as we age is that:

“…senescent cells secrete abnormally large amounts of proteins that inflame the immune system and degrade the normal supporting tissue architecture. The relatively small number of such cells in youthful tissue is so small as to be harmless, but after decades of accumulation, the number becomes large enough that their abnormal metabolic state begins to pose a threat to surrounding, healthy tissues. Larger numbers of senescent cells in a tissue make it more vulnerable to the spread of cancer, contribute to inflammation, and skew the local activity of the immune system.” [2]

Published in the journal Nature in 2011, the work of Baker et al suggested that cellular senescence was a driving force behind aging and its associated diseases. When the researchers induced the elimination of senescent cells in transgenic mice, the subject mice retained the fat layers in the skin that usually thin out with age. Furthermore, the clearance of senescent cells slowed development of cataracts and age related muscle wasting, and increased stamina and endurance. [6][12]

NOW, BACK TO THE STUDY I READ ABOUT THIS WEEK 

The team of researchers from The Scripps Research Institute, Mayo Clinic and other institutions found that in senescent cells there was an increased expression of ‘pro-survival’ networks, “consistent with their established resistance to apoptosis.” [9]

Targeting key factors in these 'pro-survival' networks with the aim of selectively killing senescent cells, the team narrowed their focus onto two drugs: dasatinib, a cancer drug and quercetin, an antihistamine and anti-inflammatory. 

Administered individually, the drugs proved capable of selectively inducing death of senescent cells in vitro:

“The two compounds had different strong points. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells.” [7] 

When the two drugs were applied together, researchers observed a synergistic effect:

"Within five days of a single dose of the drugs, cardiovascular function was improved in the oldest mice. A single dose of the drug cocktail led to improved exercise capacity — as measured by the mice running on miniature treadmills — with the positive effects lasting for seven months or more. When the drugs were given periodically, the mice demonstrated delayed age-related symptoms, spine degeneration, and osteoporosis." [8]

“Our findings here give preliminary support for the speculation that these agents may one day find use for treating cardiovascular diseases, frailty, loss of resilience, including delayed recovery or dysfunction after chemotherapy or radiation, neurodegenerative disorders, osteoporosis, osteoarthritis, other bone and joint disorders, and adverse phenotypes related to chronological aging.” [9]

Preliminary support, yes; that said, the authors also note several of the issues still remaining to be addressed, including: the effects of age, type of disability or disease, sex, drug metabolism and immune function. And that the effects of these drugs on healthspan (duration of life spent in good health) and lifespan have yet to be tested on chronologically aged mice. [9] (Animal models of accelerated aging were used extensively in this study.) 

***

FIN

REFERENCES & RESOURCES

[1] Campisi, Judith (February 2013). "Aging, Cellular Senescence, and Cancer". Annual Review of Physiology 75: 685–705.doi:10.1146/annurev-physiol-030212-183653. PMID 23140366.

[2] http://www.sens.org/research/introduction-to-sens-research/deathresistant-cells

[3] http://www.ncbi.nlm.nih.gov/pubmed/17634581
[4] http://en.wikipedia.org/wiki/P53

[5] http://en.wikipedia.org/wiki/Telomere

[6]Baker, D.; Wijshake, T.; Tchkonia, T.; LeBrasseur, N.; Childs, B.; van de Sluis, B.; Kirkland, J.; van Deursen, J. (10 November 2011). "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders". Nature 479: 232–6.doi:10.1038/nature10600.

[7] New class of drugs dramatically increases healthy lifespan, mouse study suggests March 9, 2015 ScienceDaily 
Scripps Research Institute. "New class of drugs dramatically increases healthy lifespan, mouse study suggests." ScienceDaily. ScienceDaily, 9 March 2015. <www.sciencedaily.com/releases/2015/03/150309144823.htm>.

[8] Why Old Age May Soon Look Very Different: Senolytics, A New Class of Drugs, Slows Aging Process March 11, 2015 MedicalDaily

[9] Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava, Adam Gower, Husheng Ding, Nino Giorgadze, Allyson K. Palmer, Yuji Ikeno, Gene Borden, Marc Lenburg, Steven P. O'Hara, Nicholas F. LaRusso, Jordan D. Miller, Carolyn M. Roos, Grace C. Verzosa, Nathan K. LeBrasseur, Jonathan D. Wren, Joshua N. Farr, Sundeep Khosla, Michael B. Stout, Sara J. McGowan, Heike Fuhrmann-Stroissnigg, Aditi U. Gurkar, Jing Zhao, Debora Colangelo, Akaitz Dorronsoro, Yuan Yuan Ling, Amira S. Barghouthy, Diana C. Navarro, Tokio Sano, Paul D. Robbins, Laura J. Niedernhofer, James L. Kirkland. The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell, 2015; DOI: 10.1111/acel.12344

[11] http://en.wikipedia.org/wiki/Senolytics

[12] http://en.wikipedia.org/wiki/Senescence

Quick, Darren (March 10, 2015). "Senolytics: A new class of drugs with the potential to slow the aging process".

http://www.nature.com/nature/journal/v509/n7501/full/nature13193.html May 2014 Nature

The Independent (March 10, 2015) "Senolytics: Scientists identify new drug that slows the ageing process and could dramatically increase our life expectancy"

IMAGE CREDITS

"SABG MEFs" by Y tambe - Y tambe's file. Licensed under CC BY-SA 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:SABG_MEFs.jpg#/media/File:SABG_MEFs.jpg

"P53 pathways" by Thierry Soussi - Own work. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:P53_pathways.jpg#/media/File:P53_pathways.jpg

"Telomere caps" by U.S. Department of Energy Human Genome Program - Transferred from en.wikipedia; transfer was stated to be made by User:gustavocarra.(Original text : http://science.nasa.gov/media/medialibrary/2006/03/16/22mar_telomeres_resources/caps.gif). Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Telomere_caps.gif#/media/File:Telomere_caps.gif

"Irvington statue of Rip van Winkle" by Daryl Samuel - Own work. Via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Irvington_statue_of_Rip_van_Winkle.jpg#/media/File:Irvington_statue_of_Rip_van_Winkle.jpg