Identification and Targeting of Noncanonical Death Resistant Cells

SENS Research Foundation Research Center

Forever Healthy Foundation Fellowship in Rejuvenation Biotechnology

Principal Investigator: Tesfahun Admasu

When cells age, they lose their proliferative capacity and stop dividing in a phenomenon called senescence. Cellular senescence decreases the regenerative capacity of cells and tissues.

Throughout the aging process senescent cells accumulate and secrete a characteristic set of proteins, called a senescence-associated secretory phenotype (SASP). Although SASPs act as tumor suppressors and recruit immune cells to repair damage, they also mediate the deleterious effects of senescence to cause different pathologies, such as cancer, neurodegenerative diseases and diabetes. Furthermore, SASPs induce senescence in the surrounding cells (secondary senescence), which aggravates the effect.

Small molecules, called senolytics, eliminate senescent cells and reduce certain age-associated disorders.

Project Goals

This project seeks to test the hypothesis that secondary senescent cells are different from primary senescent cells and would therefore need a different set of senolytics to eradicate. In addition, the project will study the role of the different SASP components involved in the spreading of senescence, and test the hypothesis that intervening in SASP signaling could be therapeutically viable.

Job Opportunity: Research Assistant (ImmunoSENS)

SENS Research Foundation (SRF) is hiring a Research Assistant for our Research Center (RC) located in Mountain View, CA. SRF is an exciting, cutting edge non-profit dedicated to transforming the way the world researches and treats age-related disease.

We are seeking a Research Assistant in our ImmunoSENS group for a project geared toward developing therapeutic interventions to rejuvenate immune clearance of senescent cells. This project involves working with human blood samples and primary human cells. This is a full-time position.

Qualified candidates will have a BS or MS in the chemical/biological sciences and substantial bench experience. Duties will include mostly bench work in a small team-oriented environment.

Candidates should have experience in WBC purification, culturing primary cells, quantitative real-time PCR, western blot, immunofluorescence, ELISA, micro plate readers, FACS analysis, and data analysis. Candidates with experience in 2nd and 3rd generation lentivirus system are particularly encouraged to apply.

Interested candidates should submit a cover letter and resume to [email protected].

We offer an excellent benefits package including paid vacation and sick leave, fully covered health insurance (inclusive of dependents), an FSA program, and a company matched 401(k) plan, all of which is offered after a 90-day introductory period. SENS Research Foundation is an equal opportunity employer.

The position is available now and will be filled as soon as the qualified candidate is found. Salary is commensurate with job title.

Job Type: Full-time
Salary: $48,000 to $50,000/year

Question of the Month: Senolytics – Solution or Self-Defeating for Senescent Cells?

Q: When senolytic drugs cause senescent cells to die, other (younger) cells need to divide and take the place of the dead cells. This cell division causes telomere shortening, thus possibly creating new senescent cells. How is it that the process of killing senescent cells is not self-defeating if new senescent cells are being created?

There are a couple of ways to come at this question. The first is to just look at the astonishing beneficial effects of senolytic drugs or gene therapies in aging mice and mouse models of age-related disease.1,2 In these studies, senolytic drugs have restored exercise capacity1 and capacity to form new blood and immune precursor cells3 in aging mice to near youthful norms, while preventing age-related lung hypofunction,4 fatty infiltration into the liver,5 weakening or failure of the heart,1,6,7 osteoporosis,8 and hair loss.9 These treatments have also prevented or treated mouse models of diseases of aging like osteoarthritis,10 fibrotic lung disease,11,12 nonalcoholic fatty liver disease (NAFLD),5 atherosclerosis,13,14 cancer15 and the side-effects of conventional chemotherapy,2,16 as well as neurodegenerative diseases of aging like Parkinson’s17 and Alzheimer’s18,19,20 diseases… and on and on! So whatever collateral damage might ensue from ablating senescent cells, it’s pretty clear that senolytic treatments are doing a lot more good than harm.

But let’s drill down on the underlying reasoning of the question a little more. Suppose (as the question posits) that every time you destroy a senescent cell, a progenitor cell (one of the partly-specialized tissue-specific cells that repopulate a tissue with mature cells specific to that tissue) replicates to create a new cell to take its place. In fact, studies do show that when senescent cells are killed in a tissue, the progenitor cells begin to multiply and/or to function better as stem cells. This benefit is not due to the progenitor cells automatically replicating themselves and taking the place of the senescent cell, but because the baleful secretions spewed out of senescent cells inhibit the progenitor cells’ regenerative function, such that destroying senescent cells allows the progenitor cells to begin working properly again. This is observed in blood-cell-forming cells,3 cardiac progenitor cells,6 bone-forming cells,8 and the cells that form new fat cells — in both mice21 and now (in a small, short-term clinical trial) even in humans!22

So does this support the worry behind the question? Not really. It just takes a moment’s thought to realize that just one such replication can’t possibly be enough to drive a stem/progenitor cell into senescence: if it did, of course, senolytic therapies would fail to reduce the net burden of senescent cells. But studies clearly show that administering senolytics does lower the overall number of senescent cells in aging and diseased tissues.

Also, if these drugs were not killing more senescent cells than they indirectly produced, you wouldn’t get relief from the harmful effects of having a high burden of senescent cells — and, of course, you do, in multiple tissues and in multiple models of aging and age-related disease.

Going Back to the Well for More

Still, even if a single round of senolytics isn’t enough to drive your stem cells senescent, what if you turn one tissue stem cell senescent for every two times they are triggered to proliferate by senolytic therapy — or every three, or four, or ten? Might a single round of senolytic drugs be a net benefit, whereas repeated treatments over a lifetime would deplete tissue stem cells step by step, eventually riddling the body with senescent cells and leaving the patient (murine or human) worse off over the long term?

Fortunately, we have long-term studies to address that question — and they tell us again that the answer is “no.”

In a study that played a critical role in launching the senolytic drug revolution,15 mice were engineered with a genetic self-destruct mechanism built into all of their cells, which would lie dormant until activated by a two-part command: one, the expression of the gene p16, which is characteristic of senescent cells; and two, an activating drug that scientists could administer to control the pace of senolytic activity. The researchers then waited until the animals were 12 months old (in human terms, this is similar to a person in his or her early 40s) before administering the drug for the first time. They then continued administering the drug every two weeks for the next six months — at which point the animals had received thirteen rounds of senescent cell-clearing therapy, and were roughly similar to humans in their mid-fifties.15

The study clearly showed that the animals benefitted from senolytic therapy, even after undergoing round after round of treatment across the span of their natural middle age through to early natural seniority.15 For instance, the animals whose senescent cell autodestruct mechanism had been triggered subsequently retained more functioning filtering units in their kidneys with age, and fewer of them died in middle age and early seniority.15

More directly on point with our question, the researchers looked to see the effects of multiple rounds of senolytic therapy on total senescent cell burden, and whether they substantially depleted the animals’ reserves of functional progenitor cells by forcing them to divide their way into senescent doom.14 To do this, the investigators looked at the effects of treatment on the preadipocytes (the progenitor cells that form fat cells (adipocytes)) in the animals’ fat tissue — a convenient place to look, because it’s easy to get at, and because it accumulates substantial numbers of senescent cells with age.

After some 13 rounds of senolytic therapy, the treated animals had only one eighth the number of senescent preadipocytes as controls (Figure 1(a)) — a very substantial net reduction. Yet even so, the treated animals still had just as many functional progenitors left — or so close to as many that the difference was indistinguishable from chance (Figure 1(b)).15

Figure 1.

Activating senolytic “self-destruct” genes throughout midlife sustainably slashes senescent cell count (a) with no or very small effects on progenitor numbers (b) in adipose tissue. Bars in (b) with # are differences that were statistically significant. Redrawn from (15).

In another study,23 researchers administered the natural senolytic compound fisetin to mice every single day, starting from the point when they were already in early seniority (and thus already had both a large number of senescent cells, and a dwindling supply of progenitor cells) and continuing on until their death. The extended treatment slashed the number of senescent cells in most tissues in the order of 50%. On top of that, the animals lived substantially longer, and their tissues suffered less severe age-related degenerative lesions than control animals.23

Out with the Old - and In With the New

That said, it is important to have plenty of functional cells around in order to reap the full benefits of senolytic therapy. This was illustrated in a study using senolytic drugs or “self-destruct” genes to treat animal models of osteoarthritis.10 When joint disease was initiated by injury in young animals, the insult led to chronic joint damage and an accumulation of senescent cells in the synovium (the membrane surrounding the joint, where is the cells that maintain the complex fluid that lubricates the joint reside). Eliminating senescent cells reduced the inflammation in the joint, prevented joint erosion, and alleviated signs of pain in the animals.10

But senolytic treatment was much less effective when the scientists repeated the experiment in old animals, and the reasons why shed some light on our original question. Compared to young animals, the old animals accumulated many more senescent cells after their joints were injured, and those cells developed at deeper layers of the tissue, accompanied by more severe osteoarthritis.10 Perhaps this is because in the aging animals, more cells had already suffered significant aging damage, and were thus primed to be tipped over into senescence when injured. And when old animals were then administered senolytic treatment, the remaining healthy cells didn’t respond as well: the burden of zombie cells went down, and the old animals still got some pain relief, but genes that helped the young animals regenerate their damaged joints were not activated, and the cartilage quality score did not improve. The researchers suggest that this could be due to a decline in the number or functional capacity of the non-senescent cartilage-forming cells, driven by degenerative aging processes.10

Similarly, destroying senescent cells in aging mice reduced the excessive numbers of osteoclasts (cells that break down bone) that accumulate in aging bone, but did not restore the dwindling supply of bone-forming osteoblasts, lack of which no doubt constrained the rejuvenating effects of senolytic treatment in restoring the aging bone.8

In both of these cases, the lack of a boost to the number or activity of youthful cells was not the result of damage from the senolytic drug: the failing supply of such cells had already occurred before treatment was initiated. So the problem is not that senolytic therapies stop working or become counterproductive over time: rather, it’s that they only target one kind of aging damage, whereas aging drives disease and disability because of the accumulation of multiple kinds of cellular and molecular damage in our tissues with age. The solution is to pair the killing of senescent cells with the introduction of fresh, new functional cells via cell therapy. (See our analysis of a previous study on senolytic therapy in models of Parkinson’s disease for the clinical path ahead on such combination therapies).

And to return more directly to the original question, this would also be the solution if it ultimately turns out that many decades of of senolytic therapy really did drive too many tissue stem cells into senescence. But as we’ve seen, all the evidence suggests that this won’t be a problem during the decades of our current lifespans.

References

  1. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22. PubMed PMID: 25754370; PubMed Central PMCID: PMC4531078.
  2. Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031. PubMed PMID: 28340339; PubMed Central PMCID: PMC5556182.
  3. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016 Jan;22(1):78-83. doi: 10.1038/nm.4010. Epub 2015 Dec 14. PubMed PMID: 26657143; PubMed Central PMCID: PMC4762215.
  4. Hashimoto M, Asai A, Kawagishi H, Mikawa R, Iwashita Y, Kanayama K, Sugimoto K, Sato T, Maruyama M, Sugimoto M. Elimination of p19(ARF)-expressing cells enhances pulmonary function in mice. JCI Insight. 2016 Aug 4;1(12):e87732. doi: 10.1172/jci.insight.87732. PubMed PMID: 27699227; PubMed Central PMCID: PMC5033852.
  5. Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, Day CP, Burt A, Palmer A, Anstee QM, Grellscheid SN, Hoeijmakers JHJ, Barnhoorn S, Mann DA, Bird TG, Vermeij WP, Kirkland JL, Passos JF, von Zglinicki T, Jurk D. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017 Jun 13;8:15691. doi: 10.1038/ncomms15691. PubMed PMID: 28608850; PubMed Central PMCID: PMC5474745.
  6. Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, Shin Teoh T, Prata L, Cottle BJ, Clark JE, Punjabi PP, Awad W, Torella D, Tchkonia T, Kirkland JL, Ellison-Hughes GM. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019 Jun;18(3):e12931. doi: 10.1111/acel.12931. Epub 2019 Mar 10. PubMed PMID: 30854802; PubMed Central PMCID: PMC6516154.
  7. Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, Proctor C, Correia-Melo C, Victorelli S, Fielder E, Berlinguer-Palmini R, Owens A, Greaves LC, Kolsky KL, Parini A, Douin-Echinard V, LeBrasseur NK, Arthur HM, Tual-Chalot S, Schafer MJ, Roos CM, Miller JD, Robertson N, Mann J, Adams PD, Tchkonia T, Kirkland JL, Mialet-Perez J, Richardson GD, Passos JF. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019 Mar 1;38(5). pii: e100492. doi: 10.15252/embj.2018100492. Epub 2019 Feb 8. PubMed PMID: 30737259; PubMed Central PMCID: PMC6396144.
  8. Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, Negley BA, Sfeir JG, Ogrodnik MB, Hachfeld CM, LeBrasseur NK, Drake MT, Pignolo RJ, Pirtskhalava T, Tchkonia T, Oursler MJ, Kirkland JL, Khosla S. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017 Sep;23(9):1072-1079. doi: 10.1038/nm.4385. Epub 2017 Aug 21. Erratum in: Nat Med. 2017 Nov 7;23 (11):1384. PubMed PMID: 28825716; PubMed Central PMCID: PMC5657592.
  9. Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y, Cohen S, Vadai E, Dassa L, Shahar E, Condiotti R, Ben-Porath I, Krizhanovsky V. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016 Apr 6;7:11190. doi: 10.1038/ncomms11190. PubMed PMID: 27048913; PubMed Central PMCID: PMC4823827.
  10. Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017 Jun;23(6):775-781. doi: 10.1038/nm.4324. Epub 2017 Apr 24. PubMed PMID: 28436958; PubMed Central PMCID: PMC5785239.
  11. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532. doi: 10.1038/ncomms14532. PubMed PMID: 28230051; PubMed Central PMCID: PMC5331226.
  12. Pan J, Li D, Xu Y, Zhang J, Wang Y, Chen M, Lin S, Huang L, Chung EJ, Citrin DE, Wang Y, Hauer-Jensen M, Zhou D, Meng A. Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice. Int J Radiat Oncol Biol Phys. 2017 Oct 1;99(2):353-361. doi: 10.1016/j.ijrobp.2017.02.216. Epub 2017 Mar 4. PubMed PMID: 28479002.
  13. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016 Oct;15(5):973-7. doi: 10.1111/acel.12458. Epub 2016 Aug 5. PubMed PMID: 26864908; PubMed Central PMCID: PMC5013022.
  14. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016 Oct 28;354(6311):472-477. Epub 2016 Oct 27. PubMed PMID: 27789842; PubMed Central PMCID: PMC5112585.
  15. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3. PubMed PMID: 26840489; PubMed Central PMCID: PMC4845101.
  16. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017 Feb;7(2):165-176. doi: 10.1158/2159-8290.CD-16-0241. Epub 2016 Dec 15. PubMed PMID: 27979832; PubMed Central PMCID: PMC5296251.
  17. Chinta SJ, Woods G, Demaria M, Rane A, Zou Y, McQuade A, Rajagopalan S, Limbad C, Madden DT, Campisi J, Andersen JK. Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson’s Disease. Cell Rep. 2018 Jan 23;22(4):930-940. doi: 10.1016/j.celrep.2017.12.092. Epub 2018 Jan 28. PubMed PMID: 29386135; PubMed Central PMCID: PMC5806534.
  18. Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019 May;22(5):719-728. doi: 10.1038/s41593-019-0372-9. Epub 2019 Apr 1. PubMed PMID: 30936558; PubMed Central PMCID: PMC6605052.
  19. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018 Oct;562(7728):578-582. doi: 10.1038/s41586-018-0543-y. Epub 2018 Sep 19. PubMed PMID: 30232451; PubMed Central PMCID: PMC6206507.
  20. Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018 Dec;17(6):e12840. doi: 10.1111/acel.12840. Epub 2018 Oct 11. PubMed PMID: 30126037; PubMed Central PMCID: PMC6260915.
  21. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015 Dec 19;4:e12997. doi: 10.7554/eLife.12997. PubMed PMID: 26687007; PubMed Central PMCID: PMC4758946.
  22. Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18. PubMed PMID: 31542391.
  23. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PubMed PMID: 30279143; PubMed Central PMCID: PMC6197652.

SRF Research Center Immunologist Application Form

UPDATE: This post has been filled.

Immunologist

SENS Research Foundation (SRF) is seeking a full-time researcher for a Scientist position to work at our Research Center located in Mountain View, California. The position is to lead a new intramural research project geared toward performing translational research studying aging as it relates to the immune system, with a possibility of developing a new therapeutic. This is a collaborative effort between SRF and the Campisi Lab at the Buck Institute for Research on Aging, located in Novato, CA. The collaboration allows the researcher to work with two institutions at the forefront of the anti-aging field, and allow for mentorship from experts in the field. The successful applicant will work with, and be guided by, senior researchers at both SRF and the Buck, and as such this position is available to new PhDs as an alternative to doing a Postdoc (or a 2nd postdoc). The position offers the opportunity for upward mobility into a more senior, PI level position. Leading a team at SRF is an exciting career opportunity in a team environment where everyone is dedicated to discovering new treatments for the diseases and disabilities of aging.

Required Experience

  • PhD or equivalent doctoral degree in the chemical/biological sciences
  • Expertise in the innate immune system

Desired Capabilities

  • Independent planning and project design
  • NK cell knowledge or experience
  • Proficient at the bench and with data analysis
  • Management / mentoring experience
  • Comfortable working in a small team environment and with collaborations with other institutions

Compensation

SRF is proud to offer a competitive salary of $65-75,000/yr for this position, which includes paid vacation and sick leave, fully covered health insurance, inclusive of dependents, an FSA program, and a company matched 401(k) plan offered after a 90-day introductory period. SRF is an equal opportunity employer.

Interested candidates should apply by email to Dr. Matthew O’Connor, taking care to include all of the information and documentation listed below.

Applicants moving onto the second phase of the application process will be contacted by email by a SRF representative for an interview.

Application Information

Contact Information:

  • Last Name / Surname
  • First Name / Given Name
  • Email Address
  • Phone Number
  • Full Mailing Address

Academic Information:

  • Graduate Institution
  • Program or Department
  • Graduation Date
  • First available date to begin position

Documents:

Attach documents in PDF, DOC or DOCX format.

  • CV or Resume.  Please limit your CV or resume to a maximum of 2 pages. Highlight any prior laboratory or research experience. A brief 1- or 2-line description of your specific contribution to each research project is particularly helpful. For instance, the statement “created the expression construct that allowed us to determine protein localization” quickly clarifies your role in the project.
  • Cover Letter.  A cover letter describing your knowledge of SRF’s damage repair approach to aging as well as your experience in immunology; please limit your letter to one page.

A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis

SENS Research Foundation Research Center

Principal Investigator: Matthew O’Connor
Research TeamAmelia Anderson, Carolyn Barnes, Angielyn Campo, Anne Corwin, Sirish Narayanan

Many diseases of aging are driven in part by the accumulation of “junk inside cells:” stubborn, damaged waste products derived from the metabolic processes particular to specific cell types. The accumulation of these wastes disables the cell type in question and leads to their dysfunction; when, after decades of silent accrual, a critical number of these cells become dysfunctional, diseases of aging characteristic of that tissue erupt. For example, atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity, only to ultimately fall prey to that same toxicity themselves. These macrophages – now dysfunctional “foam cells” – become immobilized in the arterial wall and spew off inflammatory molecules that in turn promote advanced atherosclerosis, heart attack, and stroke. In other organs, the accumulation of damaged molecules inside vulnerable cells drives Alzheimer’s and Parkinson’s diseases, as well as age-related macular degeneration.

Dr. O’Connor’s team have identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood. If effective, these small molecules could serve as the basis for a groundbreaking therapy that would prevent and potentially reverse atherosclerosis and, possibly, heart failure.

Research Highlights:

A lead compound was identified following evaluation of data from human blood sample tests in conjunction with computer modeling to predict the likely behavior of rationally-designed molecules. Preliminary testing has indicated performance consistent with enhanced activity relative to the existing family of compounds: specifically, the candidate molecules exhibit selective targeting of toxic cholesterol byproducts, with significantly reduced affinity for native cholesterol. A patent application for this lead compound and others to be derived from it has now been submitted.

The team is now working to refine their original assay with the expectation that it will more accurately reflect the desired activity on toxic and native cholesterol, and also on an entirely different chemical approach to improved molecules derived from the original family. We are also working with a potential contract laboratory to test the absorption, circulation to tissues, and disposal of our lead candidate, and to perform toxicity assays. SRF has recently acquired a new robotic system to run the assay, which our in-house engineer, Anne Corwin, is now working to set up and program; the end result will be an increase in throughput that allows more rapid testing of more molecules.

Engineering New Mitochondrial Genes to Restore Mitochondrial Function (MitoSENS)

SENS Research Foundation Research Center

Principal Investigator: Amutha Boominathan
Research Team: Bhavna Dixit, Carter Hall, Caitlin Lewis, Matthew O’Connor, Martina Velichkovska

Mitochondria are the tiny cellular “power plants” in our cells, which take energy from our food and convert it into a form that can be used to power the cell’s energy-intensive processes. Like other power plants, they generate waste in the process – in this case, free radicals – which over time damage mitochondrial DNA. As a result, a small but rising number of our cells get taken over by such dysfunctional mitochondria as we age. These damaged cells in turn export toxic molecules to far-flung tissues, contributing to Parkinson’s disease, age-related muscle dysfunction, and other conditions.

The MitoSENS goal is to achieve a grand engineering solution to the problem of accumulation of cells with these mutation-bearing mitochondria: allotopic expression of functional mitochondrial genes. Allotopic expression involves placing “backup copies” of all of the protein-coding genes of the mitochondria in the cell’s nucleus. From this “safe harbor”, the copied genes can then direct the cell’s machinery to produce engineered versions of the missing mitochondrial proteins and deliver them to the mitochondria. With their full complement of proteins restored, mitochondria can resume producing energy normally, despite lacking the genes to produce them on their own.

Research Highlights:

In 2016, the MitoSENS team achieved a major breakthrough in successfully demonstrating efficient replacement of the missing mitochondrial ATP8 gene in cells from a human patient with an ATP8 mutation, restoring their ability to produce energy using the most efficient pathway.

After significant work to extend 2016’s breakthrough to other genes, the team discovered that an established method already widely used in biotechnology could also be applied to enable significantly more consistent production of allotopically-expressed protein.

To test this novel method more broadly, the MitoSENS group first briefly allotopically expressed each of the thirteen vulnerable mitochondrial genes via a transient loop of DNA located in the cytosol. Versions of the genes engineered the new way produced a great deal more RNA (the “working copies” of the gene that the cellular machinery uses to make protein) than the same genes engineered in the way that all previous investigators have used.

All thirteen of the genes engineered in this new way were able to produce actual protein, versus only a fraction of the conventionally-engineered genes. This milestone achievement is being prepared for publication in a scientific journal as of this writing, and tests are now underway to verify that all proteins thus expressed are properly incorporated into the mitochondria’s energy-production system.

The team has compared performance between ‘traditional’ and novel systems for producing allotopic ATP8 in cells derived from FVB mice. These mice bear a minor but significant mutation in ATP8 that causes functional problems, e.g., a tendency to poorly metabolize incoming blood sugar after a meal. The cells engineered using this novel method produced significantly more ATP8 protein than those engineered the conventional way – and it is important to note that in this experiment, the new genes were actually cemented into the nucleus and expressed from there, thus mimicking the goal for human MitoSENS therapies. The allotopically-expressed protein works as intended when using the improved system: it enters the mitochondria, incorporates properly into the energy-producing machinery, and significantly enhances these cells’ ability to survive when they are forced to rely on the mitochondria’s primary energy-generation mechanism.

Next, the MitoSENS team plans to demonstrate efficacy in living, breathing mice – specifically,  Maximally Modifiable Mice (MMM) from the SRF funded work at ASC. The new MMM-derived mouse model will have the allotopic ATP8 construct engineered into their nuclear genomes from conception, but will have mitochondria (and thus mitochondrial DNA) derived from FVB mice, with their mutant ATP8 gene. This work, in conjunction with behavioral studies to be performed in collaboration with the Brand lab at the Buck Institute, is expected to prove that the allotopic gene actually functions in vivo, restoring the mice’s ability to generate cellular energy efficiently.

Enhancing Innate Immune Surveillance of Senescent Cells

Buck Institute for Research on Aging

Principal Investigator: Judith Campisi
Research Team: Abhijit Kale

SENS Research Foundation Research Center

Principal Investigator: Amit Sharma
Research Team: Elena Fulon

When normal cells lose their ability to replicate, they become senescent cells. Over time, senescent cells accumulate in aging tissues, spewing off a cocktail of inflammatory and growth factors, as well as enzymes that break down surrounding tissue (the “senescence-associated secretory phenotype” (SASP)). The charge sheet against senescent cells has now expanded into a remarkable litany of the diseases of aging.

Multiple studies have now, on a more encouraging note, documented that “senolytic” drugs and gene therapies that destroy senescent cells exert sweeping rejuvenating effects in aging, both in laboratory animals and animal models of multiple diseases of aging. But in theory, senolytic therapies shouldn’t be necessary. The body’s immune system is on continuous patrol against senescent cells: our natural killer (NK) cells, recognize senescent cells as abnormal, bind to them, and release substances that trigger the senescent cells to self-destruct.

In a Foundation-donor-funded collaboration between Dr. Judith Campisi’s lab at the Buck Institute and the SRF Research Center, this project seeks to answer the critical question of why senescent cells accumulate with age, and what might we do to enhance immune surveillance and elimination of these cellular saboteurs?

Research Highlights:

Dr. Campisi has found that about ten percent of senescent cells are resistant to being killed, even by fresh NK cells, suggesting that these resistant cells are the ones that escape immunosurveillance and accumulate in aging tissues. Her research team and other scientists have developed preliminary data suggesting mechanisms whereby senescent cells can make themselves invisible to NK cells, thus protecting themselves from destruction.

The Buck-SRF-RC collaboration is now seeking to drill further down into these questions and test possible means to intervene in the process. The Campisi lab is looking into further elaborating the biology of one of senescent cells’ two self-protective mechanisms, and also testing a potential role for another kind of immune cell (macrophages) in defending the body against senescent cell accumulation.

At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process, and will begin testing two potential therapeutic targets identified in the Campisi lab. The SRF-RC scientists are also working for the first time with NK cells derived directly from aged human donors (rather than long-cultured lines of NK cells, or NK cells artificially “aged” by exposure to oxidative stress or extensive replication in culture, as has been done in the past). Using these cells will allow them for the first time to observe any direct effects of aging on NK cell senolytic activity. The team is also developing an algorithm for the SRF-RC’s automated microscope imaging system to rapidly analyze stained plates of cells for quantitative analysis of senescent cell-killing ability — a job hitherto done by laborious human visual microscopy.

Functional Neuron Replacement to Rejuvenate the Neocortex

Albert Einstein College of Medicine

Principal Investigator: Dr. Jean Hébert
Research TeamHiroko Nobuta, Joanna Krzyspiak, Alexander Quesada, Marta Gronska-Peski, Jayleecia Smith

Of all the challenges in cell therapy, replacement of neurons in the neocortex is both the most important (the brain being the seat of consciousness and identity) and perhaps the most formidable. Only recently have any researchers succeeded in integrating new neurons into this area of the brain. Moreover, the vast majority of transplanted cells in these cases have failed to survive, and the few survivors have achieved only limited function and integration into existing circuits.

SRF is now supporting Dr. Jean Hébert’s work to advance two innovative strategies to address different aspects of the challenge. First, Dr. Hébert’s team will transplant neuronal precursors (from both mice and humans) along with precursors of the blood vessels needed to nourish new neurons, in order to enhance their survival and integration. Second, because new neurons will be needed throughout the aging neocortex but transplanting neurons throughout the entire tisssue would be extremely invasive and risk injury to a tissue we cannot afford to damage, the AECOM team will engineer microglia (which, unlike neurons and their precursors, are highly mobile cells) to disperse widely from the site of transplant and then be reprogrammed into cortical projection neurons at their destination. From there, the team will characterize the integration of the transplanted microglia-cum-neurons into host circuits of converted neurons derived from our engineered transplanted microglia, and determine whether depleting host microglia enhances these processes in different models.

Glucosepane Crosslinks and Undoing Age-Related Tissue Damage

Yale University

Principal Investigator: David Spiegel
Research Team: Prof. Jason Crawford, Nam Kim, Venkata Sabbasani, Matthew Streeter

The long-lived collagen proteins that give structure to our arteries and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to tissue collagen by sheer chemistry, and if not quickly reversed these initial links will in turn bind adjacent strands of collagen, reducing the range of motion of the tissue like the legs of runners in a three-legged race. As a result, these tissues slowly stiffen with age, leading to rising systolic blood pressure, kidney damage, and increased risk of stroke and other damage to the brain.

It is currently thought that the single most common of these Advanced Glycation End-products (AGE) crosslinks is a molecule called glucosepane. A rejuvenation biotechnology that could cleave glucosepane crosslinks would allow bound arterial proteins to move freely again, maintaining and restoring the elasticity of the vessels and preventing the terrible effects of their age-related stiffening. SRF has provided funding to the Yale GlycoSENS group for several years now, in order to develop tools necessary for enabling the development of glucosepane-cleaving drugs.

Research Highlights:

The Yale group’s first major milestone – the first complete synthesis of glucosepane itself – was a sufficient tour de force to earn publication in the prestigious journal Science. In 2018, they were able to scale up this pilot-level method to produce glucosepane in quantities useful for industrial production, and also to synthesize three conformational variants (diastereomers) of glucosepane that may occur in vivo. They are now working on two more such variants. They have also used their synthetic glucosepane to develop glucosepane-targeting antibodies capable of labeling glucosepane in aging tissues, which they are now working up into a monoclonal antibody for mass production that will be compatible with human metabolism and will allow researchers to track the effects of potential glucosepane-cleaving drugs.

Finally, and most excitingly, they have now identified a lead candidate glucosepane-cleaving biocatalyst, and completed the evaluation of seven significant variants and their AGE-breaking mechanism. Today, work continues on synthesizing pentosinane (another common AGE crosslink) and additionally on the AGE-related compounds iso-imidazole and 2-aminoimidazole.

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