An SRF-sponsored new organization and Longevity Summer Camp

SRF is a proud sponsor of LessDeath and the Longevity Summer Camp! LessDeath is a new organization and event series dedicated to helping people join the Longevity Biotechnology industry through education, career and community strategizing, job opportunities, and more.

You don’t need a biology PhD to get involved! The industry needs many types of scientists, engineers, programmers, founders, technicians, operations experts and more. If you’re passionate about maximizing human health and lifespan, LessDeath’s mission is to help you find effective ways to contribute!

LessDeath’s Longevity Summer Camp will be hosted July 20th-24th in California. Our very own Vice President of Research, Dr. Alexandra Stolzing, will be one of the camp counselors. Visit the link below to learn more and to apply to the summer camp.

Follow them on Twitter: @LessDeath.org

A Message from the SRF Board of Directors

The offer of a Director position was refused by Dr. Aubrey de Grey, as stated in a public forum and taken as response in absence of other communication.

Invitation for Dr. De Grey and Richard Heart to join the Board of Directors

The SENS Research Foundation Board of Directors has a singular focus – to help the Foundation develop, promote, and ensure widespread access to therapies that cure and prevent the diseases and disabilities of aging. As the body responsible for ensuring the organization’s alignment with its mission, it is important our Board comprise leaders within the longevity field – visionaries dedicated to defeating the effects of aging permanently.

Many supporters have followed with interest our recent separation from our co-Founder Dr. Aubrey de Grey, and some have expressed concern regarding the possibility of our mission focus drifting off course. We remain firmly on-mission and continue to make real progress in our field, however, we acknowledge that we are the foundation we are today because of Dr. de Grey’s vision and leadership within the longevity movement. With this in mind, we have formally offered Dr. de Grey a Directorship within the Board of Directors.

His installment as a Director will be effective immediately upon the successful completion of the recommendations made by the accredited professional he has personally engaged, with a subsequent letter of recommendation to the Board of Directors supporting Dr. de Grey’s ability to fulfill the duties of Directorship. In this capacity, Dr. de Grey would lend his expertise to help steer the vision of the Foundation. Consistent with good governance and past practices, Dr. de Grey and the other members of the Board will approve the annual budget, review the annual audit, interview and hire executives, act as advocates for SRF, and largely ensure that the mission is being adhered to by the organization.

With an eye toward continued growth, we have also extended an invitation to Richard Heart to join the SRF Board. Richard is a passionate advocate within the longevity movement, a visionary in his own right, and the organizer of the largest fundraising campaign in SRF history. Both SRF and the longevity movement at large would benefit greatly from Richard joining our Board, and we are grateful for his sincere consideration.

We share these invitations with the public both in the interest of transparency and to be clear about the desired direction of our Board and, by extension, our continued growth in and service to the longevity field.

We will share more as we continue to plan for our future. Until then, thank you for your support of our important work.

The SENS Research Foundation Board of Directors

New Peer-Reviewed Paper from SENS Research Foundation Researchers Reveals Tools to Harness Immune Cells to Seek and Destroy Senescent Cells

Senolytics — drugs that selectively destroy senescent cells (senolytics) — have been shown to powerfully rejuvenate mice and to reverse multiple diseases of aging in animals, from atherosclerosis, to kidney disease, to osteoporosis, to Parkinson’s disease — and beyond. But because these drugs target pathways that are necessary for normal cell function, they can come with side-effects — the most notable being the crash in platelets (and resulting risk of fatal bleeds or strokes) that can accompany the experimental senolytic navitoclax.

But our bodies are actually equipped with an inborn army of immune cells that selectively identify and destroy senescent cells. To date, the most important of these “immunosenolytic” soldiers have seemed to be Natural Killer cells (NK cells) — though we will have an announcement to make on this front in the coming months. But if the body already has this defensive force, how do senescent cells still manage to accumulate in our tissues with age and wreak havoc on our health?

SENS Research Foundation scientists are working to harness NK cells to more safely and effectively clear senescent cells out of our tissues. Dr. Amit Sharma and his team at SRF are developing ways to either rejuvenate our own NK cells’ ability to detect and destroy senescent cells in aging tissues, or to augment that capacity with NK cells engineered to be more lethal senescent cell hunters. To reach those goals, they realized they needed a more efficient way to create large numbers of NK cells from mixed white blood cells isolated from human blood. In new peer-reviewed scientific paper, they showed other scientists how they did it. Their main innovation might seem to be an obvious one: to actually isolate NK cells to study them. Previous scientists have mostly used very mixed populations of blood cells, sometimes removing T-cells or other specific cell types but never isolating NK cells exclusively. Dr. Sharma used an existing kit to make sure that what they were seeing came from the NK cells and not from other cell types.

They also saw that the way that previous researchers had studied NK cells’ ability to destroy senescent cells was quite different from the conditions NK cells actually confront as they patrol for NK cells in the body, potentially leading scientists to chase after interventions that work well in a Petri dish but have no effect or are unsafe when carried out in living, breathing humans. This is probably because most scientists conducting these studies don’t have a specialized background in immunology: instead, they design their experiments based on a general background in the biology of aging or cancer biology, or as specialists in senescence per se, but The biggest problem the SRF group corrected is that previous studies have cultured low numbers of senescent cells together with very high numbers of NK cells, creating a situation where NK cells are effectively shooting zombie fish in a barrel. The Sharma lab tested more realistic conditions in which one NK cell encounters one senescent cell, or no more than three, instead of ratios as high as one NK to 20 or even 80 senescent targets.

Conversely, having given NK cells so many senescent cell targets that they can hardly fail to kill some, most previous studies have only set NK cells loose for a few hours, when NK cells have a half-life in the body of ten hours. So the Sharma lab gave NK cells an amount of time to engage their enemies that reflects how long they actually hang out in tissues, with experiments running from 16 hours to four days. This also gives the NK cells the ability to reveal their full range of powers, since some of their cell-killing weapons only engage over extended time periods.

Finally, previous studies on NK cells’ immune surveillance of senescent cells have cultured them in very high levels of interleukin-2 (IL-2), an immune-signaling molecule that triggers NK cells to create more of themselves and makes them more aggressive. At SRF, Dr. Sharma used levels that reflect levels in the body. 

The first set of discoveries revealed by this new system: NK cells are actually most selective for senescent cells when the ratio between NK and their potential targets are quite low. As you introduce more and more targets into the mix, NK cells tend to kill more senescent cells, but also kill more and more healthy bystander cells. Additionally, their preliminary evidence suggests that NK cells from younger male subjects were more effective at killing senescent cells compared to female subjects, and also more effectively than older people of either gender. This is consistent with previous reports that older people’s NK cell armies included more dysfunctional or exhausted NK cells, which release less of the key immune signaling molecule interferon gamma (IFN-γ) and produce less of the chemicals needed to execute their targets. IF their initial finding of reduced senescent cell-killing ability pans out in a larger study, they can look at these and other mechanisms as potential reasons why and then look for ways to reverse or sidestep the effect of aging.

All around, the new paper sets up the SRF immunosenolytic team — and other scientists who can now read the findings for themselves — on a better path to identify ways to rejuvenate or reinforce senescent cell immune surveillance, reinvigorating NK cells to make them battle-ready once again.

Reference

Kim K, Admasu TD, Stolzing A, Sharma A. Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells. Aging (Albany NY). 2022 Mar 4;14(5):2131-2147. doi: 10.18632/aging.203931. Epub 2022 Mar 4. PMID: 35245208; PMCID: PMC8954966.

Lipofuscin Degradation by Bacterial Hydrolases

German Institute of Human Nutrition

Principal Investigator: Tilman Grune
Research Team: Annett Braune, Annika Höhn, Tim Baldesperger

Prof. Grune is the Scientific Director of the German Institute of Human Nutrition and has been working on protein degradation of damaged proteins and aging.

Lipofuscin (LF) is a strongly oxidized material composed of covalently cross-linked proteins, lipids, and carbohydrates. Cellular LF increases with age and negatively correlates with the remaining life span of cells. Lipofuscin accumulation is especially pronounced in postmitotic cells (including cardiomyocytes and neurons) as these cells are unable to “dilute” their lipofuscin via cell division. LF by itself impairs cardiomyocyte function by declining its contractility. Importantly, no known mammalian enzyme degrades lipofuscin, therefore LF accumulates within the cell, mostly within the lysosomes.

Microorganisms, particularly bacteria, possess a wide array of enzymes that allow the degradation of any conceivable molecule formed in nature. The project, therefore, aims at identifying bacterial enzymes able to degrade LF. The project includes the following tasks:

  • isolation of human LF and identification of its components,
  • identification of microbial hydrolases able to degrade LF, and
  • testing the effect of identified hydrolases and their products in living cardiomyocytes.

Research Highlights:

Prof. Grune has previously studied the role of lipofuscin in proteasomal inhibition in human cell culture models using artificial lipofuscin. Later, he worked with isolated lipofuscin from human retinal epithelial cells and described the effects of this material on microglial cells. After securing a reliable source of human hearts, the Grune team began isolating real tissue lipofuscin. They are presently working to analyze composition and quantify degradation of LF.  In recent years, the team has also worked with “artificial” lipofuscin and shown in a preliminary experiment that degradation by bacterial enzymes is possible. Upgrades to primary human material will allow optimization of the process of identifying bacterial enzymes with the ability to degrade the material.

Catalyzing Degradation of Tau Aggregates

  • Research Info
  • Team Members
  • Publications
  • Photos
  • Funding
  • Research Info
  • Team Members
  • Publications
  • Photos
  • Funding

Tau is the major microtubule-associated protein (MAP) in mature neurons in the central nervous system. The MAPT (microtubule-associated protein tau) gene encodes for six splice variants that are highly soluble; their main function is interacting and stabilizing microtubules, along with other MAPs. The ability of tau to stabilize the microtubule is aided by its phosphorylation.

Hyperphosphorylation of tau depresses its biological activity and can lead to destabilization of microtubules. Also, hyperphosphorylation of tau proteins can cause it to aggregate into oligomers, which in turn assemble into helical and straight insoluble filaments and ultimately mature into neurofibrillary tangles (NFTs).

In Alzheimer’s disease brain, tau is three to four-fold more hyperphosphorylated than in the normal adult brain, leading to a pathological buildup of NFTs. The accumulation of NFTs comprising hyperphosphorylated tau is also observed in normal aging (PMID: 24548606).

Various other neurodegenerative diseases, collectively called tauopathies – including Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal lobar dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and dementia pugilistica – are also caused by tau aggregation.

In consultation with SRF-supported biotech company Covalent Bioscience, SENS Research Foundation has initiated a project to develop a novel way to remove abnormally aggregated tau as a therapeutic intervention with potential relevance to mitigating normal age-dependent cognitive decline, as well as for tauopathies like Alzheimer’s disease and related dementias.

Covalent Bioscience have previously demonstrated the therapeutic potential of catabodies in a recent publication targeting Transthyretin (TTR) that forms misfolded b-sheet aggregates responsible for age-associated amyloidosis. In this paper they have described catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR) (PMID: 24648510).

Team Members

We’re Hiring!

Please visit the Work With Us page to learn about available positions.

Principal Investigator

Dr. Amit Sharma

Dr. Amit Sharma

Dr. Amit Sharma was awarded a Master’s degree in Biomedical Sciences from Delhi University, India.  He received his PhD in 2009 in Biotechnology from University of Pune for his work demonstrating microRNA regulation of cytokines involved in allergic inflammation in mice model. Dr. Sharma’s postdoctoral research at the Buck Institute, Novato California involved investigating novel molecular regulatory pathways involved in genotoxic stress and cellular senescence in invertebrate and mammalian models.

Dr. Sharma has recently joined SENS Research Foundation as Group Lead in the Senescence Immunology Research Group. His research focus involves studying how aging and senescence affects the immune system and his research group will also investigate strategies to harness the immune system in mitigating deleterious effects of senescent cells with translational focus.

Publications

Previous Publications by Dr. Sharma

Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari S.K, Agrawal A and Ghosh B. Post-Transcriptional Regulation of Interleukin-10 Expression by hsa-miR-106a. Proc Natl Acad Sci U S A. 2009; 106: 5761-6. PMC 2659714

Sharma A, Kumar M, Ahmad T, Mabalirajan U, Aich J, Agrawal A and Ghosh B. Antagonism of mmu- mir-106a attenuates asthma features in allergic murine model. JAP, 2012.

Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B. Let-7 microRNA- mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol. 2011. PMID 21616524 

Kumar S, Sharma A and Madan B, Singhal V and Ghosh B. Isoliquiritigenin inhibits IkappaB kinase activity 
and ROS generation to block TNF-alpha induced expression of cell adhesion molecules on human 
endothelial cells. Biochem Pharmacol. 2007; 73:1602-12. 


Tanveer A, Mabalirajan U, Sharma A, Ghosh B, Agrawal A. Simvastatin Improves Epithelial Dysfunction 
and Airway Hyperresponsiveness: From ADMA to Asthma. Am J Respir Cell Mol Biol. 2011 Apr;44 (4):531- 
9. PMID 2055877

Ghosh B, Kumar S, Balwani S, Sharma A. Cell adhesion molecules: therapeutic targets for developing 
novel anti-inflammatory drugs. Advanced Biotech. 2005; 4:13-20. 


Sharma S, Sharma A, Kumar S, Sharma S.K. and Ghosh B. Association of TNF haplotypes with Asthma, 
Serum IgE levels and correlation with serum TNF-α levels. Am J Respir Cell Mol Biol. 2006; 35: 488-95.

Sharma A, Joseph Wu. MicroRNA Expression Profiling of Human Induced Pluripotent and Embryonic Stem Cells. Methods in molecular biology, a part in Springer Science. PMC 3638037

Sharma A, Diecke S, Zhang WY, Lan F, He C, Mordwinkin NM, Chua KF, Wu JC. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013. PMID 23653361.

Lang S, Bose N, Wilson K, Brackman D, Hilsabeck T, Watson M, Beck J, Sharma A, Chen L, Killlilea D, Ho S, Kahn A, Giacomini K, Stoller M, Chi T, Kapahi P. A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster. bioRxiv 387779

Akagi K, Wilson K, Katewa SD, Ortega M, Simmons J, Kapuria S, Sharma A, Jasper H, Kapahi P. Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster. PloS Genet. 2018 Nov 1; 14(11):e1007777. PMC6233930.

Sharma A, Akagi K, Pattavina B, Wilson KA, Nelson C, Watson M, Maksoud E, Ortega M, Brem R, Kapahi P. Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival in Drosophila. Sci Reports. 2020 Nov 5;10(1):19080.

Full list of published work as found in My Bibliography:

https://www.ncbi.nlm.nih.gov/sites/myncbi/amit.sharma.2/bibliography/55316754/public/?sort=date&direction=ascending

Photos

Resources

Funding

To support our work please consider making a donation to SENS Research Foundation!

Thanks to our existing funders:

Engineering New Mitochondrial Genes to Restore Mitochondrial Function (MitoSENS)

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  • Team Members
  • Publications
  • Photos
  • Funding
  • Research Info
  • Team Members
  • Publications
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  • Funding

Mitochondria perform and support several vital functions in a cell, and the alternate genome, mtDNA, plays a critical role in organelle maintenance. There is increasing evidence that mitochondrial function declines with age, and that dysfunctional mitochondria adversely contribute to several metabolic and neuromuscular diseases. Our goal is to address age-acquired and inborn errors of mutation in the mtDNA using a gene therapy approach. We are exploring:

  1. allotopic expression (expressing mtDNA genes from the nucleus), and
  2. whole-organelle replacement

as strategies to revitalize mitochondrial function. Our multidisciplinary approach employs cell culture and mouse models to achieve our objectives.

Allotopic Expression of Proteins Encoded in the Mitochondrial DNA

Mitochondria are the ‘power plants’ in every mammalian cell responsible for the efficient conversion of nutrients to energy. Impaired mitochondrial function and mutations in mtDNA contribute to several age-related illnesses, including Alzheimer’s Disease, Parkinson’s disease, and sarcopenia. Point mutations in any of the 13 protein-coding regions, as well as micro- and macro- deletions in the mtDNA, lead to several monogenic and organelle-specific diseases (MELAS, MEERF, LHON, Leigh’s disease to name a few). However, alterations in the OriH / OriL regions in the mtDNA can lead to global impairment in the transcription and translation of the mitochondrial genome. The mitochondrial proteome, however, consists of ~1400 proteins of which all except for the 13 polypeptides translated on the mitochondrial genome originate from the host’ nucleus. Over the course of evolution, mitochondria have developed sophisticated mechanisms to import these nuclear mitochondrial proteins. These mechanisms employ intricate translocases and signals, which are directed to different regions within the organelle.

The goal of this project is to determine how we might achieve optimal parameters for coding and non-coding regions to efficiently express and target the 13 mtDNA genes to the respiratory chain from the nucleus. Toward this end, we employ molecular biology, biochemistry and computational strategies, and refine and build on our existing knowledge of import conditions for the numerous nuclear mitochondrial proteins already delineated. We use patient-derived cybrids and animal models in assessing the functional utility of our constructs. Ultimately, we aim to express the mtDNA genes individually or in combination to overcome age-related changes to the mtDNA and improve overall organelle fitness. Please see here for recent progress on this project.

Reversing Age-Induced Mitochondrial Damage through Organelle Transplantation

Intercellular mitochondria exchange occurs naturally in the human body between cell types, typically between healthy and damaged cells. Three different transfer mechanisms have been observed:

  1. stem cells release naked mitochondria that are taken up by other cells,
  2. mitochondria are released extracellularly, enclosed in vesicles that are in turn taken up by recipient cells (possibly via endocytosis), or
  3. mitochondria migrate from one cell to another through specialized structures in vivo, such as nanotubes.

The goal of this project is to evaluate the potential of mitochondrial transfer to counteract age-related loss of tissue function. We aim to develop strategies to purify viable mitochondria and deliver them to target regions in the body.

Team Members

We’re Hiring!

Please visit the Work With Us page to learn about available positions.

Principal Investigator

amutha-boominathan

Amutha Boominathan, PhD

Research Staff

BhavnaDixit-1a-o

Bhavna Dixit, MS (Research Associate II)

begelman

David Begelman, BS (Research Associate I)

Carly Truong_headshot

Carly Truong, BS (Research Technician)

Postbaccalaureate Fellows

Summer Scholars

Placeholder-Person-1

Jay-Miguel Fonticella (Class of 2022, Tufts University, BS)

Emily Wallace_headshot

Emily Wallace (Class of 2024, U Mich. BSE)

Lab Alumni

Research Staff

  • Jayanthi Vengalam (2012-2015) – now at Protagonist Therapeutics
  • Shon Vanhoozer (2014-2017)
  • Kathleen Powers (2015-2017) – now at Bristol Myers Squibb
  • Caitlin Lewis (2017-2021) – now at SENS Research Foundation CSO Team

Summer Scholars and Postbaccalaureate Fellows

Publications

Photos

Resources

Funding

To support our work please consider making a donation to SENS Research Foundation!

Thanks to our existing funders:

The Foster Foundation

Enhancing Innate Immune Surveillance of Senescent Cells

  • Research Info
  • Team Members
  • Publications
  • Resources
  • Photos
  • Funding
  • Research Info
  • Team Members
  • Publications
  • Resources
  • Photos
  • Funding

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 and cause inflammation. This phenomenon is known as the “senescence-associated secretory phenotype” (SASP). Senescent cells – and the downstream impact of the SASP – are now implicated in a remarkable litany of the diseases of aging.

On a more encouraging note, multiple studies have now 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. In theory, however, 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.

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

Research Highlights:

The Campisi lab has recently published three papers describing the underlying mechanism of immune evasion by resistant senescent cells (Pereira et al., 2019, Munoz et al., 2019, and Kale et al., 2020). Dr. Campisi has found that a significant proportion of senescent cells manage to evade destruction, even by fresh NK cells. These ‘resistant’ cells escape immunosurveillance and accumulate in aging tissues. Senescent cells moreover shed decoy ligands binding to NK cell receptors; another aim of this work is to screen for more such ligands shed by senescent cells.

The Buck-SRF-RC collaboration is now seeking to drill further into the mechanism of senescent cell accumulation, and test interventions. At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process;  next, we will begin testing therapeutic interventions.

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 to observe any direct effects of aging on NK cell senolytic activity.

Goals:

The primary goal of the laboratory is to find ways to avoid the accumulation with a focus on the immune system:

  • Reversing diminished immune surveillance
  • Use of NK cells to remove senescent cells

Goal 1: Natural killer cells are primary drivers of immune surveillance of senescent cells. This project involves isolation and characterization of age-dependent changes in the phenotypes of Natural Killer cells. This is to investigate if the age of subjects effects the ability of NK cells to eliminate senescent cells in vitro and in vivo.

Goal 2: We have identified several unique antigens expressed on the surface of senescent cells. The goal of this project is the targeted elimination of senescent cells by CAR-NK therapy. We are characterizing the surface an antigen on senescent cells and investigate if targeting this antigen can enhance NK cell-mediated clearance of senescent cells from patient-derived primary endothelial cells and fetal lung fibroblasts. The ultimate goal of the project is to demonstrate that the CAR-NK cells that are capable of eliminating senescent cells in ex vivo and mouse models.

Goal 3: Senescent cells are known to secrete a unique mixture of proinflammatory cytokines, chemokines and matrix modifying proteins called the SASP (Senescence Associated Secretory Phenotype). We have identified several SASP factors that may block immune surveillance by NK cells. Proof of principle experiments are currently being performed to investigate if selective removal of specific SASP factors can enhance immune surveillance of senescent cells. The long-term goal of this project is to develop therapeutic interventions based on removal of these SASP proteins for aging and related diseases.

Team Members

We’re Hiring!

Please visit the Work With Us page to learn about available positions.

Principal Investigator

Dr. Amit Sharma

Dr. Amit Sharma

Dr. Amit Sharma was awarded a Master’s degree in Biomedical Sciences from Delhi University, India.  He received his PhD in 2009 in Biotechnology from University of Pune for his work demonstrating microRNA regulation of cytokines involved in allergic inflammation in mice model. Dr. Sharma’s postdoctoral research at the Buck Institute, Novato California involved investigating novel molecular regulatory pathways involved in genotoxic stress and cellular senescence in invertebrate and mammalian models.

Dr. Sharma has recently joined SENS Research Foundation as Group Lead in the Senescence Immunology Research Group. His research focus involves studying how aging and senescence affects the immune system and his research group will also investigate strategies to harness the immune system in mitigating deleterious effects of senescent cells with translational focus.

Postdoctoral Fellow

Research Associate

Kristie_web

Kristie Kim
Identification and characterization of the surfaceome of senescent cells and development of CAR-NK cells to enhance immune surveillance

Postbaccalaureate Fellow

Gina Zhu (Postbaccalaureate Fellow, 2020-2021)
Identifying Novel Mechanisms to Enhance Natural Killer Cell Mediated Surveillance and Clearance of Senescent Cells

Summer Scholar

Chloe Lindberg

Chloe Amber Lindberg (Summer Scholar, 2021)
Investigating the effect of senescence-associated secretory phenotype (SASP) factors on NK cell function

Lab Alumni

Elena Fulton (Postbaccalaureate Fellow, 2019-2020)
Characterization of age dependent changes in peripheral NK cell phenotypes in humans

Mikayla Stabile (Summer Scholar, 2020)
Characterization of age dependent changes in peripheral NK cell phenotypes in humans

Publications

  • Kale A, Sharma A, Stolzing A, Desprez PY, Campisi J. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing 2020 Jun 3;17:16. PubMed: 32518575.

Previous Publications by Dr. Sharma

Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari S.K, Agrawal A and Ghosh B. Post-Transcriptional Regulation of Interleukin-10 Expression by hsa-miR-106a. Proc Natl Acad Sci U S A. 2009; 106: 5761-6. PMC 2659714

Sharma A, Kumar M, Ahmad T, Mabalirajan U, Aich J, Agrawal A and Ghosh B. Antagonism of mmu- mir-106a attenuates asthma features in allergic murine model. JAP, 2012.

Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B. Let-7 microRNA- mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol. 2011. PMID 21616524 

Kumar S, Sharma A and Madan B, Singhal V and Ghosh B. Isoliquiritigenin inhibits IkappaB kinase activity 
and ROS generation to block TNF-alpha induced expression of cell adhesion molecules on human 
endothelial cells. Biochem Pharmacol. 2007; 73:1602-12. 


Tanveer A, Mabalirajan U, Sharma A, Ghosh B, Agrawal A. Simvastatin Improves Epithelial Dysfunction 
and Airway Hyperresponsiveness: From ADMA to Asthma. Am J Respir Cell Mol Biol. 2011 Apr;44 (4):531- 
9. PMID 2055877

Ghosh B, Kumar S, Balwani S, Sharma A. Cell adhesion molecules: therapeutic targets for developing 
novel anti-inflammatory drugs. Advanced Biotech. 2005; 4:13-20. 


Sharma S, Sharma A, Kumar S, Sharma S.K. and Ghosh B. Association of TNF haplotypes with Asthma, 
Serum IgE levels and correlation with serum TNF-α levels. Am J Respir Cell Mol Biol. 2006; 35: 488-95.

Sharma A, Joseph Wu. MicroRNA Expression Profiling of Human Induced Pluripotent and Embryonic Stem Cells. Methods in molecular biology, a part in Springer Science. PMC 3638037

Sharma A, Diecke S, Zhang WY, Lan F, He C, Mordwinkin NM, Chua KF, Wu JC. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013. PMID 23653361.

Lang S, Bose N, Wilson K, Brackman D, Hilsabeck T, Watson M, Beck J, Sharma A, Chen L, Killlilea D, Ho S, Kahn A, Giacomini K, Stoller M, Chi T, Kapahi P. A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster. bioRxiv 387779

Akagi K, Wilson K, Katewa SD, Ortega M, Simmons J, Kapuria S, Sharma A, Jasper H, Kapahi P. Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster. PloS Genet. 2018 Nov 1; 14(11):e1007777. PMC6233930.

Sharma A, Akagi K, Pattavina B, Wilson KA, Nelson C, Watson M, Maksoud E, Ortega M, Brem R, Kapahi P. Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival in Drosophila. Sci Reports. 2020 Nov 5;10(1):19080.

Full list of published work as found in My Bibliography:

https://www.ncbi.nlm.nih.gov/sites/myncbi/amit.sharma.2/bibliography/55316754/public/?sort=date&direction=ascending

Photos

Funding

To support our work please consider making a donation to SENS Research Foundation!

Thanks to our existing funders:

Catalysing ApoptoSENS

We are pleased to announce that the ApoptoSENS team led by Dr. Amit Sharma at the SRF Research Center has recently been granted a Catalyst award, courtesy of the Healthy Longevity Global Competition, to continue and expand their critical work on the interactions between senescent cells and natural killer (NK) cells.

The Healthy Longevity Global Competition, administered by the U.S. National Academy of Medicine (NAM) with support from Johnson & Johnson Innovation, will issue up to 24 Catalyst Awards per year between 2020 and 2022. Each Catalyst Award includes a $50,000 cash prize and travel costs to attend an annual Innovator Summit, beginning in summer 2021. The American Federation for Aging Research (AFAR) will collaborate with the NAM on the application and scientific review process.

The major consequence of unresolved DNA damage is a state of growth arrest termed cellular senescence. Although senescence can prevent mutated cells from transforming into cancer, it can also contribute to age-related disease – largely because senescent cells secrete pro-inflammatory factors, collectively known as the Senescence Associated Secretory Phenotype (SASP).

Strong correlations between the accumulation of senescent cells with increasing age and various negative outcomes, as well as the improvements in healthspan observed in several animal models upon their removal, have made senescent cells attractive targets for rejuvenation therapies. The ApoptoSENS strand of the SENS platform is dedicated to the development of those treatments.

Natural Killer (NK) cells are innate immune cells that surveil the body for precancerous cells and cells infected with viruses and other intracellular pathogens. Once the NK cells recognize a target (based on its display of activating and inhibitory receptors), they release cytotoxic proteins such as perforin and granzymes, which induce programmed death – apoptosis – in the target cells.

Recent reports indicate that NK cells can also selectively eliminate senescent cells in cell culture and animal models, opening up a new avenue to develop therapeutic interventions.

This field of research is still in its infancy, and there are several unanswered questions, such as:

  1. can senescent cells escape immune clearance by secreting or presenting decoy receptors, and
  2. how does immune senescence (NK cell aging) impact the cytotoxic potential of NK cells towards senescent cells?

Supported by the Catalyst Award, the ApoptoSENS team will now investigate whether the age-related loss of cytotoxic potential of NK cells toward senescent cells is reversible and, if so, whether and how this may provide routes for therapeutic intervention. If successful, this work will clear a major hurdle to realizing NK cell-based treatments for senescent cell elimination.

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