Sharma Lab
Developing strategies to harness immune mechanisms for targeting and clearing senescent cells.
Photo by Erin Ashford
Sharma Lab Lab Focus
At the Sharma Lab at the Lifespan Research Institute we focus on the mechanistic dissection and therapeutic targeting of cellular senescence, a fundamental driver of aging and chronic diseases. Using cutting-edge technologies that span multi-omics, immunotherapy, and drug development, our goal is to develop transformative interventions that precisely eliminate or modulate senescent cells (SEN).
Our aim is to bridge fundamental biology and translational innovation to create the next generation of diagnostics and therapeutics that target senescent cells. By combining systems biology, immunology, and pharmacology, we aim to develop interventions that extend healthspan, reduce the burden of chronic diseases, and enhance resilience in the aging process.
For collaboration, funding inquiries, or open positions, contact: [email protected].
Program 1: Senescence Vulnerabilities & Mechanism-Based Therapies
Uncovering molecular liabilities of senescent cells to develop next-generation senolytics and senomorphics
Senescent cells arise in response to key forms of biological stress, including persistent DNA damage, telomere attrition, mitochondrial dysfunction, and others. However, unlike transient damage, senescent cells persist, secreting a complex mix of pro-inflammatory, matrix-remodeling, and immunosuppressive factors known as the senescence-associated secretory phenotype (SASP). This secretory phenotype acts as a pathogenic amplifier, promoting stem cell exhaustion, tissue fibrosis, immune dysfunction, and chronic inflammation.
In essence, senescence is both a cause and a consequence of aging, forming a feed-forward loop that accelerates physiological decline and disease vulnerability.
Multiple aging hallmarks—such as persistent DNA damage, telomere shortening, mitochondrial dysfunction, stem cell exhaustion, immune senescence, protein aggregation, and extracellular matrix stiffening—either trigger the onset of senescence or are exacerbated by the senescence-associated secretory phenotype (SASP). As senescent cells accumulate, they amplify tissue dysfunction and systemic inflammation, accelerating the aging process. This bidirectional relationship underscores senescence as a central target for therapeutic intervention in age-related diseases.
Despite their limited numbers, senescent cells exert disproportionate influence over tissue health, regenerative capacity, and immune competence. Intervening at this node—by clearing senescent cells, blocking their harmful secretions, or restoring immune surveillance—offers a uniquely powerful lever to reverse or prevent multiple age-associated pathologies at once. This is why our lab is devoted to uncovering the molecular vulnerabilities of senescent cells, decoding their interactions with the immune system, and translating these insights into targeted immunotherapies and senescence-modifying treatments.
Program Budget
Annual Budget: 450,000 USD
Program Projects
LAMP1: A Universal Surface Marker of Senescence
Research Info
We identified cell-surface LAMP1 as a senescence-specific biomarker in human and mouse tissues. LAMP1 expression strongly correlates with canonical senescence markers (p16, p21, Glb1) and is elevated in fibrotic lung. We developed LAMP1-targeting ADCs to eliminate these cells selectively. [Cell-Surface LAMP1 Study, 2025]
Historical SENS Program:
Related Hallmarks of Aging:
Iron Dyshomeostasis & Ferroptosis-Based Senolytics
Research Info
Senescent cells accumulate labile iron (Fe²⁺), sensitizing them to ferroptosis. Using an Fe²⁺-activatable prodrug (TRX-CBI), we achieved selective senolysis of both primary and paracrine senescent cells, including those resistant to current senolytics. [Cell Reports, 2023]
Historical SENS Program:
Related Hallmarks of Aging:
Harnessing Existing Medication to Target and Destroy Senescent Cells
Research Info
Senescent cells rely on lysosomal exocytosis for survival. We found that apilimod, a PIKfyve inhibitor, induces methuosis and selectively kills senescent cells. In IPF models, this reduces fibrosis and improves lung function. [bioRxiv, 2025]
Historical SENS Program:
Related Hallmarks of Aging:
Program 2: Immune Surveillance & Senescence-Directed Immunotherapy
Harnessing the immune system’s intrinsic ability to recognize and eliminate senescent cells
As we age, the immune system’s ability to recognize and eliminate senescent cells deteriorates, allowing these pro-inflammatory cells to persist and drive chronic diseases. The Sharma Lab is investigating how aging disrupts immune surveillance and how it can be restored to promote healthy longevity.
Senescent cells secrete cytokines and ligands that normally recruit immune cells, particularly natural killer (NK) cells, to eliminate them. However, aging impairs this clearance mechanism. Aged NK cells exhibit reduced cytotoxicity, altered receptor expression, and diminished ability to respond to senescent ligands, allowing senescent cells to evade immune attack and accumulate in tissues. This immunosenescence contributes to the development of persistent inflammation, fibrosis, and impaired tissue repair.
Our lab has developed ex vivo platforms to enhance human NK cell activity against senescent targets, demonstrating that NK function can be rejuvenated and leveraged therapeutically. We also identified γδ T cells as novel senolytic immune effectors that recognize senescent cells through stress ligands such as BTN3A1 and NKG2D, functioning independently of MHC. These findings offer powerful opportunities to engineer cell-based immunotherapies that can remove senescent cells, even in aged or immunocompromised hosts.
In parallel, we explore how senescent cells blunt inflammation resolution. This bidirectional crosstalk between senescent cells and immune cells represents a critical node in age-related tissue dysfunction.
By decoding these interactions, we aim to rebuild immune-mediated senescence surveillance, enhance tissue homeostasis, and develop the next generation of immunotherapeutic strategies against aging.
Program Budget
Annual Budget: 400,000 USD
Program Projects
γδ T Cells as Senolytic Immune Effectors
Research Info
We discovered that human γδ T cells (Vγ9Vδ2) selectively eliminate senescent cells through recognition of BTN3A1 and other ligands. Adoptive transfer of γδ T cells into IPF models reduces senescence burden and fibrosis, offering a cell-based senolytic strategy. [bioRxiv, 2025]
Historical SENS Program:
Related Hallmarks of Aging:
Enhancing NK Cell-Mediated Clearance of SEN
Research Info
We developed a robust, physiologically relevant NK co-culture platform to study senescence immunosurveillance. Enriched human NK cells exhibit enhanced and selective killing of senescent cells, facilitating drug screening and the development of immunotherapy. [Aging, 2022]
Historical SENS Program:
Related Hallmarks of Aging:
Team Members
Principal Investigator
Dr. Amit Sharma
Dr. Amit Sharma’s work focuses on the intricate cellular and molecular mechanisms underlying aging, inflammation, and senescence, through the investigation of interactions that occur within cells and between cells and their microenvironments. The primary goal of his research is to gain a deeper understanding of how cells communicate and adapt within their environments – as these processes play crucial roles in aging and inflammation – and leveraging this deeper understanding to develop therapeutic interventions for aging and the prevention of age-related diseases.
He is deeply committed to education and mentorship. He trains the next generation of scientists in molecular and cellular biology, emphasizing an interdisciplinary approach that integrates genetics, cell biology, biochemistry, and molecular biology.
He spends his spare time reading science fiction books, going on hikes with his husky, and playing soccer with his kids.
Current Research Staff
Please visit the Work With Us page to learn about available positions.
Anna Barkovskaya
Staff Scientist I
Anna is a cancer biologist, now specializing in aging biology. She uses her experience in molecular cell biology to study how and why cells become senescent and dysfunctional as we age, aiming to use their unique traits against them to clear them away therapeutically. Outside the lab, she’s an avid photographer and keen hiker, and enjoys sharing with anyone who’ll listen with random facts about San Francisco and its history.
Gabriel Meca Laguna
Research Associate I
Gabriel holds a BSc in Biotechnology and is currently completing an MSc in Molecular Precision Medicine. He has experience working in multidisciplinary international teams in industry and academia. In the past, he has worked on synthesizing breast cancer drugs and testing interventions in glioblastoma. He shifted to aging by studying the epitranscriptome of senescent cells. His primary interests are age-related health decline, cell heterogeneity, and immune-based approaches to harness the body’s cells for therapeutic purposes. At LRI, He is working on biomarker discovery and senolytic immune-based interventions by combining computational and experimental biology to tackle aging and age-related health decline. In his free time, he enjoys working out and discovering new restaurants around the Bay Area.
Apoorva Shankar
Research Associate I
Apoorva enjoys contributing to research with real-world impact, particularly in combating age-related diseases. As a member of the Sharma lab, she has been exposed to innovative approaches to studying aging, particularly through the development of disease models and an emphasis on the roles of senescent cells and the innate immune system. Being part of this work has strengthened her awareness of how fundamental research can lead to meaningful advancements in science. Outside the lab, she enjoys painting as a creative outlet that helps her unwind and recharge.
Current Students
Lauren holds a Bachelor of Science in Chemistry and a Master of Science in (Bio)Organic Chemistry from Ghent University (Belgium). Her interest in the translational aspects of peptide chemistry in biomedicine led her to LRI, where she aims to gain more insights and hands-on experience in biological applications and techniques. As a graduate intern at LRI, she is working on the discovery of a universal biomarker of senescent cells. This discovery is based on peptide phage display experiments and in vitro analysis of positive hits, both in cell cultures and in tissue samples. Outside of the lab, she enjoys participating in sports and traveling.
Adita is a recent college graduate from the University of California, Davis, and a post-baccalaureate scholar at LRI. In the Sharma lab, She currently focuses on investigating the effect of the secretome from senescent cells on inflammaging and immune dysfunction, as well as its impact on the aging body.
Previous Research Staff
Dr. Tesfahun Admasu
Identification and Targeting of Noncanonical Death Resistant Cells
Dr. Manikandan Samidurai
Dr. Yafei Hou
Kristie Kim
Identification and characterization of the surfaceome of senescent cells and development of CAR-NK cells to enhance immune surveillance
Ashley Brauning
Phage Display Derived Novel Surface-Binding Peptides as Biomarkers for Senescent Cells
Previous Students
Elena Fulton (Postbaccalaureate Fellow, 2019-2020)
Characterization of age dependent changes in peripheral NK cell phenotypes in humans
Gina Zhu (Postbaccalaureate Fellow, 2020-2021)
Identifying Novel Mechanisms to Enhance Natural Killer Cell Mediated Surveillance and Clearance of Senescent Cells
Isaac Colilbee
Michael Qiu
Kriti Bhardwaj
Suhanee Zaroo
Tam Vo Da Gia
Mikayla Stabile (Summer Scholar, 2020)
Characterization of age dependent changes in peripheral NK cell phenotypes in humans
Caroline He
Chloe Amber Lindberg (Summer Scholar, 2021)
Investigating the effect of senescence-associated secretory phenotype (SASP) factors on NK cell function
Publications
Meca-Laguna, G., Admasu, T. D., Shankar, A., Barkovskaya, A., Collibee, I., Krakauer, A., Tran, T., Rae, M., & Sharma, A. (May 9, 2025). γδ T Cells Target and Ablate Senescent Cells in Aging and Alleviate Pulmonary Fibrosis. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.05.05.652251
Barkovskaya, A., Kim, K., Shankar, A., Meca-Laguna, G., Rae, M., Saux, C. J. L., & Sharma, A. (March 19, 2025). Inhibition of PIKfyve kinase induces senescent cell death by suppressing lysosomal exocytosis and leads to improved outcomes in a mouse model of idiopathic pulmonary fibrosis. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.03.19.644224
Mecalaguna, G., Qiu, M., Barkovskaya, A., Shankar, A., Rae, M., & Sharma, A. (March 11, 2025). Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.03.04.640878
Frost, O. G., Barkovskaya, A., Rae, M., Atzori, M., Rebbaa, A., & Sharma, A. (Feb 25, 2025). Analysis of the current state of frailty indexes and their implementation for aging intervention studies. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.02.24.639506
Barkovskaya, A., Brauning, A., Chamoli, M., Rane, A., Andersen, J. K., & Sharma, A. (Jan 8, 2025). Mitigating Proinflammatory SASP and DAMP with Urolithin A: A Novel Senomorphic Strategy. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.01.07.631588
Tesfahun Dessale Admasu, Kristie Kim, Michael Rae, Roberto Avelar, Ryan L. Gonciarz, Abdelhadi Rebbaa, João Pedro de Magalhães, Adam R. Renslo, Alexandra Stolzing, Amit Sharma (Feb 28, 2023). Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis. Cell Reports, Volume 42, Issue 2, 112058, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2023.112058.
. Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells. Aging (Albany NY). 2022 Mar 4; 14:2131-2147 . https://doi.org/10.18632/aging.203931
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:
Funding
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