Activated Macrophages: a New Player in Senescence-Driven Damage

The Problem

The immune system has an ability to patrol for and destroy senescent, or aged cells, a function which deteriorates over time, permitting senescent cells to accumulate and drive age-related disease. The negative impacts from senescence may actually result from a joint attack by both senescent cells and activated macrophages – a type of immune cell. These cells can be mistaken for senescent cells, as they are present in aged tissues and have some of the same identifiers. 

The Goal

Using specific senolytics – or drugs that remove senescent cells – to eliminate both senescent cells and activated macrophages selectively through their abnormally high iron levels and other proven methods will allow the different cell types to be destroyed selectively rather than indiscriminately. We will learn which, or both, are drivers of age-related disease, how they interact, and how to achieve maximum benefit with minimal side-effects.  

The Status

This is a new project with work just beginning. 


Targeting Iron Metabolism to Untangle Senescent Cells from Activated Macrophages

Preliminary evidence suggests that the effects of senescent cells (SEN) may result from the combined effects of SEN and M1 (activated inflammatory) macrophages. The two cell types are frequently both recruited by the SASP, found in the same tissues, and cooperate in the pathogenesis of age-related diseases such as atherosclerosis and cancer. The two most widely-used biomarkers for the identification of SEN (p16INK4A and senescence-associated beta-galactosidase (SA-β-gal)), as well as several SASP factors, are shared in common with M1 macrophages. This can create misattribution of the presence and effects of either cell type to the other.  

To disentangle the roles of activated macrophages in aging from those of SEN, this project will compare the effects of simultaneous ablation of SEN and M1 macrophages against those of selective ablation of each cell type individually. Clodronate‐loaded liposomes can destroy high numbers of activated macrophages, and doing so has been reported to ameliorate aging phenotypes. The Sharma lab has demonstrated that prodrugs can exploit the aberrantly high levels of labile iron in SEN to trigger cell death in a broader range of SEN than do previous senolytics. Macrophages have a similar retention of iron during phenotypic switching to M1 activation, which may make the iron-activated prodrug capable of simultaneously destroying them and SEN. 

Comparing and contrasting the effects of these various interventions would allow the Sharma lab to disentangle the joint and individual roles of SEN and M1 macrophages in aging phenotypes an age-related disease, as well as answer important questions about their interactions, including the role of M1 macrophages SEN immunosurveillance and in propagating secondary senescence. The results will inform protocols to target each of these cell types to achieve maximum rejuvenation while minimizing side-effects.


Team Members

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

Dr. Amit Sharma

Dr. Amit Sharma

Principal Investigator

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 is the SENS Research Foundation 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.


Funding

Annual Budget
100,000 USD

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