Research Project Details
Development of senotherapeutics: Senescence refers to a cell fate where damaged that lose the ability to proliferate, yet are resistant to death. Senescent cells also secrete inflammatory cytokines, chemokines, and proteases, termed the Senescence-Associated Secretory Phenotype (SASP), which contributes to driving aging and age-related diseases. The burden of senescent cells increases with age and the reduction in their burden in transgenic mouse models extends healthspan. Our lab is identifying, optimizing and characterizing senolytics, able to specifically target and destroy these dysfunctional senescent cells, as well as senomorphics, able to suppress expression of the SASP. These senotherapeutics extend healthspan in mouse models of aging and thus have the potential to extend human healthspan.
Identifying, characterizing and spatially mapping senescent cells with murine and human aging: Our laboratory is part of the SenNet Consortium, supported by the NIH Director’s Common Fund, that is developing a 4D map of senescent cells in 18 tissues with aging using cutting edge single cell and spatial transcriptomics and proteomics technologies. In particular, the laboratory is focused on examining senescent cell types in liver and adipose tissue in humans and brain, liver, adipose, lung and muscle in mice.
Stem cells and extracellular vesicles: The loss of functional stem cells leads to aging and its associated degenerative diseases, but the mechanisms behind this remain unclear. Our lab studies the pathways that cause stem cell dysfunction as we age in order to improve aged stem cell function as well as exploring the use of transplantation of young, functional stem cells into old mice therapeutically to increase their healthspan. In addition, we have identified extracellular vesicles (EVs) derived from young, functional stem cells as able to function as senomorphics, suppressing expression of SASP factors and reducing paracrine senescence in old mice. In addition, we have identified a subset of miRNAs in the functional stem cell-derived EVs important for suppressing markers of senescence/SASP. Interestingly, we also have identified miRNAs able to not only reduce markers of senescence, but also rejuvenate aged cells.
IKK/NF-κB signaling: An increase in DNA damage and a reduced ability for DNA repair occurs with age. These processes combine to form one of the primary hallmarks of aging: genome instability. The DNA damage response (DDR) is critical for driving cells into senescence and inducing the inflammatory SASP. At least one family of transcription factors, NF-κB, has been linked to senescence, aging and age-related diseases. Our lab uses genetically engineered mouse models with accelerated aging phenotype to explore this link between DNA damage, NF-κB activation, senescence and aging. In addition, the lab is developing small molecules that can prevent the induction of NF-κB by DNA damage, able to reduce senescence and the SASP and extend healthspan.
Identifying longevity-associated rare variants in centenarians to guide drug development: Centenarians (people living to 100 years or more) possess unique rare genetic variants that protect them from disease and slow the aging process. In collaboration with investigators at Albert Einstein and Columbia Universities and the University of Rochester, we have identified coding and non-coding rare variants in multiple genes including SIRT6, Smad3, and NF-κB family members that are being validated in human iPSCs and in mouse models. Our lab is screening for compounds that mimic the positive effects of these rare variants, many of which increase DNA repair and suppress senescence and inflammation.
Immune aging: The immune system is critically important for fighting off infection and disease. However, as our immune system ages, it becomes not only less efficient in its ability to ward off diseases, but also can contribute to driving systemic aging. Using mouse models where the immune system can be aged specifically, we have observed increased senescence in non-immune tissues and a shortened lifespan. Our laboratory is determining the key immune cell types that drive systemic paracrine senescence and aging as well as screening and testing for compounds that can improve immune function in aged mice, thereby increasing resilience to pathogen exposure.
Mitochondrial plaques and Alzheimer's disease: Using a newly established AD mitophagy reporter mouse model (APP/PSEN1/mt-keima), the laboratory has shown impaired mitophagy and formation of dystrophic neurites enriched with mitochondria. We have termed these mitochondria-enriched structures mitochondrial plaques (MPs). MPs develop earlier and independently from Aβ plaques, but eventually merge into mixed plaques. The laboratory now is identifying biomarkers of MPs as well as screening for compounds that prevent the formation or clear MPs.