Deconstructing aging with senolytic CAR T cells

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SUMMARY Gaining a better understanding of aging biology is a pressing health and socioeconomic issue. In this regard, cellular senescence is a key, but poorly understood determinant of organismal aging. Senescence is a stress response program characterized by stable cell cycle arrest. Initially described as a tumor suppressor mechanism, it involves the interplay between the tumor suppressors p53 and RB leading to a transcriptional program of gene repression that silences proliferation associated genes. Beyond their arrest, senescent cells secrete the senescence associated secretory phenotype (SASP) composed of cytokines and matrix remodeling enzymes. The SASP contributes to the induction of paracrine senescence as well as to the recruitment of immune cells, whose role is to clear the senescent cells and restore tissue homeostasis. Indeed, this is what happens in the context of wound healing or tumor suppression. However, for mechanisms that remain unclear, in certain settings such as aging or age-related diseases, senescent cells accumulate over time generating a pathological chronic pro-inflammatory milieu that plays a key role in the pathophysiology of these conditions. Our goals are to identify cell surface markers that are selectively expressed in senescent cells in aging for the purpose of better identifying, isolating and characterizing the senescence program in aging. In parallel, we will exploit the selective features of these molecules with the aim of developing better imaging strategies to monitor senescent cells in vivo as well as of developing CAR T cells able to selectively eliminate senescent cells in aging. We will use these senolytic CAR T cells to functionally interrogate senescence biology in vivo as well as to study their therapeutic potential in preclinical models of age-related diseases. Preliminary data strongly supports the feasibility of the proposed work: we have already identified one cell surface molecule expressed on senescent cells in aging and validated the potential of CAR T cells targeting it as effective and safe senolytics in aging. In our application, we continue to identify and validate additional markers, characterize the molecular program of senescence in aging and optimize cellular therapy designs for aging conditions. Cold Spring Harbor Laboratory has a longstanding history of nurturing successful early scientist through their Independent Fellows program. This highly supportive environment is an ideal niche to develop this project and launch my own research program as an Independent Fellow. Completion of the proposed work will better define the senescence state in aging, produce new insights into the biology of senescence immune surveillance and generate a new modality to both interrogate senescence and treat age- related diseases.