Project description:Cells expressing features of cellular senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Using skeletal fracture as a model of acute injury, we identified rapidly-appearing senescent-like cells, marked by p21 expression, that negatively affected fracture healing. p21+ callus cells, which consisted predominantly of neutrophils and osteochondroprogenitors, existed as transient cells specific to injury and expressed high levels of senescence-associated factors known to impair bone formation and induce paracrine senescence. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Together, our findings establish contextual roles of senescent/senescent-like cells that may be leveraged for therapeutic opportunities.
Project description:Senescent cells are a major cause of organismal aging and a key target for anti-aging therapies. Persistent DNA damage signaling is a primary driver of the induction and maintenance of cellular senescence. However, many DNA damaging stimuli that induce senescence, such as irradiation or transient exposure to genotoxic drugs, are transient. The mechanisms underlying persistent damage signaling in senescent cells, and why senescent cells fail to repair damaged DNA, remain unknown. Here, we were able to assess the mechanisms underlying persistence of DNA damage and senescence maintenance by designing a precisely controllable senescence system that does not require potent stressors to induce senescence. We demonstrate that sustained mTORC1 signaling in senescent cells causes gradually accumulating DNA damage and an inflammatory response that maintains cell-cycle arrest. Markedly, activation of E2F transcription, which promotes expression of DNA repair proteins, can reverse accumulated DNA damage. Thus, persistent DNA damage signaling arises in senescent cells by uncoupling of mTORC1 and E2F signaling, whereby prolonged mTORC1 activity causes gradually increasing DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
Project description:Diet profoundly shapes human physiology and health, including aging and age-related diseases marked by senescent cell accumulation. However, the underlying mechanisms remain unclear. Here, we report vanadyl sulfate (VS), a mineral dietary supplement, as a senolytic agent. Oral VS extends lifespan and ameliorates phenotypes of aging and diverse age-related disorders. Integrated functional-omics analyses show that senescent cells exhibit globally reduced proteome cysteine reactivity, but upregulated expression of proteins essential for endoplasmic reticulum (ER) proteostasis, accompanied by increased apparent cysteine reactivity. This redox-proteostasis state is linked to glutathione disulfide (GSSG) accumulation that can be recapitulated by GSSG delivery in non-senescent cells. Mechanistically, VS inactivates reactive cysteines and promotes disulfide bond formation in senescent cells, leading to protein misfolding, aggregation and ultimately cell death. Glutathione reductase (GSR) downregulation promotes GSSG accumulation, distinguishing senescent from non-senescent cells and conferring selective susceptibility to VS. Our findings reveal an exploitable redox-proteostasis vulnerability of senescent cells with therapeutic potential to ameliorate aging.
Project description:Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, long-term presence of senescent cells might promote tissue degeneration and malignant transformation via secreted pro-inflammatory and matrix-remodeling factors. These factors lead to immune-cell recruitment and senescent-cell clearance. Senescent cells accumulate in tissues in advanced age. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. Here we show that mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation. They suffer from multiple age-related disorders and significantly lower survival. Strikingly, pharmacological elimination of senescent-cells by ABT-737 partially alleviates accelerated aging phenotype in these mice. In progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival. Our findings shed new light on mechanisms governing senescent-cell presence in aging, and could motivate new strategies for regenerative medicine.
Project description:The accumulation of irreparable cellular damage restricts healthy lifespan after acute stress or natural aging. Senescent cells are thought to impair tissue function and their genetic clearance can successfully delay features of aging. Identifying how senescent cells avoid apoptosis would allow for the prospective design of anti-senescence compounds to address whether homeostasis can be restored. Here, we identify FOXO4 as a pivot in the maintenance of senescent cell viability. We designed a FOXO4-based peptide which selectively competes for interaction of FOXO4 with p53. In senescent cells, this results in p53 nuclear exclusion and cell-intrinsic apoptosis. Importantly, under conditions where it was well tolerated, the FOXO4 peptide restored liver function after Doxorubicin-induced chemotoxicity. Moreover, in fast aging XpdTTD/TTD, as well as in naturally aged mice the FOXO4 peptide could counteract the loss of fitness, fur density and renal function. Thus, it is possible to therapeutically target senescent cells and thereby effectively counteract senescence-associated loss of tissue homeostasis.
Project description:Aging of the hematopoietic system impairs HSC function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, we employed the novel BCL-xL/BCL-2-targeted senolytic 753b to pharmacologically clear senescent cells in aged animals, evaluating its safety, efficacy, and restorative benefits to hematopoiesis.