Reducing Senescent Cell Burden in Aging and Disease

Accumulation of senescent cells is a fundamental aging process that contributes to age-onset disease, compromises health-span, and shortens life-span. Senescent cells have been cleared genetically in animal models and pharmacologically in animals and humans. Reduction in senescent cell burden can be accomplished pharmacologically by targeting antiapoptotic networks or SASP. Early, proof-of-principle pilot clinical studies on senolytic agents are addressing safety and target engagement. Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In preclinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multimorbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine. Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In preclinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multimorbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine. programed cell death during normal growth, development, and removal of potentially harmful cells, such as those that are precancerous or virus-infected. process by which cells undergo irreversible growth arrest, usually secondary to toxic insults or unchecked mitogenic signals. Senescent cells are characterized by several dramatic changes, including epigenetic remodeling of chromatin, changes in the abundance and functionality of organelles, and the enhanced secretion of proinflammatory molecules; however, many of these alterations are not universal and will depend on the cell type and type of inducing stimuli. reduction in the lifetime burden of illness when onset of chronic disease is postponed to a greater extent than the increase in life expectancy. repertoire of molecules released from damaged or necrotic cells that activate the innate immune system by binding to pattern recognition receptors. They promote pathological inflammatory responses and induce cellular senescence. proposition that since aging underlies most chronic disease and debilitating states, interventions that retard primary aging processes would also concomitantly prevent, delay, or alleviate multiple age-related conditions. in mammals, the principal regulatory mechanism for a wide array of cytokines and growth factors. The JAK pathway is more highly active in senescent cells and its inhibition can suppress the SASP. resembling the aging phenotype in older individuals, usually in reference to premature or accelerated aging. p16 is an inhibitor of cyclin-dependent kinases (CDKs) that prevents CDK4/6-binding of cyclin D and formation of an active protein complex that phosphorylates retinoblastoma protein (pRB). If Rb is phosphorylated by CDKs, it dissociates from E2F family transcription factors (E2F 1–3), enters the nucleus, and promotes transcription of target genes necessary for G1 to S phase cell cycle transition. For clarity, we have simplified this pathway, however, it should be noted that other players may be involved, including several non-E2F target genes of Rb. p16 hypermethylation, mutation, or deletion leads to dysregulation of cell cycle progression. Increased expression of p16 is associated with cell senescence. p53-dependent cell cycle arrest is the primary response to DNA damage. p21, an inhibitor of cyclin-dependent kinases, is the primary mediator of downstream cell cycle arrest due to p53 activation. The p21 protein functions as a regulator of cell cycle progression at both G1 and S phases. Activation of p21 is associated with cell senescence. region of repetitive nucleotide sequences at chromosome ends; associated with a protein complex to form a protective loop structure that prevents against deterioration or fusion with adjacent chromosomes. With replication cycles telomeres grow shorter or dysfunctional and when critically short or dysfunctional are associated with a DNA damage response that triggers cellular senescence. elements within DNA that can be translated into RNA, be reverse-transcribed into DNA, and re-inserted at new sites in chromosomes (‘jumping genes’). Transposons can disrupt chromosomal structure and elicit responses within cells that contribute to inflammation and the SASP.