The transition to cellular senescence can be initiated by a loss of epigenetic information, as well as telomere shortening, irreparable DNA damage, and cytoplasmic DNA. Senescence is associated with alterations in cell morphology, chromatin architecture, and the release of inflammatory factors in a process referred to as the senescence-associated secretory phenotype (SASP). Ĭellular senescence is a state of permanent cell cycle arrest that facilitates wound repair, tissue remodeling, and avoidance of cancer by halting proliferation in aged and damaged cells. We have previously shown in mice that cell injuries, such as DNA double-strand breaks and cell crushing, promote epigenetic information loss, which can lead to what appears to be an acceleration of aging and age-related disease. These findings are consistent with the Information Theory of Aging, which proposes that a decline in information, specifically epigenetic information, triggers a cascade of events, including mitochondrial dysfunction, inflammation, and cellular senescence, leading to a progressive decline in cell and tissue function, manifesting as aging and age-related diseases. We and other researchers have gathered compelling evidence, from yeast to mammals, supporting the idea that a loss of epigenetic information, resulting in changes in gene expression, leads to the loss of cellular identity. In contrast, epigenetic information is encoded by a less stable digital-analog system, varying between cells and changing in response to the environment and over time.Īt least a dozen “hallmarks of aging” are known to contribute to the deterioration and dysfunction of cells as they age. Genetic information is digital and largely consistent across all cells in the body throughout an individual’s lifespan. Though these information repositories work interdependently to coordinate the production and operation of life’s molecular machinery, they are different in fundamental ways. In eukaryotes, there are two main repositories of information: the genome and the epigenome. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.Īll life depends on the storage and preservation of information. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation.
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