KAT7 Inhibition via Gene Therapy Reduces Cellular Senescence in the Liver and Extends Life in Mice

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Since the confirmation of cellular senescence as an important contributing cause of aging, a great many research initiatives have focused on the biochemistry of senescent cells, in search of new approaches to rejuvenation therapies. A common strategy in the life sciences is to deactivate genes one by one and observe the results, in search of suitable regulators to change cell behavior. In today's open access paper, researchers report on the results of such a screen of gene functions, identifying KAT7 as a gene important in the regulation of cellular senescence in at least the liver.

The researchers screened for gene function in cell cultures, but they used gene therapy in mice to demonstrate that KAT7 knockdown via CRISPR methods reduces cellular senescence in the liver, improves liver function, and extends mouse life span. They did not comment on other organ systems. The liver is the focus of this study most likely because it is the easiest organ to target via present gene therapy vectors. Something like 80% to 90% of any vector that is injected intravenously will end up in the liver. It is not completely clear how KAT7 reduces senescence, whether it is involved in more efficient destruction of senescent cells, or lowers the number of cells that become senescent in response to damage or signaling.

The question with all novel approaches to reducing the burden of senescence is whether they will do more harm than good - which is why it is important to check on longer term health and life span outcomes when conducting animal studies. Selectively destroying senescent cells is confirmed to be beneficial, increasing mouse health and life span. Preventing cells from becoming senescent, on the other hand, is beneficial in the short term, lowering the burden of inflammatory signaling generated by senescent cells, but could in principle raise the risk of cancer and other issues in the longer term, by allowing damaged cells to continue replicating. In the KAT7 work, the treated mice lived longer, an interesting outcome.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

Cellular senescence, a state of permanent growth arrest, has recently emerged as both a hallmark of aging and a fundamental driver of the aging processes. Senescent cells accumulate in tissues over time, triggering natural features of organismal aging and contributing to aging-related diseases (for example, hepatic steatosis and osteoarthritis). Prophylactic ablation of senescent cells expressing the senescence marker p16INK4A mitigates tissue degeneration and extends the health span in mice, indicating that senescent cells play a causative role in organismal aging. For example, senescent cells gradually accumulate in the degenerated liver, whereas clearing senescent cells from the liver attenuates the development of hepatic steatosis.

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9-based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models.

Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24-/- mice that exhibit a premature aging phenotype. KAT7 may represent a therapeutic target for developing aging interventions.

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source https://www.fightaging.org/archives/2021/01/kat7-inhibition-via-gene-therapy-reduces-cellular-senescence-in-the-liver-and-extends-life-in-mice/