Fight Aging!

Cells become senescent throughout life, because of stress or damage or reaching the Hayflick limit on replication, but senescent cells only begin to accumulate with age. When a cell becomes senescent, it grows in size, ceases to replicate, and turns its energies to creating signals promoting inflammation and growth. The immune system is responsible for destroying senescent cells after they have served their purpose, which is usually to attract the attention of immune cells to locations where they are needed to prevent or repair issues. While clearance of senescent cells is efficient in young people, it becomes much less efficient with age, allowing a population of lingering senescent cells to grow over time in tissues throughout the body. The pro-growth, pro-inflammatory signals that are helpful in the short term become harmful when sustained over the long term, disruptive to tissue structure and function and helping to promote the damaging state of chronic inflammation that is characteristic of later life.

Senolytic therapies to selectively destroy senescent cells exist, such as the dasatinib and quercetin combination, but are not widely used, conclusive clinical trial data has not yet been generated, because these are low cost drugs and supplements. No-one can make enough money from them to justify investment in large clinical trials. Meanwhile many companies are working to develop novel, patent-protected senolytic therapies that will be able attract sufficient funding for conclusive clinical trials, and those will be the (much more expensive) drugs that make their way into widespread use. This is the way that modern regulated medicine works.

Meanwhile, another faction of the research community is more interested in finding ways to suppress the inflammatory signaling of senescent cells rather than destroy them. This approach also has its low cost drugs, such as rapamycin, that are unlikely to be the subject of very large clinical trials for their ability to suppress the bad behavior of senescent cells any time soon. Nowhere near as many companies are actively working on novel drugs to alter senescent cell behavior, but the academic research community is identifying new possibilities at a fair pace. Today's open access paper, for example, describes a novel way in which mitochondria support the generation of inflammatory signaling by senescent cells, which opens up a few possible targets for careful sabotage.

Mitochondrial metabolism and epigenetic crosstalk drive SASP

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP). Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes.

Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation, and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.