Fight Aging!

The research materials here cover the recent work of one of many groups digging deeper in the mechanisms of cellular senescence, in search of novel ways to make senescent cells less harmful to surrounding tissues, or means to selectively destroy them outright. The accumulation of senescent cells with age is now well proven to contribute to aging, generating chronic inflammation and disrupting tissue function via a potent mix of signals known as the senescence-associated secretory phenotype, or SASP. The scientists involved here have discovered that HDAC inhibitors can to some degree suppress the SASP, and this intervention also makes these errant cells function more normally in other respects as well.

It is an open question as to whether making senescent cells act more normally is in fact a sensible goal, versus selective destruction using one of the many senolytic therapies under development. Senescent cells are senescent for a reason: they are damaged in some way, or at the end of their replicative life span. It is plausible to argue that helping senescent cells to survive, even while controlling their bad behavior, will meaningfully increase the risk of cancer due to accumulated mutational damage - protecting cells that really should be destroyed. No-one yet has good data to back one position or another in that argument, but given tools such as HDAC inhibition, and other approaches shown to suppress the SASP to various degrees, that data should emerge in the years ahead.

Interestingly, HDAC inhibitors were already identified as a class of drug capable of modestly slowing aging in short-lived species. The mechanisms of action are still unclear and much debated, however, as HDAC inhibition affects numerous systems in the cell. That it can suppress the SASP makes this a more plausible mechanism for slowed aging, given what is known of cellular senescence in aging, than some of the other possibilities, perhaps.

A deep dive into cellular aging

The number of Americans who are age 65 or older is projected to double to more than 90 million in 2060, translating to nearly 25% of the population, due to the natural aging of the Baby Boomer generation. Today, approximately 80% of older adults have at least two chronic diseases, such as heart disease, cancer, stroke, or diabetes. This trend creates a need to solve the projected onslaught of health problems we face and is fueling scientists to dive into the molecular causes of aging and find medicines that help people live long, healthy lives.

Clusters of chromatin - the mix of DNA and protein normally found in the cell nucleus - leak out to the cytoplasm in senescent cells, triggering inflammatory signals that can promote a number of undesirable health conditions. Researchers set out to find what prompts the formation of chromatin clusters in the first place, embarking on a series of experiments using a human lung cell model of senescence. They found that mitochondria were the culprits driving the formation of pro-inflammatory cytoplastic chromatin and did so through a retrograde communication path to the nucleus.

The scientists also found that an HDAC inhibitor, an FDA-approved drug currently used to treat certain cancers, transformed senescent cells from a large and flat form to a healthier and more visually youthful condition. The HDAC inhibitor-treated cells also had better mitochondrial function, less cytoplasmic chromatin and produced less inflammatory signals. The scientists observed similar beneficial effects when examining the livers of mice in which senescence was induced through radiation or high doses of acetaminophen. However, the side effects of HDAC inhibitors - which include fatigue, nausea and more - make the drugs too toxic for use in preventing disease in healthy individuals.

Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence

Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS-STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown.

Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS-JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction.

Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP.