Biomarker Discovery Reveals Role of Lipids in Age-Related Pathologies
By Deborah Borfitz
April 21, 2021 | Senescent cells can be good or bad actors when it comes to human health, but their steady accumulation with aging has adverse consequences that pharmaceutical companies are keen on reversing. Determining if a senolytic drug is working in the human body is a tough proposition, however, since the testing process often involves a biopsy and waiting long periods of time to determine whether a pathology has been ameliorated.
A novel, non-invasive biomarker test under development by scientists at the Buck Institute for Research on Aging could make tracking the efficacy of senolytic treatments as easy to do in people as it is in a petri dish and mice, according to Buck professor Judith Campisi, Ph.D., whose lab focuses on taming cellular senescence when stressed or damaged cells permanently stop dividing. The first senolytics entered clinical trials only a few years ago, and growing numbers of compounds are in the anti-aging pipeline—many failed anti-cancer drugs.
The goal with senolytics, unlike chemotherapy, is to preserve a portion of the targets, says Campisi. “With a typical senolytic regimen, you knock down the number of senescent cells by somewhere between 70% and 80%. That seems to be enough for a lot of diseases, at least in mice.”
As more such therapeutics enter trials, the new lipid-metabolite biomarker discovered by Buck Institute researchers could be making its debut. Details of the discovery appear in an article in press with Cell Metabolism (DOI: 10.1016/j.cmet.2021.03.008). Campisi was senior scientist on the study and first author was Christopher Wiley, now working independently at Tufts University’s Human Nutrition Research Center on Aging.
The biomarker is easily detectable in plasma or urine, allowing for rapid assessment of whether a senolytic drug is working as intended. One large pharmaceutical company is particularly interested in teaming up with basic scientists at Buck to “identify novel senolytics and take on the onus of clinical trials,” Campisi says.
The new biomarker is a fatty acid known as dihomo-prostaglandin (DPG), released by senescent cells when they are forced to die, she explains. Its level would therefore be expected to rise with treatment, provided the senolytic is effective. The biomarker is presumably short-lived in the body, meaning testing would need to be done “rather frequently” before, during, and after the drug is administered to trial participants.
In the new study in mice, chemotherapy was used to induce widespread senescence, followed by a senolytic drug. The biomarker was only detected in the blood and urine of mice treated with both agents, but not with either on its own, confirming specificity for senolysis.
Inhibiting the synthesis of DPG also allowed a subset of cells to escape senescence and continue dividing and drove a less inflammatory senescence-associated secretory phenotype (SASP) profile. SASP describes the collection of bioactive molecules that cells spew out during cellular senescence. Addition of DPG to non-senescent cell drove them into senescence by activating a cancer-promoting gene that is also known to cause biological aging.
For most of human history, people did not age, Campisi notes. They died by age 40 or 50 of infection, starvation, predation, or other agents that would normally kill an organism living in an unprotected environment. “Any trait we have… was by definition under positive selection.”
There is no quick answer as to why evolution would want senescent cells to arise, says Campisi. What is known is that in mice as well as humans “waves” of senescent cells appear as an embryo is developing to help fine-tune development of certain structures as well as in the placenta during pregnancy to ensure labor occurs on time.
Additionally, senescent cells show up at the site of a wound or damage to a tissue, she continues. In mice, Buck researchers were able to show that skin wounds take much longer to heal and are more fibrotic if senescent cells were eliminated, suggesting they aid in repair.
The downside of senescent cells is that they have been implicated in a long list of diseases that include Alzheimer’s, Parkinson’s, fatty liver disease, some forms of diabetes, cataracts, and cancer metastasis. “These are diseases that did not appear when we were being shaped by evolution,” says Campisi.
The “big unknown” is whether the good guys and bad guys are molecularly different, she adds. “[But] we know if you eliminate senescent cells, at least in mice, you can delay or… soften the symptoms or in some cases even begin to reverse certain age-related pathologies.”
No one is proposing giving senolytic drugs to pregnant women, says Campisi. And she has broached the idea of creating an “antidote” to senolytic drugs in the event a user gets into a car accident involving massive wounds, although the risk is quite slim, and companies are not enthusiastic about pursuing that path.
Senolytics are fast-acting drugs that patients would probably not take for a prolonged period, Campisi says. On the other hand, humans have a lifespan far longer than the three years of mice so treatments may need to be given over longer timeframes than the three to five days typical with animal testing.
The timeframe in which the senolytic drug UBX0101 was tested in a phase 2 trial last year may have contributed to its failure to demonstrate efficacy, says Campisi, a founder of the sponsoring company, UNITY Biotechnology. UBX0101 was administered as a single, direct injection into the knee to treat osteoarthritis. Lengthening the trial with repeat dosing, while more expensive, could serve to prove the drug’s effectiveness.
Campisi’s research is currently focused on prostaglandins, bioactive lipids that are thought to trigger labor and, over the short term, can also promote tissue repair. On the other hand, “if you have too much of them or [for] too long, you have an inflammatory response that can destroy a tissue.” Consequently, “the biggest challenge in the field of aging research is knowing when to intervene and how to intelligently intervene so we are not doing harm.”
Discovery of the DPG biomarker provides a new way of understanding and studying senescence-driven pathology, Campisi says. The lipids components of the SASP have been vastly understudied.
As recently shown by the efforts of her team, senescent cells synthesize a large array of oxylipins, precursors to lipids that include prostaglandins and leukotrienes. Oxylipins have been associated with inflammatory conditions, including cardiovascular disease and pain response, and their synthesis is prevented by commonly used drugs such as aspirin and ibuprofen.
Her team has previously worked with pharmaceutical companies looking to identify novel targets inside senescent cells—including proteins, enzymes, and molecules like metabolites and lipids—and then do mass screenings on drugs to identify those that would selectively kill them off, Campisi says. At least one such novel target was previously identified via industry collaboration.
The ideal order of events is for Buck scientists to work with human cell cultures to identify something interesting and, after ensuring mouse cells respond similarly, begin preclinical studies in mice. Partnering companies would then do the drug screening and conduct clinical trials in humans, she adds, using DPG as a biomarker and potential future companion diagnostic.