“The list of age-related diseases definitively linked to cellular
senescence keeps growing, as does the number of biotech companies racing
to develop drugs to eliminate senescent cells,” said Judith Campisi,
PhD, professor at the Buck Institute and the study’s senior scientist.
“While the field has never been more promising, the lack of a simple
biomarker to measure and track efficacy of these treatments has been a
hindrance to progress. We are excited to bring this new biomarker to the
field and look forward to it being used in the clinic.”
Campisi and colleagues reported on their findings in Cell Metabolism, in a paper titled, “Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis.”
During cellular senescence, stressed or damaged cells permanently
stop dividing, a putative mechanism to safeguard against cancer.
Senescent cells are not dead, however, and they release a stew of
bioactive molecules that promote wound healing and chronic inflammation,
the latter playing a major role in many age-related diseases as the
cells accumulate over time. This bioactive stew is known as the
senescence-associated secretory phenotype (SASP), and its protein
composition, and deleterious effects have been well studied. “This
senescence-associated secretory phenotype has been characterized largely
for secreted proteins that participate in embryogenesis, wound healing,
inflammation, and many age-related pathologies,” the authors wrote. In
contrast, the lipid components of SASP have been less well studied.
Through their newly reported studies, the Buck Institute team showed
that senescent cells also synthesize a large array of oxylipins, which
are bioactive metabolites derived from the oxygenation of
polyunsaturated fatty acids. “Lipid components of the SASP have been
vastly understudied,” said lead scientist Christopher Wiley, PhD, a
former assistant research professor at the Buck, now at the Jean Mayer
USDA Human Nutrition Research Center on Aging at Tufts University. Yet,
as the researchers noted, “Oxylipins have diverse physiological effects,
including inflammation, fever, vasoconstriction and vasodilation, pain,
hair loss, asthma, and fibrosis.”
Wiley and Campisi had previously shown that senescence and SASP are
associated with significant changes in metabolism, including lipid
metabolism. Fatty acid metabolism is changed in such a way that free
polyunsaturated fatty acids accumulate inside the arrested cells, where
they are used to manufacture oxylipins. The team’s lipid profiling
studies in cultured senescent cells highlighted some of these changes. “
… certain subsets of lipids significantly increased or decreased upon
senescence,” they wrote. “Most notable were striking elevations in the
relative abundance of oxylipins: a class of potent signaling lipids
derived from 20-and 22-carbon fatty acids such as arachidonic (AA) and
adrenic acid (AdA).” Wiley further explained, “The biosynthesis of these
signaling lipids promotes segments of the SASP and reinforces the
permanent growth arrest of senescent cells.
The researchers identified one of these fatty acids, dihomo-15d-PGJ2,
as unique to senescent cells. They found that this oxylipin accumulates
inside senescent cells, and is released when the cells die. “Notably,
senescent cells synthesize and accumulate an unstudied intracellular
prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin,” they
wrote. A series of in vivo studies was then carried out in mice that
were given chemotherapy—which induces widespread senescence—followed by a
senolytic drug. The results confirmed that the dihomo-15d-PGJ2
biomarker was only detected in the blood and urine of animals treated
with both chemotherapy and the senolytic drug, and not with either
treatment on its own, confirming specificity for senolysis.
The researchers also showed that dihomo-15d-PGJ2 had a functional
role in senescence. Inhibiting its synthesis allowed a subset of cells
to escape senescence and continue dividing, and demonstrate a less
inflammatory SASP profile. Conversely, addition of dihomo-15d-PGJ2 to
non-senescent cells drove them into senescence by activating RAS, a
cancer-promoting gene that is also known to cause senescence. “Given
that prostaglandin synthesis is required for senescence, the data
indicate that prostaglandin-mediated RAS activation is a common and
necessary feature of at least some forms of cellular senescence,” the
team concluded.
“ … our finding that released dihomo-15d-PGJ2 can be used as a
biomarker for senolysis has several potential applications,” the team
concluded. “Senolytic drugs are increasingly being used in aging and
related research and—importantly—have entered early clinical trials.
Determining that senolysis is taking place is essential for evaluating
these compounds as therapeutic agents. Detection of dihomo-15d-PGJ2 in
biological fluids may allow rapid evaluation of the efficacy of these
compounds.”
Campisi commented, “We hope that identifying and including these
bioactive lipids as part of the SASP will encourage researchers working
in a broad range of fields to take a new look at cellular senescence.
The fact that one of these lipids ends up being a simple non-invasive
biomarker for tracking the efficacy of treatments is a huge plus for
those of us working to stem the ravages of age-related disease.”
Wiley added, “This work provides a new way of understanding and
studying senescence-driven pathology,” he said. Oxylipins are implicated
in many inflammatory conditions including cardiovascular disease and
pain response. Many commonly used drugs, such as aspirin and ibuprofen,
act by preventing oxylipin synthesis.