44 THE SCIENTIST | the-scientist.com
researchers conducting animal and clin-
ical studies administer these targeted
senolytics locally to reduce the risk of
such side effects, and have reported good
outcomes. For instance, in 201 7, Campisi
and her colleagues put Unity’s UBX0101
to the test in mice whose knees had been
injured to induce osteoarthritis, injecting
the senolytic drug at the site of injury.^9 To
the researchers’ surprise, elimination of
senescent cells not only reduced inflam-
mation, as expected, but also boosted car-
tilage development. “It was unexpected
that by simple removal of the cells...
you could actually repair the tissue,” notes
Jennifer Elisseeff, a biomedical engineer
at Johns Hopkins University who was
involved in the research.
More than 20 senolytic drugs have
been described so far, some of which
have already been tested in mice, and
researchers are working on finding more
and trying out new approaches for doing
so. Serrano, who now runs a lab at Bar-
celona’s Institute for Research in Bio-
medicine and advises a senolytics com-
pany that he cofounded, says some of his
colleagues are working on engineering T
cells to target senescent cells and destroy
them, a strategy similar to some recently
approved cancer immunotherapies. And
Harries’s research suggests that, con-
trary to a long-held view that senescence
is permanent, the process may in fact bereversible by repairing old cells’ ability
to maintain correct gene expression—a
capacity that is thought to decline with
age.^17 She holds a patent on particular
compounds that may induce this change
in senescent cells.
As researchers continue to explore dif-
ferent ways to manipulate senescent cells,
some are moving ahead to test senolytics
in clinical trials, with a handful of Phase
1 trials now underway pitting senolytics
against age-related diseases in humans.
“The data that we see in mice is amazingly
strong—perhaps to my taste a little bit too
strong, meaning maybe we’re not looking
carefully enough at possible side effects,”
notes Felipe Sierra, who directs the divi-
sion of aging biology at the National
Institute on Aging. Nevertheless, he is
optimistic: “I think that our possibilities
of translation are pretty high.”Cautiously into humans
In February 2019, Kirkland, together
with collaborators at the University of
Te x a s and Wake Forest University in
North Carolina, published results from
14 IPF patients participating in a Phase
1 trial of a dasatinib/quercetin cocktail.^18
Although the primary goal was to evalu-
ate the treatment’s safety, they did see
signs that the drugs could be working.
After taking three oral doses a week for
three weeks, patients could walk furtherin six minutes than they could at the
start of the trial, and they performed bet-
ter on other tests of their physical abili-
ties, such as standing up from a chair.
Last September, the team reported
another encouraging finding in the
form of preliminary data from nine
patients with diabetes-related kidney
disease who had received the senolytic
combo as part of an ongoing Phase
1 safety trial.^19 Based on biopsies of
fat tissue extracted from the patients
before and after the treatment, Kirk-
land’s team found that cells positive for
p16, the senescence marker, were sig-
nificantly decreased in blood, fat, and
skin. To Kirkland, these results are the
first indication that the drugs could be
clearing senescent cells in people.
Meanwhile, Unity Biotechnologies is
moving forward with initial trials of its
senolytic drug candidates. In a Phase 1
study of four dozen patients with osteoar-
thritis, participants said they experienced
less pain in their knees three months after
receiving one injection of UBX0101 into
their knee joints. Physicians found over-
all improvements in the patients’ joint
function over this same time period com-
pared to a control group that received a
placebo. Although the study was primar-
ily designed to assess safety, Unity CEO
Keith Leonard takes the results as a posi-
tive sign. “[The effect] was dose-related:
the higher the dose we put in, the greater
the signal,” he says.
All three treatments appeared to clear
the hurdle for safety, and the US Food and
Drug Administration (FDA) has approved
Phase 2 studies of the dasatinib/quercetin
cocktail for IPF and for diabetes-related
kidney fibrosis. For Unity researchers, the
FDA greenlighted a Phase 1B extension of
the UBX0101/osteoarthritis trial, as well
as a Phase 2 study of the compound in 180
osteoarthritis patients. Neither the Mayo
group nor Unity expect side effects from
the drugs themselves. Unity’s researchers
argue that their local administration of
senolytics makes this unlikely, and Kirk-
land stresses that dasatinib and quercetin
already have good safety records in peo-
ple. But Kirkland is worried that there BIRGIT RITSCHKA, RESEARCH INSTITUTE OF MOLECULAR PATHOLOGY, VIENNA, FORMERLY OF THE KEYES LABSenescent cells in culture