03.2020 | THE SCIENTIST 43BIRGIT RITSCHKA, RESEARCH INSTITUTE OF MOLECULAR PATHOLOGY, VIENNA, FORMERLY OF THE KEYES LAB
mulate with age. There are still many
unanswered questions about how these
cells function, but it is already clear to
scientists in the field that senescent
cells influence a range of age-related
pathologies, at least in rodents. Genetic
ablation of senescent cells reduces the
number of atherosclerotic plaques in
mice, improves cartilage development
in mouse models of osteoarthritis,
boosts bone strength in murine models
of osteoporosis, and even staves off neu-
rodegenerative symptoms in models of
Alzheimer’s disease.8,9,10,11
These findings have a number of
scientists thinking: If clearing senes-
cent cells had such beneficial effects on
health, could drugs be developed to do
just that?The birth of senolytics
Kirkland’s group at Mayo had started to
search for senolytic agents long before
the scientific community was convinced
of senescent cells’ role in aging, but it
took him years to work out a good strat-
egy to identify them. In the mid-2000s,
his team tried developing toxins or anti-
bodies that target senescent cells, but
none of these approaches succeeded
in killing senescent cells while sparing
non-senescent ones.
In 2013, it occurred to Kirkland’s
team to target the molecular machin-
ery known to be used by senescent cells
to defy death. The cells must have those
mechanisms in place to avoid undergo-
ing the apoptotic processes that would
typically follow exposure to the high
levels of harmful proteins they are pro-
ducing, the team reasoned. Using a bio-
informatics approach, the researchers
identified several anti-apoptotic path-
ways that are upregulated in senescent
cells, including certain pathways used by
malignant B cells to avoid apoptosis and
cause lymphoma.^12 They then screened
for approved drugs and natural products
that targeted those pathways and thus
selectively killed senescent cells.
To the group’s surprise, two com-
pounds appeared very effective in kill-
ing senescent cells in vitro as well as inmice: dasatinib, approved in the US to
treat certain leukemias and lympho-
mas, and quercetin, which is used as a
nutritional supplement. “I thought we’d
have to screen millions of compounds
to get drugs that regulate senescence,”
recalls Robbins, who was involved in
the effort. But it took fewer than 50
drugs to get the first hits.
The drugs’ effectiveness varied
starkly depending on the cell type,
because different types of senescent
cells appeared to use distinct pathways
to prevent cell death. Dasatinib, which
blocks an enzyme that regulates cell sur-
vival, only kills senescent mesenchymal
cells, such as adipocyte progenitors and
certain myoblasts. Quercetin, which
interferes with several anti-apoptotic
pathways, mainly takes out senescent
endothelial cells, which line animals’
blood vessels and lymphatic vessels.
Used in combination in a mouse model
of a severe degenerative lung disease
called idiopathic pulmonary fibrosis
(IPF), infusions of dasatinib and quer-
cetin improved lung function and phys-
ical health.^13 And in a mouse model of
Alzheimer’s disease, researchers at the
NIH reported that the same drug cock-
tail reduced brain damage and inflam-
mation and slowed the pace of memory
loss in those models.^14
Although these results are promis-
ing, van Deursen questions the seno-
lytic mechanism thought to underlie
the observed therapeutic effects. Dasat-
inib and quercetin each act on numer-
ous biological pathways, he notes, mak-
ing it difficult to ascribe their effects
solely to the killing of senescent cells.
But Kirkland argues his observations
are most likely due to the killing of
senescent cells. Because the drugs are
short-lived and are administered inter-
mittently, they disappear before they
have any consequences other than their
senolytic effect, he explains.
Still, many researchers are pursu-
ing compounds that more precisely tar-
get pathways involved in senescence.
Working in human and mouse cells in
vitro, three separate research groups,including Kirkland’s, have identified
senolytic properties of navitoclax, an
experimental chemotherapy drug that
inhibits components of particular B cell
lymphoma (BCL) pathways.15,16 Compa-
nies such as San Francisco–based Unity
Biotechnology are also getting in on the
hunt for senolytic compounds. Since
founder Nathaniel David launched
the company in 2011 after seeing van
Deursen’s influential study on destroy-
ing senescent cells, Unity’s scientists
have developed three targeted seno-
lytic compounds and started to test
them in early-stage trials: UBX1967
and UBX1325, which both inhibit
BCL pathways, and UBX0101, which
unleashes the tumor suppressor gene
p53 to trigger apoptosis. (Both van
Deursen and Campisi are long-time col-
laborators of Unity.)
Such targeted approaches can also
affect non-senescent cells that happen to
produce high levels of survival proteins,
Kirkland cautions. For instance, navito-
clax could have side effects on platelets
and neutrophils, which naturally make
large amounts of BCL proteins. SomeBIG SENESCENTS: The top panel shows mouse
keratinocytes in a state of oncogene-induced
senescence; the bottom panel shows normal,
proliferating cells.