Clearing out the clutter: ‘senolytic’ drugs improve vascular health in mice

(Left) Normal coronary artery with normal blood flow. Right: a coronary artery narrowed by plaque, limiting the flow of oxygen-rich blood through the artery. (credit: NIH)

Mayo Clinic researchers have demonstrated the first study in which repeated treatments to remove senescent cells (cells that stop dividing due to age or stress) in mice improve age-related vascular conditions — and may possibly reduce cardiovascular disease and death.

The researchers intermittently gave the mice a cocktail of two senolytic drugs (ones that selectively induce cell death): dasatinib (a cancer drug, trade name Sprycel) and quercetin*. The drugs cleared (killed off) senescent cells in naturally aged and atherosclerotic mice. The treatment did not reduce the size of plaques in mice with high cholesterol, but did reduce calcification of existing plaques on the interior of vessel walls.**

The findings appear online (open access) in Aging Cell.

“Our finding that senolytic drugs can reduce cardiovascular calcification is very exciting, since blood vessels with calcified plaques are notoriously difficult to reduce in size, and patients with heart-valve calcification currently do not have any treatment options other than surgery,” says Jordan Miller, Ph.D., Mayo cardiovascular surgery researcher and senior author of the paper.

“While more research is needed, our findings are encouraging that one day removal of senescent cells in humans may be used as a complementary therapy along with traditional management of risk factors to reduce surgery, disability, or death resulting from cardiovascular disease.”

The coauthors include two researchers from Newcastle University. The research was supported by the National Institutes of Health, Mayo Clinic Center for Regenerative Medicine, and the Connor Group and Noaber Foundation. Drs. Kirkland, Tchkonia, Zhu, Pirtskhalava, and Ms. Palmer have a financial interest related to the research.

* Quercetin is found in many fruits, vegetables, leaves and grains. It can be used as an ingredient in supplements, beverages, or foods. — Wikipedia

** Prior studies at Mayo showed chronic removal of the cells from genetically-altered mice can alter or delay many of these conditions, and short-term treatment with drugs that remove senescent cells can improve the function of the endothelial cells that line the blood vessels. This study, however, looked at the structural and functional impacts of cell clearance using a unique combination of drugs on blood vessels over time. Mice were 24 months old when the drugs were administered orally over a three-month period following those initial two years. A separate set of mice with high cholesterol was allowed to develop atherosclerotic plaques for 4 months and were then treated with the drug cocktail for two months. — Mayo Clinic


Abstract of Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

Rationale: While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown.

Objective: To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease.

Methods and Results: Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF+ cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment.

Conclusions: This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

‘We have detected gravitational waves’ — LIGO scientists

Numerical simulations of the gravitational waves emitted by the inspiral and merger of two black holes. The colored contours around each black hole represent the amplitude of the gravitational radiation; the blue lines represent the orbits of the black holes and the green arrows represent their spins. (credit: C. Henze/NASA Ames Research Center)

On Sept. 14, 2015 at 5:51 a.m. EDT (09:51 UTC) for the first time, scientists observed ripples in the fabric of spacetime called gravitational waves, arriving at Earth from a cataclysmic event in the distant universe, the National Science Foundation and scientists at the LIGO Scientific Collaboration announced today. This confirms a major prediction of Albert Einstein’s 1915 general theory of relativity and opens an unprecedented new window to the cosmos.

Gravitational waves carry information about their dramatic origins and about the nature of gravity that cannot be obtained from elsewhere. Physicists have concluded that the detected gravitational waves were produced during the final fraction of a second of the merger of two black holes to produce a single, more massive spinning black hole. This collision of two black holes had been predicted but never observed.

The gravitational-wave event on Sept. 14, 2015 at 09:50:45 UTC was observed by the two LIGO detectors in Livingston, Loiusiana (blue) and Hanford, Washington (orange). The matching waveforms represent gravitational-wave strain inferred to be generated by the merger of two inspiraling black holes. (credit: B. P. Abbott et al./PhysRevLett)

The gravitational waves were detected  by both of the twin Laser Interferometer Gravitational-wave Observatory (LIGO) detectors, located in Livingston, Louisiana, and Hanford, Washington. The LIGO observatories are funded by the National Science Foundation (NSF), and were conceived, built and are operated by the California Institute of Technology (Caltech) and the Massachusetts Institute of Technology (MIT). The discovery, accepted for publication in the journal Physical Review Letters, was made by the LIGO Scientific Collaboration (which includes the GEO Collaboration and the Australian Consortium for Interferometric Gravitational Astronomy) and the Virgo Collaboration using data from the two LIGO detectors.

The signal sweeps upwards in frequency from 35 to 250 Hz with a peak gravitational-wave strain of 1.0×10−21.

Illustration of the collision of two black holes — an event detected for the first time ever by the Laser Interferometer Gravitational-Wave Observatory, or LIGO — is seen in this still from a computer simulation. LIGO detected gravitational waves, or ripples in space and time, generated as the black holes merged. (credit: SXS)

Based on the observed signals, LIGO scientists estimate that the black holes for this event were about 29 and 36 times the mass of the Sun, and the event took place 1.3 billion years ago. About three times the mass of the Sun was converted into gravitational waves in a fraction of a second — with a peak power output about 50 times that of the whole visible universe. By looking at the time of arrival of the signals — the detector in Livingston recorded the event 7 milliseconds before the detector in Hanford — scientists can say that the source was located in the Southern Hemisphere.

According to general relativity, a pair of black holes orbiting around each other lose energy through the emission of gravitational waves, causing them to gradually approach each other over billions of years, and then much more quickly in the final minutes. During the final fraction of a second, the two black holes collide at nearly half the speed of light and form a single more massive black hole, converting a portion of the combined black holes’ mass to energy, according to Einstein’s formula E=mc2. This energy is emitted as a final strong burst of gravitational waves. These are the gravitational waves that LIGO observed.

How our sun and Earth warp spacetime is represented here with a green grid. As Albert Einstein demonstrated in his theory of general relativity, the gravity of massive bodies warps the fabric of space and time — and those bodies move along paths determined by this geometry. His theory also predicted the existence of gravitational waves, which are ripples in space and time. These waves, which move at the speed of light, are created when massive bodies accelerate through space and time. (credit: T. Pyle/LIGO)

The existence of gravitational waves was first demonstrated in the 1970s and 1980s by Joseph Taylor, Jr., and colleagues. In 1974, Taylor and Russell Hulse discovered a binary system composed of a pulsar in orbit around a neutron star. Taylor and Joel M. Weisberg in 1982 found that the orbit of the pulsar was slowly shrinking over time because of the release of energy in the form of gravitational waves. For discovering the pulsar and showing that it would make possible this particular gravitational wave measurement, Hulse and Taylor were awarded the 1993 Nobel Prize in Physics.

The new LIGO discovery is the first observation of gravitational waves themselves, made by measuring the tiny disturbances the waves make to space and time as they pass through the earth.

“Our observation of gravitational waves accomplishes an ambitious goal set out over five decades ago to directly detect this elusive phenomenon and better understand the universe, and, fittingly, fulfills Einstein’s legacy on the 100th anniversary of his general theory of relativity,” says Caltech’s David H. Reitze, executive director of the LIGO Laboratory.

An aerial view of the Laser Interferometer Gravitational-wave Observatory (LIGO) detector in Livingston, Louisiana. LIGO has two detectors: one in Livingston and the other in Hanford, Washington. (credit: LIGO Laboratory)

LIGO research

The discovery was made possible by the enhanced capabilities of Advanced LIGO, a major upgrade that increases the sensitivity of the instruments compared to the first generation LIGO detectors, enabling a large increase in the volume of the universe probed — and the discovery of gravitational waves during its first observation run. NSF is the lead financial supporter of Advanced LIGO. Funding organizations in Germany (Max Planck Society), the U.K. (Science and Technology Facilities Council, STFC) and Australia (Australian Research Council) also have made significant commitments to the project.

LIGO research is carried out by the LIGO Scientific Collaboration (LSC), a group of more than 1,000 scientists from universities around the United States and in 14 other countries. More than 90 universities and research institutes in the LSC develop detector technology and analyze data; approximately 250 students are strong contributing members of the collaboration. The LSC detector network includes the LIGO interferometers and the GEO600 detector. The GEO team includes scientists at the Max Planck Institute for Gravitational Physics (Albert Einstein Institute, AEI), Leibniz Universität Hannover, along with partners at the University of Glasgow, Cardiff University, the University of Birmingham, other universities in the United Kingdom and the University of the Balearic Islands in Spain.

“This detection is the beginning of a new era: The field of gravitational wave astronomy is now a reality,” says Gabriela González, LSC spokesperson and professor of physics and astronomy at Louisiana State University.

LIGO was originally proposed as a means of detecting gravitational waves in the 1980s by Rainer Weiss, professor of physics, emeritus, from MIT; Kip Thorne, Caltech’s Richard P. Feynman Professor of Theoretical Physics, emeritus; and Ronald Drever, professor of physics, emeritus, also from Caltech.

“The description of this observation is beautifully described in the Einstein theory of general relativity formulated 100 years ago and comprises the first test of the theory in strong gravitation. It would have been wonderful to watch Einstein’s face had we been able to tell him,” says Weiss.

“With this discovery, we humans are embarking on a marvelous new quest: the quest to explore the warped side of the universe — objects and phenomena that are made from warped spacetime. Colliding black holes and gravitational waves are our first beautiful examples,” says Thorne.

Virgo research is carried out by the Virgo Collaboration, consisting of more than 250 physicists and engineers belonging to 19 different European research groups: six from Centre National de la Recherche Scientifique (CNRS) in France; eight from the Istituto Nazionale di Fisica Nucleare (INFN) in Italy; two in the Netherlands with Nikhef; the Wigner RCP in Hungary; the POLGRAW group in Poland; and the European Gravitational Observatory (EGO), the laboratory hosting the Virgo detector near Pisa in Italy.

At each observatory, the 2 1/2-mile (4-km) long, L-shaped LIGO interferometer uses laser light split into two beams that travel back and forth down the arms (four-foot diameter tubes kept under a near-perfect vacuum). The beams are used to monitor the distance between mirrors precisely positioned at the ends of the arms. According to Einstein’s theory, the distance between the mirrors will change by an infinitesimal amount when a gravitational wave passes by the detector. A change in the lengths of the arms smaller than one-ten-thousandth the diameter of a proton (10-19 meter) can be detected.

Independent and widely separated observatories are necessary to determine the direction of the event causing the gravitational waves, and also to verify that the signals come from space and are not from some other local phenomenon.

Toward this end, the LIGO Laboratory is working closely with scientists in India at the Inter-University Centre for Astronomy and Astrophysics, the Raja Ramanna Centre for Advanced Technology, and the Institute for Plasma to establish a third Advanced LIGO detector on the Indian subcontinent. Awaiting approval by the government of India, it could be operational early in the next decade. The additional detector will greatly improve the ability of the global detector network to localize gravitational-wave sources.

“Hopefully this first observation will accelerate the construction of a global network of detectors to enable accurate source location in the era of multi-messenger astronomy,” says David McClelland, professor of physics and director of the Centre for Gravitational Physics at the Australian National University.

The finding is described in an open-access paper in Physical Review Letters today (Feb. 11).


National Science Foundation | LIGO detects gravitational waves **Begin viewing at 27:14**