Fisetin

Drugs that selectively kill senescent cells may benefit otherwise healthy older women but are not a 'one-size-fits-all' remedy, Mayo Clinic researchers have found. Specifically, these drugs may only benefit people with a high number of senescent cells, according to findings publishing July 2 in Nature Medicine. Drugs that selectively kill senescent cells may benefit otherwise healthy older women but are not a "one-size-fits-all" remedy, Mayo Clinic researchers have found. Specifically, these drugs may only benefit people with a high number of senescent cells, according to findings publishing July 2 in Nature Medicine. Senescent cells are malfunctioning cells in the body that lapse into a state of dormancy. These cells, also known as "zombie cells," can't divide but can drive chronic inflammation and tissue dysfunction linked to aging and chronic diseases. Senolytic drugs clear tissues of senescent cells. In the 20-week, phase 2 randomized controlled trial, 60 healthy women past menopause intermittently received a senolytic combination composed of FDA-approved dasatinib and quercetin, a natural product found in some foods. It is the first randomized controlled trial of intermittent senolytic treatment in healthy aging women, and the investigators used bone metabolism as a marker for efficacy. Researchers found that this combination, known as D+Q, had beneficial effects on bone formation but did not reduce bone resorption or the breakdown and removal of bone tissue. Furthermore, D+Q mainly benefited people with evidence of a high number of senescent cells. This group had more robust increases in bone formation, decreases in bone resorption, and an increase in bone mineral density at the wrist. "Our findings argue against what many people are already doing -- using commercial products like quercetin or related compounds like fisetin that may show some senolytic properties," says senior author Sundeep Khosla, M.D., an endocrinologist at Mayo Clinic in Rochester, Minnesota. "They're using them as anti-aging agents without knowing if they have high enough senescent cell numbers to benefit, or what dose or dosing regimen is needed to be effective yet safe." Dr. Khosla says more research is needed to better identify people who may benefit from senolytic treatments and to develop more specific and potent senolytic drugs that may show efficacy in more people. People who have experienced "accelerated aging" -- such as cancer survivors after chemotherapy, or those with progeroid syndromes -- may have increased numbers of senescent cells. Besides their application to aging, senolytic drugs may be useful against certain diseases, such as idiopathic pulmonary fibrosis, dementia, diabetes, heart disease and others, Dr. Khosla says. However, these drugs will likely need to be customized according to their potency and the amounts of senescent cells in the diseased tissues. The study was supported by National Institutes of Health grant nos. R21 AG065868, P01 AG062413, R01 AG 076515, R01 DK128552, R01 AG055529, R37 AG13925 and R33 AG61456. Co-authors are Joshua Farr, Ph.D., Elizabeth Atkinson, Sara Achenbach, Tammie Volkman, Amanda Tweed, Stephanie Vos, Ming Ruan, Jad Sfeir, M.D., Matthew Drake, M.D., Ph.D., Dominik Saul, M.D., Madison Doolittle, Ph.D., Irina Bancos, M.D., Kai Yu, M.D., Tamara Tchkonia, Ph.D., Nathan LeBrasseur, Ph.D., James Kirkland, M.D., Ph.D., and David Monroe, Ph.D. Drs. LeBrasseur, Tchkonia and Kirkland have financial interests related to this research, including Mayo Clinic patents and pending patents covering senolytic drugs and their uses. The remaining authors declare no competing interests.

In a new study, researchers show that elevated levels of proteins related to cellular senescence, or aging, in the blood and the placenta are linked to this form of heart failure. A form of heart failure that occurs during late pregnancy or early postpartum, peripartum cardiomyopathy (PPCM) is a major cause of maternal death. New research led by investigators from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, reveals new insights into the mechanisms behind PPCM's development and points to potential new strategies for therapeutic development. The results are published in Science Translational Medicine. "Even though heart disease now represents the leading cause of maternal death in the US, our understanding of the biology driving many of these diseases is still very limited," said co-lead author Jason Roh, MD, MHS, a cardiologist who runs a cardiovascular aging laboratory in the Massachusetts General Hospital Cardiovascular Research Center. "Our study identifies some underlying aging-related biology that contributes to the development of maternal heart failure in pregnancy and provides evidence from both patients and animal models." Roh and his colleagues work began with an unexpected finding. While studying the role of senescent (or aged) cells in older adults with heart failure, they were surprised to find that proteins secreted by these aged cells were being detected at even higher levels in the blood of young pregnant women with heart failure. Based on these initial findings, the researchers conducted experiments to see whether these senescence proteins might be contributing to the development of PPCM as well as preeclampsia, a hypertensive disorder of pregnancy that is a leading risk factor for PPCM and postpartum heart failure. Their reasoning was based on prior work showing that the placenta, a hybrid maternal-fetal organ unique to pregnancy, manifests markers of increased senescence towards the end of pregnancy. When the team assessed placentas from women with preeclampsia, they found that they displayed multiple markers of amplified senescence and tissue aging, as well as increased expression of many of the senescence proteins that were detected in the blood of women with preeclampsia or PPCM. The most highly expressed cellular senescence protein in these placentas was activin A, and higher levels of this protein were linked to either more severe heart dysfunction or heart failure in women with preeclampsia or PPCM. "While the placenta undergoes a normal physiological process of aging (or senescence) throughout pregnancy, this seems to be further amplified in those who develop heart failure during pregnancy," said Roh. "We believe this causes it to secrete various factors into the mom's blood that can negatively impact the function of the heart." In experiments conducted in mice, the placentas of mice with PPCM showed similarly increased expression of cellular senescence-associated proteins. Treating these mice with fisetin, a drug that can selectively clear highly senescent cells, during mid to late pregnancy partially reduced placental senescence and improved heart function. Treatment with an antibody directed against the receptor for activin A, after pregnancy, had similar effects in these animals. "Although we are still in the very early stages of understanding how amplified placental senescence can affect the function of the mom's heart, we believe our findings answer some fundamental questions about the biology underlying heart failure in pregnancy," said Roh. "It is important to note that placental senescence is a normal part of pregnancy. Fully understanding why this process becomes perturbed in pregnancy-related heart disease and rigorously determining how to safely regulate it are critical next steps before translating these findings."