Senolytics can rejuvenate the reparative capacity of human cardiomyocytes and endothelial cells, says new research.
The global population is aging rapidly – and people are living longer. In fact, the number of people aged 65 years or above are expected to increase by double or more by 2050.
Increased life expectancy can result in increased incidence of disabilities and chronic conditions, and aging is the most important risk factor for several life-threatening conditions such as cardiovascular diseases, cancer and neurodegenerative disorders. Aging or its hallmarks results in the deterioration of most organ and tissue functions, and the upshot of this is that interventions that help to regenerate organs and tissues are required immediately to reverse and prevent age-related damages and diseases.
One important hallmark of aging is cell senescence. Leonard Hayflick and Paul Moorhead first described the phenomenon of cellular senescence in 1961 . Senescent cells exit from the cell cycle and lose proliferative capacity but remain metabolically active. They can produce and secrete proinflammatory factors, known as the senescence-associated secretory phenotype (SASP). Cellular senescence not only contributes to aging but also to several age-related diseases, and such effects are mediated by increased expression of SASP factors such as TGF-β family members and chemokines .
Longevity.Technology: Accumulation of senescent cells in tissues with aging can have adverse pathophysiological effects and lead to organ deterioration. Previous studies have indicated that the accumulation of senescent cells with disease and aging is associated with decreased lifespan, and the removal of senescent cells through genetic clearance as well as senolytics has been observed to reduce the adverse effects of cardiac aging and cause renewal and replacement of cardiomyocytes.
A new study published in The Journal of Cardiovascular Aging aimed to determine the effects of senescence and senolytics in vitro in a human cardiac cell model system by using the senolytics Dasatanib+Quercetin (D+Q) .
The results indicated that doxorubicin, which is a senescence-inducing agent, could induce 80 percent of human stromal cardiac progenitor cells (CPCs) to express SA-β -gal activity after 28 days. Co-culture of human iPSC-cardiomyocytes (iPSC-CMs) with senescent CPCs (senCPCs) was observed to reduce the number of iPSC-CMs as well as decrease iPSC-CM DNA synthesis.
D+Q treatment was observed to cause senCPC clearance. However, no changes were observed in iPSC-CM survival or cell cycle activity on treatment with D+Q alone. HUVECs, which were cells cultured to reach a deep senescent state, were found to decrease in number when cultured in conditioned media from senCPCs. Treatment of HUVECs with D+Q conditioned media led to an increase in their number as compared with when treated with senCPCs but was still significantly less compared with control normal growth media.
Results from the Matrigel tube network formation assay indicated a decrease in tube formation when HUVECs were treated with senCPC-conditioned media which increased with D+Q-conditioned media. Co-culturing of senescent HUVECS (senHUVECS) with non-senescent ones was reported to decrease the number of non-senescent ones. However, treatment with D+Q was observed to clear the senHUVECs. Tube formation of HUVECs with D+Q conditioned media was reported to be improved as compared with senHUVEC conditioned media but was significantly reduced than the normal control growth medium . Moreover, HUVEC migration was also reported to be decreased for HUVECs with conditioned media from senHUVECs.
Co-culturing of senCPCs with iPSCCMs was observed to upregulate 6 out of 8 SASP factors, and application of D+Q was observed to decrease the levels of nearly all SASP factors. Co-culturing of HUVECs with HUVECs was also observed to upregulate 3 out of 8 SASP factors, and application of D+Q was reported to decrease the level of these factors.
Therefore, the current study suggests that D+Q treatment can remove senescent cells and rejuvenate the activity of human cardiomyocytes and endothelial cells. Thus D+Q can be used for the improvement of endogenous cardiac regeneration mechanisms as well as in vivo cell therapy transplantation.
Back in 2020, The Forever Healthy Foundation published a risk-benefit analysis, which explores the use D+Q as a senolytic therapy. After screening more than 3300 scientific papers and analysing more than 150 clinical and pre-clinical studies, Forever Healthy concluded that the use of D+Q as a senolytic therapy should be avoided – “until there are more published results showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on treatment protocols.”
However, the Cardiovascular Aging study and another published in Geroscience suggest that the tide is turning. In the latter, D+Q treatment effectively reduced cellular senescence in subcutaneous tissue in monkeys .
The D+Q treatment showed anti-inflammatory effects, with notable shifts in blood cell composition. Combining caloric restriction with D+Q treatment further reduced inflammation, showing a mild synergistic effect. The treatment also significantly improved markers of intestinal barrier integrity and kidney function, as indicated by improved blood urea nitrogen (BUN) levels.
Of note is the composition of the study group, which included three diabetic monkeys; these exhibited three times greater senolysis compared with non-diabetic counterparts, suggesting potential benefits for diabetic individuals.
The Geroscience study was conducted over six months – a relevant duration for human clinical trials. It demonstrated the safety and feasibility of systemic administration of D+Q, showed senescent cell reduction, and additional benefits including lower inflammation. Add into the mix the observed synergy between senolytic treatment and caloric restriction, and further exploration of D+Q seems absolutely warranted.