The combination of dasatinib and quercetin was the first practical senolytic therapy explored in mice and human trials. Treatments tended to be one-time (a few doses a few days apart) or weekly over a period of a few months. Here, researchers try a longer term approach, weekly intervals for much of the adult life of mice.
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Senolytic therapies produce rejuvenation in animal studies by selectively destroying senescent cells, which cause pathology as they accumulate in tissues. Present thinking is that this accumulation is more a matter of increased creation and slowed clearance rather than individual senescent cells lingering for the long term. Is the best dosing strategy a frequent one or an infrequent one. Or does it not much matter, so long as cells are periodically cleared?
That the study here shows greater benefits in terms of slowed disc degeneration when the senolytic treatement is started earlier in adult life suggests a few things. Firstly that some forms of structural damage do not tend to recover, even when their causes are removed. Secondly that senescent cells are causing some degree of harm earlier in adult life than we might otherwise have suspected. Assessments of the burden of cellular senescence by age do exist, but are not yet robust. Results like this might cause some reassessment of the ideal strategy for those who would like to take advantage of the existence of readily available senolytic drugs.
Studies of human tissues and mouse models have shown an increased incidence of senescent cells during intervertebral disc aging and degeneration. Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice.
We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types.
Our results show that the D + Q combination could target senescence in the mouse disc, and these results provide proof of principle that senolytics may be useful in mitigating age-dependent disc degeneration by decreasing local senescence status, fibrosis and matrix degradation, while promoting cell viability, healthy matrix deposition and lower levels of systemic inflammation.
Link: https://doi.org/10.1038/s41467-021-25453-2
Source: Fight Aging!