Senescent cell accumulation is an important contributing cause of aging. Senescent cells secrete a mix of signals that provokes growth and inflammation, useful in the short term in circumstances such as wound healing and cancer suppression, but damaging to tissue function and health when sustained over the long term. Senolytic drugs that can selectively destroy senescent cells have produced impressive displays of rejuvenation when used in aged mice. Some are in human trials, while many others are in development.
The most studied of present senolytic treatments are navitoclax, the dasatinib and quercetin combination, and fisetin, a mix of small molecule chemotherapeutics and plant extract supplements. Navitoclax has side-effects that make it undesirable. Administration of dasatinib and qercetin is the most proven of senolytic therapies, with data in human patients showing a similar reduction in senescent cells to that observed in mice. Fisetin is undergoing human trials, but results have yet to be reported.
Researchers here report on a study of earlier life intermittent administration of dasatinib and quercetin, and fisetin: monthly administration from 4 months to 13 months of age in mice. Mouse age does not correspond linearly to human age, if going by the usual exterior manifestations of aging. A 3 month old mouse is equivalent to a mid-20s human. A 12 month old mouse is equivalent to a 60 year old human. A 24 month old mouse is equivalent to a 70 year old human. The results here suggest that earlier life administration of current senolytics can have long term downsides that vary by gender and treatment, at least at the frequency used here.
This caution is aimed at those who would like to use senolytic therapies as a preventative approach to aging, starting earlier to stop the senescent cell burden from increasing at all - or at least to slow its progession considerably. To do so, senolytic therapies with better side-effect profiles are needed. Highly targeted small molecule approaches such as the prodrugs that only take effect in cells expressing high levels of β-galactosidase are one possible path towards achieving this goal.
Fisetin and quercetin (Q) are plant-derived flavonoids that offer cytoprotection against cellular stress and act as anti-inflammatory, chemopreventive, chemotherapeutic, and senotherapeutic agents. Dasatinib (D) is a tyrosine kinase inhibitor used to treat leukemia and is routinely used in combination with Q to improve the senotherapeutic potency. Fisetin and D+Q selectively clear senescent cells, thereby delaying aging-associated disorders and improving healthspan and lifespan. This has been observed after reducing senescent cell burden in progeroid mice or in 22-24 month old C57BL/6 mice. Moreover, deletion of senescent cells from the brain genetically or pharmacologically with senolytic drugs led to functional improvements in mouse models of neurodegenerative diseases such as Parkinson's and Alzheimer's=. These studies have shown senolytics can reduce senescent cell burden and have positive impacts on animals with accelerated aging, advanced age, or neurodegenerative disorders. Accordingly, senotherapeutics are currently marketed as anti-aging therapies where young, healthy adults can take these products as dietary supplements.
However, less is known regarding their anti-aging effects of these compounds when administered prior to significant senescent cell accumulation. Thus, the experiments were designed to examine the long-term effects of monthly oral treatment with Fisetin or a D+Q cocktail when administered to C57BL/6 mice starting at 4 months age. Since aging alters numerous biological functions, we examined morphological, metabolic, and cognitive components that are known to be affected by senescent cell accumulation. The results presented here indicate that monthly administration of Fisetin or D+Q had sexually dimorphic effects which also depended on treatment type in C57BL/6 mice.
Our study indicates that both age and sex may also determine the therapeutic outcomes of senolytic treatment. When the treatment was started at 4 months of age, before the reported senescent cell accumulation, Fisetin had beneficial effects in male mice while a D+Q cocktail had adverse consequences in female mice. Fisetin treated male mice had reduced senescence-associated secretory phenotype (SASP), enhanced glucose and energy metabolism, improved cognitive performance, and increased hippocampal expression of adiponectin 1 receptor and glucose transporter 4. D+Q treated females had increased SASP expression along with accumulation of white adipose tissue, reduced energy metabolism, and cognitive performance.
These observations provide novel information with translational relevance. First, senolytic drugs can be taken at an age before significant senescent cell burden to reduce or prevent their prevalence later in life. Second, males and females have differential responses to the same senolytic treatment when initiated at younger ages. Third, a particular senolytic treatment may have beneficial, negligible or detrimental effects depending on the age, sex, or disease. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation.