Dasatinib and quercetin – two senolytic compounds shown to induce senescent (aged) cell death – have been shown to reduce age-related conditions, such as inflammation in fat tissue and increased blood sugar, in old mice.
Aging is often associated with increased inflammation and increased senescent cells – aged cells that no longer divide and grow. Senolytics – compounds shown to induce death in senescent cells – have been used to help deal with age-related concerns. A recent study shows that combining two well-known senolytics has a positive effect on aging fat tissue and metabolism.
The study, from the University of Utah and published in Aging Cell, focused on aged mice given the senolytics, dasatinib and quercetin (D+Q). D+Q decreased the number of senescent cells in the fat tissue of the old mice and led to the suppression of a subset of age-related pro-inflammatory molecules from senescent cells. Inflammatory immune cells were also reduced in the fat tissues of treated mice. The combined senolytics also improved fasting blood sugar and sugar tolerance in the aged mice. Additionally, the treatments reduced plasma triglycerides – a component of natural oils and fats, which, when increased, leads to an increased risk of stroke – and improved ingested fat tolerance in the mice. Furthermore, the livers of mice treated with D+Q showed reduced age-related fibrosis (scarring), and reduced new sugar formation in the liver, which occurs during times of insufficient or absent nutrient intake.
“These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age,” the investigators wrote.
The scientists gave 21-month-old mice (approximately 65 in human years) dasatinib (5 mg/kg) and quercetin (50 mg/kg) for three days, every two weeks for three months orally. The treatment decreased senescent cells in the animals’ fat tissue and altered the fat deposition of the aged mice to be closer to that of the young mice, suggestive of anti-aging potential. Furthermore, age-related increases in T-cells and macrophages – specifically white blood cells – were reduced in fat tissue around the genitals with D+Q treatment, indicating reduced inflammation in the fat tissue of the treated mice.
Having seen the changes in fat deposition, the scientists looked at metabolic function. Fat deposition is known to play a role in metabolic function, with increased abdominal fat (as seen in older individuals) leading to metabolic dysfunction. So in addition to improved fat deposition, the scientists found that when old mice were given D+Q, their fasting blood sugar and sugar tolerance were improved, despite not being overly affected by advanced age.
The scientists performed insulin tolerance testing, which determines the body’s sensitivity to insulin (which helps process blood sugar) by measuring blood sugar both before and after insulin administration. They found that untreated old mice had lower blood sugar levels as compared to young control mice at the 90 and 120-minute time points, indicative of an impaired ability to restore blood sugar levels after the initial decline during insulin tolerance testing. Meanwhile, those mice treated with D+Q had higher blood sugar levels at later time points, suggesting that their ability to restore blood sugar levels after insulin has been restored.
The scientist also looked at the liver due to its crucial role in nutrient metabolism. It helps metabolize carbohydrates, fat, and protein. However, during times of nutrient deprivation (or lack of insulin sensitivity, as seen with old mice), the liver helps create more sugar from non-carbohydrate sources. When the researchers looked at sugar tolerance, they found that D+Q treatment improved sugar tolerance, possibly by reducing the amount of sugar created in the liver. So while normal aging increased the activity of genes involved in sugar production, D+Q treatment reduced the activity of the same genes. Additionally, D+Q treatment was shown to reduce liver collagen – indicative of fibrosis (scarring) – in old mice, possibly enhancing liver function and leading to improved metabolic function. Notably, D+Q treatment also attenuated metabolic health by limiting fat deposition following a meal.
Islam and colleagues show here that D+Q can improve fat inflammation and deposition, as well as metabolic dysfunction in old mice. Previous studies have shown that D+Q can prevent inflammation and increase the survival of aged cardiac tissue for transplant, similar to what is seen here with fat tissue. Interestingly, other senolytics like fisetin also hold potent anti-inflammatory properties, with studies showing that it can help alleviate brain inflammation and reduce cognitive dysfunction.
Senolytics have come a long way, going so far as showing promise in preventing pancreatic cancer progression. However, as with many up-and-coming anti-aging regimens, human clinical trials with long-term follow-up are still needed. And there are those medical professionals concerned about possible adverse effects, highlighting the considerations that individuals need before jumping into a new therapy or medication. As always, please speak with your doctor before changing or starting a new medication or supplement.
Model: Male C57BL/6 mice
Dosage: Dasatinib (5 mg/kg body mass) and quercetin (50 mg/kg body mass) on three consecutive days, every 2 weeks for 3 months via oral gavage