An Apple a Day Keeps the Senescence at Bay?

Researchers have found that mice whose diet is supplemented with the fruit-based flavonoid Fisetin have extended health and lifespans. Fisetin is a natural compound present in many fruits and vegetables such as apples, persimmons, grapes, onions, cucumbers and strawberries.

Cellular senescence plays a role in driving aging and age-related diseases. Senescent cells are like tiny “zombies” in your body that appear as you age and contribute to the classic “symptoms” of aging – tissue dysfunction, frailty and a weakened immune system. Senescent cells, created by DNA damage and other stressors, can no longer divide (this is related to the expression of a cell cycle inhibitor called p16 in senescent cells). But they are also resistant to programmed cell death. Senescent cells thus sit around undead yet sending out inflammatory “SOS” signals, unknowingly (like brainless zombies) harming other healthy cells in the process.

“Senescence is a response that the cells in our body have to stress,” says Laura Niedernhofer, Director of the Institute on the Biology of Aging and Metabolism (iBAM) at the University of Minnesota and co-author of a new study investigating the ability of plant-based compounds to kill senescent cells. “Stressed cells turn on senescence to prevent them from becoming a tumor.” But while cells may become senescent to protect from becoming cancerous, once senescent they can do damage through inflammation and tissue dysfunction. They can even ironically set the stage for cancer.

“[E]ven a relatively low abundance of senescent cells is sufficient to cause tissue dysfunction. Senescent cells are rare in young individuals, but increase with age in multiple tissues, including adipose tissue, skeletal muscle, kidney, and skin of all vertebrates tested.” – Fisetin is a senotherapeutic that extends health and lifespan

Senolytic therapies or therapies that selectively kill senescent cells have been tested in animal models and in human tissue cultures. Injecting senescent cells into mice causes them to develop age-related conditions including osteoarthritis, frailty and decreased survival, while clearing senescent cells has been shown to extend healthspan and improve tissue function in mice.

One of the most popular senolytic therapies in animal research consists of a combination of chemotherapy agent dasatinib and the flavonoid (plant pigment) quercetin. However, dasatinib and similar drugs that target apoptosis or programmed cell death pathways can have toxic side effects. In a new study published in EBioMedicine, Laura Niedernhofer and colleagues set out to see if they could identify antioxidant flavonoids with more potent senolytic activity but fewer side effects than dasatinib and quercetin.

The researchers, including Laura Niedernhofer and Matt Yousefzadeh from the University of Minnesota Institute on the Biology of Aging and Metabolism, screened a range of flavonoid polyphenols for senolytic activity in both senescent mouse cells and in senescent human fibroblasts. Polyphenols are compounds found in plant-based foods that can be beneficial for their antioxidant properties, or their ability to soak up harmful free radicals that our cells produce as they use oxygen to extract energy from sugars. Among 10 different flavonoids, the researchers found that fisetin was the most powerful senolytic. Fisetin occurs naturally in strawberries, apples, persimmon, lotus root, onions, grapes, kiwi, peaches and cucumbers.

“We used mouse cells that had become senescent in response to normal stress to screen for drugs that eliminate signs of senescence,” Niedernhofer said. “Then we tested ‘hits’ from the screen in human cells that were senescent because of x-rays. If a compound attenuated senescence in two cell types, we then tested it in mice.”

Niedernhofer and colleagues investigated the senolytic activity of fisetin in mice and in explants of human fat tissue. When they treated old mice or mice with aging disorders with fisetin, at a dose between 60 and 100 mg/kg of fisetin per day, they found evidence of lowered senescent cell activity (lower p16 expression and lower levels senescence-associated inflammatory markers) and enhanced tissue function in these mice. Fisetin reduced the fraction of senescent immune cells and markers of oxidative stress in treated mice, and even resulted in extended lifespan. Fisetin also reduced the number of senescent cells and associated inflammation in human adipose cells.

“The most surprising finding was that when we gave fisetin even to old mice (say the equivalent of a 75-year-old person), it had a significant benefit, improving tissue function and extending lifespan,” Laura said. “If we want to improve the health of older individuals, it is important to find a therapy that can be given later in life, after the onset of age-related symptoms, rather than long before symptoms occur in order to prevent age-related decline. The latter scenario has safety risks.”

The study provides evidence that polyphenols such as fisetin and curcurmin might be useful for reducing harmful senescent cells and associated inflammation in humans. But there is still a lot we don’t know about safe and effective dosing of these compounds and their effects in humans at high doses. There were no harmful side effects of fisetin observed in Laura Niedernhofer’s study, and we know that fisetin is consumed through plant products in Japan at approximately 0.4 mg/day without any observed harmful effects. However, based on the effective doses of fisetin used in Niedernhofer’s study, humans can’t eat enough fruit to achieve the senolytic benefits of fisetin observed in Niedernhofer’s lab mice. We would need to take a fisetin pill (potentially at a dose of several milligrams). This wouldn’t be an every day pill, but rather a pill that we only took once a month or even once a year.

“Conceptually, senotherapeutics are not something that should be constantly administered,” Matt Yousefzadeh said. “They should periodically be used to lessen senescent cell burden.”

For fisetin, it is unclear whether eating strawberries and apples every day can have a meaningful effect on your senescent cell burden. That doesn’t mean you shouldn’t try to get plenty of strawberries, apples, persimmons, lotus root, onions, grapes, kiwi, peaches and cucumbers into your diet – these antioxidant-rich fruits may still help lower inflammation in your body without necessarily killing senescent cells. Fisetin also scavenges free radicals, blocks the PI3K/AKT/mTOR pathway (the same pathway targeted by… intermittent fasting!) with anti-cancer properties, and inhibits the activity of several pro-inflammatory cytokines including TNFα and IL-6. On the flip side, fisetin in pill form could be powerful enough that you wouldn’t want to take it every day.

“Proper safety testing will be required by the FDA,” Laura Niedernhofer said. “For now, the recommendation is to stick with fruits and vegetables. Strawberries have the highest concentration of fisetin.”

There are currently several clinical trials testing fisetin supplementation for treatment of frail elderly syndrome, diabetes and kidney disease, and cognitive impairment.