Get Rid of the Damage

Quercetin

In 1936, Albert Szent-Györgyi, who received the Nobel Prize the following year for discovering vitamin C, suggested that flavonols, a group of plant constituents, should also be considered a vitamin. (He proposed “vitamin P.”) The most common flavonol in foods is quercetin, found concentrated in onions, kale, and apples. It’s the compound that makes apple peels taste bitter. Scientists tested dozens of different components that they scraped from umbilical cords and then irradiated to force them into senescence. In 2015, they announced their result: quercetin is a natural senolytic.

For more details, see see.nf/quercetin, but the bottom line is this: quercetin doses that, when converted to humans, corresponded to a small apple a week reduced cellular senescence in older mice and extended their healthspan. For example, they lost less hair, their hearts worked better, and they could engage in sustained physical activity up to an age equivalent to human 60 years. So perhaps we should share a few kale stalks with our pet mouse, but what about us?

Quercetin sources

Quercetin is also found in its namesake—in the oak, Latin quercus—but it is “very widespread in foods of plant origin.” In fact, quercetin is so ubiquitous in the plant kingdom that it even shows up in iceberg lettuce. (Lettuce ranks fifth among the leading quercetin sources in the American diet.) Onions contain between 20 milligrams and 100 milligrams each, apples between 4 and 20 milligrams, a pound of kale can have 50 milligrams, and a cup of tea about 5 milligrams. Capers have 20 milligrams per tablespoon, but keep your hands off brands with lots of salt. (I’ve found pickled capers that contained anywhere between 0 and 200 percent of the upper limit of total salt intake for a day per serving.)

Even though the quercetin content of supplements purchased online is usually accurately stated and safety data note no significant side effects when taking up to 1000 milligrams for twelve weeks, I recommend sticking with foods as the source, just like the Mayo Clinic, which founded this line of research.

Apples and onions

It’s hard to separate the effects of quercetin from the other health effects attributed to quercetin-rich foods, such as apples and onions. In see.nf/applesonions, I show how the health advice “An apple a day keeps the doctor away” from 1866 appears to have borne fruit. Maybe valuable things shouldn’t be called the “apple of one’s eye” but rather the “apple of one’s arteries.” The fact that arterial function improves significantly more just hours after eating unpeeled apples than with peeled ones is consistent with a quercetin effect, and indeed even isolated quercetin supplements can lower blood pressure, cholesterol levels, and inflammation levels. Unfortunately, quercetin-rich onion powder was unable to improve cognitive performance in older people with or without Alzheimer’s. (For details, see see.nf/onionpowder.)

Although most studies of quercetin supplements used amounts that are not easily achievable through eating, even three quarters of a teaspoon of fresh onions compared to placebo can improve blood pressure and flow, which explains why those who consume more quercetin have only half the risk of dying from heart disease. A modeling study even suggested that everyone should be prescribed an apple a day, since it would likely prevent as many deaths from vascular disease as giving everyone a cholesterol-lowering statin drug—and with fewer side effects. (Ironically, now that drugs like Lipitor are available as generics, the pill would probably be cheaper than the apple.)

If it makes you beautiful …

In 2018, disappointing data on cognitive performance from intervention trials were met by a report that called quercetin’s senolytic effect into question. For the original quercetin studies with humans, they had worked with cells from umbilical cord blood, a convenient source of human tissue. But when the experiment was repeated with cells from adult donors, quercetin was unable to shut off senescent cells. In 2019, however, it was found that quercetin can do something even better.

Werner syndrome is a rare inherited disease in which a DNA repair enzyme is mutated, resulting in premature aging. When senescent Werner cells were exposed to the level of quercetin one can achieve through quercetin-rich food, they seemed to be repaired rather than wiped out. As if their senescence were being reversed, as if one were awakening the living dead. And what about aging, non-mutated cells? Here too, a “rejuvenating effect” on senescent cells was found. In the journal Experimental Gerontology, Greek researchers claimed to have tested topical application of quercetin on volunteers and reported “positive results in [skin] elasticity, moisture retention, and wrinkle depth,” but their data were apparently not published, which makes their claims seem questionable.

Fisetin

Given the senolytic success of a quercetin cocktail, scientists began investigating other flavonoids. In doing so, they discovered one that was almost twice as potent: fisetin. It can increase the lifespan of yeast by 55 percent and that of fruit flies by 23 percent. Fisetin can also extend the lifespan of mice, even when they are already older. When they first received it at an age roughly equivalent to 75 human years, fisetin increased the mice’s average and maximum lifespan by about 75 percent. Markers of cellular senescence and SASP were significantly reduced across all tissues, as was the pathology of aging. Another study found that fisetin also improves long-term memory in mice. And in us?

Just like quercetin, fisetin showed anti-inflammatory effects in clinical trials, but is it also senolytic? When human fat tissue removed during routine operations was exposed to fisetin, there was indeed a reduction in senescence and SASP markers. Because fisetin occurs naturally in food, no side effects are known, and it is already sold over the counter as a dietary supplement, the researchers immediately began designing studies to investigate the anti-aging potential of fisetin. Currently, more than a dozen investigations are underway in which fisetin is being tried for a range of age-related conditions, including osteoarthritis, osteoporosis, frailty, kidney disease, cognitive decline, and even complications of Covid-19. That clinical interest in a natural product is so great, despite the lack of financial incentives that traditionally drive such a large portion of biomedical research, shows how promising it is.