A Drug That Slows Aging and Improves Life Expectancy

By James H O’Keefe, MD, Evan L O’Keefe, MD, Robert Weidling, MD

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The Fountain of Youth is a mythical spring that allegedly restores youth and confers exceptional longevity for people who drink of or bathe in its waters.

Legends of such a fountain have been recounted by cultures around the world for at least 2,500 years. Legend says Spanish explorer Juan Ponce de León, following a tip from a Native American, thought he might find the Fountain of Youth in 1513 in Bimini in the present-day Bahamas, but alas, he never discovered the magical water with the ability to reverse the aging process. Indeed, through the ages, every version of the Fountain of Youth has turned out to be a hoax. That is... until now?

In a recent scientific paper, we learned that a drug class called sodium-glucose cotransporter inhibitor (SGLTi) may be a real-life therapy that slows aging and improves life expectancy.

Modifying the Aging Process

The pace of aging varies widely across species due to a combination of genetic, environmental, and evolutionary factors. For example, the domesticated dog (Canis lupus familiaris), when just 7 to 10 years old, begins to be develop age-related diseases such as cataracts, degenerative arthritis, impaired hearing, congestive heart failure, and chronic kidney disease. On the other hand, a 10-year-old human is still a kid, with youthful exuberance and no hint of chronic disease.

The oldest known living land animal is Jonathan, a Seychelles giant tortoise who remains healthy despite being born in 1832, making him 192 years old. Giant tortoises, Greenland sharks, and bowhead whales often live for 150 to 200 years or more. This variability in the pace of senescence, or biological aging, among animals suggests that the aging process may be modifiable.

Jonathan the oldest tortoiste in the world.

Aging is associated with erosion of structural integrity of our tissues and loss of function beginning at the cellular level and eventually culminating in musculoskeletal frailty and an increased risk of developing chronic cardiovascular (CV) disease, diabetes, obesity, dementia, infections, and cancer. In the past, many have assumed the rate of aging is not something we can change. But as we have begun to the understand the biological mechanisms of aging, it appears that the rate at which we grow older is malleable. 

The Holy Grail of Lifespan: Delaying Aging

Slowing or reversing the process of aging is a long-sought-after Holy Grail for improving human longevity and reducing chronic disease. Experts say that therapies to delay aging and the infirmities of old age would translate into bigger gains in life expectancy and our overall well-being than advances in treating or preventing specific diseases such as cancer or heart disease. For example, if we cured all cancer so that nobody ever died of a malignancy, the life expectancy in our population would only rise by about 3 years; the same is true for CV disease.

This is because the innate aging process is far and away the most important risk factor for most serious chronic diseases and death. As you age at the cellular level and become frail, immobile, and disabled, if one disease doesn’t get you, another one will.

An October 2023 study in the journal Health Affairs by Jay Olshansky, MD, found that shifting the focus of medical research to delaying aging instead of targeting specific diseases could lead to substantial gains in physical health and overall well-being, not only for the current population but also for future generations. These experts reported that a major advance in treatment of cancer or heart disease would improve overall life expectancy by about one year. By comparison, a therapy that delays aging even modestly would double this to two additional years—and those years would likely be enjoyed in good health. 

Healthspan versus Lifespan

Average U.S. life expectancy improved from 47 years in 1900 to 78 years in 2019, largely owing to breakthroughs in preventing and treating potentially fatal diseases like infections, atherosclerosis, and malignancies. However, in 2019, U.S. life expectancy began to fall and now is down to a 30-year low of 76 years. Even more concerning is the prevalence of people living a disabled life—being alive but not fully functional. This means the average American can expect to be alive and in good health for fewer years than the previous generation.  

If we can uncover ways to age more slowly, we could delay death as well as postpone the onset and progression of many disabling diseases. We could simultaneously improve lifespan as well as healthspan—the length of time a person is healthy with full mental and physical capabilities.

Scientific studies indicate that lifespan and healthspan are modifiable. Lifestyle habits such as maintaining social connections with family, friends, and community, doing regular exercise—both aerobic and strength training, decreasing time spent sitting, getting seven to eight hours of high-quality sleep most nights, and eating a nutritious diet full of fresh vegetables and fruits, nuts, fiber, fish, clean water, and high-quality protein all contribute to an improved healthspan.

In recent years, researchers have explored a range of drug interventions aimed at extending lifespan in yeast cells, worms, and mice. Scientists, however, are also interested in a few select drugs that have shown promise for slowing aging and augmenting lifespan and healthspan. Metformin and rapamycin, among the most promising of these geroprotective (protective against adverse effects of aging) agents, are already being prescribed off-label by some physicians to slow aging. Clinical studies showing the safety and efficacy of these potent drugs when used for this indication are almost nonexistent. In fact, up to now, we haven’t had a single drug with compelling clinical evidence in humans to suggest it slows aging and extends life expectancy.  

SGLTi: A Magic Bullet Against Aging?

SGLTi drugs, marketed as Jardiance (empagliflozin), Farxiga (dapagliflozin), and Inpefa (sotagliflozin) have been used for the treatment of type 2 diabetes for more than 10 years. A massive and rapidly growing body of data shows that these drugs reduce risks for many of the most common conditions of aging, including hospitalization for any cause, heart failure, chronic kidney disease, atrial fibrillation, cancer, atherosclerosis (heart attack and stroke), Alzheimer’s disease, Parkinson’s disease, fatty liver, gout, emphysema, and infections. SGLTi also significantly improves overall life expectancy and reduces risks of CV death and cancer death.

Our paper in the journal Progress in Cardiovascular Disease is the first ever to propose SGLTi as a therapy to slow aging, prevent or delay many of the common age-related diseases, and improve lifespan as well as healthspan in the general population.  Currently, these drugs are FDA-approved for treatment of type 2 diabetes, heart failure, and chronic kidney disease, and to decrease risk of CV death.

SGLTi treats type 2 diabetes by blocking reuptake of filtered glucose in the kidney. This relatively simple action leads to remarkable downstream actions in preventing and treating many of the most common and serious age-related diseases in individuals with or without diabetes. Normally, we shouldn’t have any sugar in our urine, but people on SGLTi will lose about 60 to 80 grams a day (about 300 calories a day) of glucose in the urine, triggering a mild diuresis—elimination of excess water. So people on SGLTi typically show subtle improvements in weight, blood pressure, and blood glucose. But the wide-ranging health benefits noted with SGLTi are largely unexplained by these modest improvements in standard CV risk factors. The mechanisms behind the astonishing health benefits of SLGTi have been shrouded in mystery; it’s as if one plus one equals 10.

How Does SGLTi Slow Aging?

It turns out that inhibiting the SGLT channel changes the way the body senses the amount of available nutrients. SGLTi tricks the body into thinking that it’s not getting enough food by causing upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling.

Genes that have been conserved via evolution for millions of years mediate this response to starvation and harsh conditions, and when they are activated, they make the organism hardier and more resilient. SGLTi triggers a process called autophagy—a fancy word for cellular housekeeping. This is a fundamental response that is normally turned on during difficult conditions like insufficient food and/or strenuous exercise. Autophagy cleans up and rejuvenates cells by breaking down and recycling damaged mitochondria (the little powerplants inside the cells that create the energy) and replacing them with brand new mitochondria that crank our energy levels back up to youthful levels.

This revitalizes old worn-out cells and restores optimal function to tissues and organs throughout the whole system. These key mechanisms of action help provide the biological plausibility to explain how and why SGLTi seem to slow aging, prevent myriad diseases, and improve life expectancy. This is a new hypothesis that will need to be tested in large, randomized placebo-controlled trials in healthy people.

SGLTi Safety and Tolerability

Any compound being considered for use as a geroprotective (a drug to prevent age-related health problems) to improve life expectancy should meet the Primum non nocere (first do no harm) maxim. In other words, a drug that is to be used for decades by healthy people must have very low risk for serious adverse effects.

SGLTi is a safe and well-tolerated, once-daily pill, with discontinuation rates that are similar to placebo. A meta-analysis of 47,000 patients in randomized controlled trials reported that SGLTi caused no significant increase in risk of adverse events, including low blood sugar, urinary tract infection, bone fractures, or low blood pressure, compared to placebo. Other studies show that SGLTi users report improved quality of life compared to the placebo group.

I have been prescribing this drug frequently for my patients over the past nine years, and they routinely come back feeling and looking better. Even so, because SLGTi causes sugar in the urine, this drug increases the risk of fungal infections in the genitalia or groin regions.

A large meta-analysis found that SGLTi use was linked to a statistically significant 3.3-fold increased risk of genital yeast infections, which occurred in 6.3% for SGLTi users versus 1.7% for placebo. This problem can usually be avoided with careful urinary hygiene, including wiping any excess urine off skin surfaces after urinating and bathing once or twice a day. SGLTi may also increase risk of urinary tract infections and can very rarely lead to dangerous infections in the perineal region or cause ketoacidosis.  

Conclusion 

SGLTi mimics starvation and promotes cellular housekeeping, which rejuvenates cells and organs, thereby improving health. Clinical studies show SGLTi lowers risks for premature death and many of the diseases of aging (Central Figure). Of the potential drugs to slow aging, SGLTi has the most compelling data for safety and efficacy in humans. Further randomized studies to assess SGLTi for reducing age-related disease and improving life expectancy in otherwise healthy people are warranted. In the meanwhile, if you are curious about whether you might be a candidate for SGLTi therapy, talk to your health care provider.

Disclosure: Dr. James O’Keefe has done scientific presentations for Boehringer Ingelheim, the company that makes Jardiance.

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Mick’s Gift

Here at Saint Luke’s Mid America Heart Institute, in our Duboc Cardio Wellness Clinic and Haverty Cardiometabolic Center of Excellence, we have been frequently prescribing the SGLTi drugs for several years. In September 2015, the EMPA-REG study results were officially released in Stockholm showing an astounding 38% decrease in CV mortality compared to placebo, with a benefit that was apparent within two weeks of starting treatment with empagliflozin. I began using this drug immediately, and Mick Haverty was one of the first of my patients for whom I prescribed empagliflozin. He has never had diabetes, but had severe coronary disease at a distressingly young age.  

Mick was born and raised in Atchison, Kansas, where four generations of his family worked on the railroad, which was common for Irish immigrants. As a teenager, Mick signed on with Santa Fe Railroad, doing back-breaking work repairing the track along the rail line. He went off to college and came back to work for Santa Fe, where he quickly rose through the administrative ranks with his ambitious, tough but fair, no-nonsense approach to the railroad business. Mick’s blossoming career seemed to be derailed when he needed emergency coronary artery bypass graft (CABG) surgery at age 33, and then required a second CABG at age 37. On both occasions, his competitors wrote him off as finished, but he roared back and was named president of Santa Fe Railroad at just 44 years-old. Since then, Mick has had 15 coronary stents and multiple heart attacks, but throughout it all, he maintained a productive and rewarding life.

Then in 2015, he began experiencing worrisome swelling, shortness of breath, and reduced stamina. We diagnosed him with heart failure, which traditionally would kill a person within 5 years of diagnosis. His heart’s pumping efficiency, or ejection fraction (EF), had deteriorated to 32% (>50% is normal). Shortly thereafter, I started Mick on empagliflozin and other effective heart failure therapies, and he made a remarkably quick and robust recovery. His EF came back up to normal, and he regained his energy and physical strength. Over the last nine years, Mick has needed no further stents, and he will celebrate his 80th birthday this June. He still travels internationally (Ireland is his favorite destination) and thoroughly enjoys an active life with his wife Marlys, their three children, and 11 grandchildren.

Mick was so impressed and grateful for his recovery that he donated $2 million to start the Haverty Cardiometabolic Center of Excellence. This was the first such center in the world devoted to using these drugs to improve health and longevity for CV patients. In the Haverty Cardiometabolic Center we standardly use SGLTi often in combination with other new therapies including semaglutide (Wegovy, Ozempic) or tirzepatide (Mounjaro, Zepbound) to help patients to lose weight and regain their health and well-being.

We have published papers in scientific journals detailing how these medications have conferred extraordinary improvements for our patients in the Haverty Cardiometabolic Center. Mick’s gift and these life-saving medications are making a real difference for getting our patients on track for longevity with vigor.