Super Agers: An Evidence-Based Approach to Longevity

by Eric Topol

Eating ultra-processed food is associated with a markedly heightened risk of cardiovascular and metabolic diseases. These foods induce abnormal lipid levels, insulin resistance, and systemic inflammation. Furthermore, a diet rich in these foods is linked to 80 percent elevated risk of metabolic syndrome, 40 percent higher risk of type 2 diabetes, 23 percent increased risk of hypertension, 55 percent risk of obesity, and 66 percent risk of cardiovascular death.

The story of nonnutritive, artificial sweeteners is a bit more complicated, with conflicting reports regarding the many nonsugar substances. A comprehensive review of all the available data from randomized and observational studies found a lack of compelling evidence for associated risk. In contrast, another large cohort of more than one hundred thousand people found a direct association between consuming such sweeteners, particularly aspartame, acesulfame potassium, and sucralose, with cardiovascular and cerebrovascular disease risk. But that was not the case when different artificial sweeteners were examined separately through a randomized trial. In 120 healthy adults given saccharin, sucralose, aspartame, and stevia, versus controls for two weeks, the first two sweeteners induced impaired glucose regulation (also known as glycemic response), and all four were associated with changes in the oral and gut microbiome. Previous work has shown that such alteration of the gut microbiome is tied to the abnormal glycemic response. Overall, the data for artificial sweeteners is unfavorable, although it is not nearly as worrisome as high sugar consumption. Certain sweeteners, such as stevia, appear to be less concerning than others.

Coffee lovers enthusiastically received reports of up to a 30 percent reduced mortality, such as from more than 170,000 participants in the UK Biobank and another UK Biobank study supporting a dose response: the more coffee, the longer the person lived.

We don’t have a cause-and-effect relationship or unequivocal proof that coffee improves health outcomes.

A more recent study of nearly thirty thousand Americans followed for nineteen years concluded that both processed and unprocessed meat, but not poultry or fish, were linked to a small increased risk of all-cause mortality. There was a twist with respect to poultry: two or more servings of unprocessed or processed meat or poultry was associated with a 4 to 7 percent increased risk of developing cardiovascular disease.

We know it includes fruits and vegetables; legumes, such as lentils and garbanzo beans; whole grains; nuts and seeds; healthy fats, such as olive oil and avocados; and fatty fish, such as salmon and tuna, rich in omega-3 fatty acids. Consumption of olive oil, per se, has been tied to about a 20 percent lower all-cause mortality, along with reduction of cardiovascular-, cancer-, and neurodegenerative-related deaths. Among more than ninety-two thousand participants followed for twenty-eight years, there was a significant lower risk of dementia: 28 percent less risk if a person consumed 7 grams (half a tablespoon) a day or more of olive oil compared with rare or no consumption. In aggregate, these foods provide good sources of dietary fiber, something we all tend to need more of. The recommendation for about 30 grams of fiber per day, adjusted by age, gender, and body size, is derived from a meta-analysis of 185 studies that showed people who consumed a high fiber diet had 31 percent less heart disease and 16 percent less type 2 diabetes or colon cancer. Fiber is the polar opposite of ultra-processed foods—it slows digestion, lessens glucose spikes, and helps reduce cholesterol. What is referred to as the Western diet, rich in ultra-processed foods, is pro-inflammatory and linked with metabolic dysfunction, cardiovascular disease, diabetes, and colon cancer. A randomized trial of a high fiber, “microbiome enhanced” diet compared to the Western diet with the same percentage of...

Compared with eating few or no nuts and seeds a day, eating just a handful is associated with a 20 percent lower risk of cardiovascular disease, as seen in more than forty studies.

(Adapted from https://www.nejm.org/doi/10.1056/NEJMoa1800389?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov)

The problem with a strict calorie-restricted diet is that it is hard to adhere to, has been associated with loss of bone density and muscle mass, and slowed brain function. Our brain is only 2 percent of our body mass but consumes 20 percent of our calorie intake. On the other hand, multiple studies support an improved immune response, and, perhaps interrelated, potential antitumor effects show up in experimental models. No calorie-restricted, time-restricted, or intermittent fasting diets have been proven to provide antiaging properties, but a small, randomized trial showed reduction of a biological age score that relied on some improvements of biomarkers (immune system, liver, glucose regulation) with multiple cycles of a fasting-mimicking diet. Until there’s more definitive evidence, perhaps the best practical advice is to eat an early dinner, at least three to four hours before going to bed, and avoid any caloric intake before the next morning’s breakfast.

Nothing surpasses regular exercise for promotion of healthy aging! Exercise can be viewed as the single most effective medical intervention that we know. If you could design a drug that exerted diverse potent salutary health impacts across all our organ systems, it would be considered a miracle breakthrough. Regular exercise leads to favorable adaptations of the cardiovascular system, brain, pancreas, skeletal muscle, gastrointestinal tract (enhanced production of short-chain fatty acids, SCFA), liver, adipose tissue, gut microbiome, and peripheral blood vessels. The metabolic trifecta of three organ systems—pancreatic, skeletal muscle, and adipose tissue—leads to increased insulin sensitivity.

A randomized trial showed inflammation biomarkers were suppressed more with exercise than with a GLP-1 drug.

Multiple studies have estimated the number of American adult deaths per year that could be prevented: with just ten minutes per day, 110,000 deaths; with thirty minutes, 270,000 deaths. Yet what is termed fragmented physical activity in older adults, of less than five-minute duration, or watching television for extended periods of time, has been associated with higher mortality risk.

The problem with using steps as a proxy for physical activity is that it doesn’t represent discrete exercise time, a nonoccupational effort. The recommendation of 150 minutes per week of moderate physical activity is meant to consist of dedicated sessions, not incidental starting and stopping, with a sustained increase in heart rate, to promote aerobic cardiovascular fitness.

People who sat mostly at work had an associated 16 percent higher all-cause mortality, and 34 percent increased cardiovascular mortality, after adjusting for potentially confounding factors.

With respect to optimal timing of exercise, our clock proteins and circadian rhythm come into play, with some studies suggesting late afternoon or early evening is better than the morning for exercise performance while others find morning is preferred. Exercise in the fasted state may have some benefit for lipid utilization and glucose regulation. Overall, there is no clear perfect time, but good support exists for an individual to maintain the same pattern, be it early or later in the day.

It may come as a surprise that beyond seven hours there were consistent signs, both acutely and during follow-up, of cognitive and mental health decline, as well as unfavorable changes in brain structure. Also consistent is the relationship of long sleep (more than eight hours) and heightened all-cause mortality (by approximately 30%) that was previously established among nearly 1.4 million people. To sum up all the studies of sleep duration and cardiovascular disease, every one hour a night decrease in sleep below the seven- to eight-hour threshold is associated with 6 percent higher risk of total cardiovascular disease. Every one hour a night increase in sleep duration above that seven- to eight-hour threshold is associated with 12 percent higher risk of total cardiovascular disease.

In 2017, Matthew Walker, a professor of neuroscience at UC Berkeley, sounded the alarm about the silent sleep loss epidemic as “the greatest public health challenge we face in the twenty-first century.”

So we’re faced with the challenge of promoting better sleep that is essential for healthy aging, while aging itself is compromising sleep quality.

There are some things that help, like maintaining the same sleep pattern every day, including weekends. That includes a regular pattern of exercise and meals, with an adequate separation of multiple hours from bedtime (think early time-restricted eating).