Six ways metabolic health affects longevity

Here are six mechanisms in our body that help us live longer, healthier lives—and that function best when we have stable blood sugar

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Today, an estimated 88 million Americans—more than a third of the adult population—have prediabetes. Of those, more than 84 percent have no idea they have a blood sugar problem—yet up to 70 percent will develop diabetes within 10 years.

The consequences of those numbers may be farther reaching than we realize. Blood sugar dysregulation and insulin resistance are just the tip of the iceberg. The ways in which these conditions disrupt our physiology can accelerate aging and reduce lifespan via their links with almost all of the most common killers.

We can draw links between blood sugar dysregulation and eight of the top 10 leading causes of death in the U.S. (pre-COVID), including cardiovascular disease, stroke, cancer, Alzheimer’s disease, chronic respiratory disease, kidney disease, and even suicide. What’s more, diabetes increases the odds of premature death from most of these conditions. For example, a person with diabetes receiving a cancer diagnosis has a significantly worse prognosis than a person without diabetes receiving the same diagnosis.

The good news is that most Type 2 diabetes cases are preventable with diet and lifestyle choices that support good metabolic health. And by understanding the specific mechanisms—like the six listed below—impacted by poor metabolic health, we can see the connections between the choices we make and a longer, healthier lifespan. For example, when we eat in a way that results in fewer blood sugar spikes and provides enough micronutrients, we can reduce oxidative stress, which protects our DNA and helps slow aging.

Here are six key drivers of longevity and how they interact with metabolic health.

1. Advanced Glycation End Products: Cellular Dysfunction and Wrinkles

The first of several well-established links between sugar and aging is a group of compounds called advanced glycation end products (AGEs). These are formed when excess glucose in the bloodstream sticks to proteins, fat, and DNA in a process called glycation. The adhesions can alter proteins’ shape, structure, and even their molecular charge, which prevents them from functioning correctly in the body. 

AGEs can quite literally make us old before our time. When they bind to receptors on the surface of our cells called RAGEs, they trigger pathological processes, including inflammation, oxidative stress, cell death, and ultimately organ damage. RAGE receptors appear to become more plentiful when our blood glucose remains high for prolonged periods, exacerbating the problem. Once formed, AGEs are stable and long-lived, meaning that they accumulate in the body as we age.

One way this accumulation manifests as we age: wrinkles. You’ve probably heard of collagen—the most abundant protein in the body and one of the core building blocks of our bones, muscles, tendons, and ligaments. It’s also what gives our skin elasticity to keep it looking plump and youthful.

Skin collagen has a slow turnover in the body (it takes around 10 years for half of our old collagen to be replaced with new), making it especially susceptible to interaction with glucose—and, therefore, AGE accumulation. When sugar binds to collagen molecules in the skin, it causes them to tangle together and form inappropriate chemical bonds in a process called cross-linking. This makes the skin stiffen and lose elasticity, and we get wrinkles.

Research suggests that we have the power to reverse some of this damage simply by avoiding blood glucose spikes. A study in adults with diabetes found that after just four months of coaching to help improve their glycemic control, levels of glycated collagen in their skin dropped by 20 percent.

The same protein cross-linking and tissue stiffening mechanism is implicated in the development and progression of many intractable age-related diseases. Reduced elasticity in the blood vessels, for instance, is linked to cardiovascular disease. In particular, stiffening in the large arteries reduces their ability to absorb the pressure generated by the pumping heart, meaning more of that force is transmitted to the organs. In the case of the brain, this may up the risk of dementia. Elsewhere, cross-links formed in the eye’s lens may lead to cataracts, and AGE accumulation in the bones can impair their ability to repair and remodel, leading to osteoporosis.

2. Oxidative Stress: Damaging Our DNA

The second type of molecule that wreaks havoc on the body’s tissues is free radicals. These are molecules with unpaired electrons—an unstable configuration that makes them highly reactive. That means they scavenge the body for electrons, attacking essential macromolecules including proteins, fats, and DNA. These assaults can cause a cascade of damage within cells through a process called oxidation.

Oxidative stress is strongly linked to a whole host of diseases of aging, including diabetes, cancer, kidney disease, arthritis, cardiovascular disease, and Alzheimer’s. The gradual accumulation of free radical damage to mitochondrial DNA may be one of the main drivers of aging.

Free radicals can enter the body via polluted air, radiation, drugs, cigarette smoke, and heavy metals, and pesticides in food and water. But they are also produced within the body as natural by-products of metabolism, and they serve as important signaling molecules in a range of essential bodily processes.

The key to good health and longevity—as is so often the case—is balance; the body must prevent the build-up of free radicals by clearing them efficiently. It does this using antioxidants: chemical compounds famously found in foods like berries, spices, green tea, and leafy greens—and also made continuously by our very own cells. Antioxidants work by binding to unpaired electrons to neutralize free radicals before they can cause damage to other molecules.

Chronically high glucose levels deliver a double whammy in terms of oxidative stress. Hyperglycemia causes our cells’ energy generation centers—the mitochondria—to generate and leak-free radicals. At the same time, excess glucose disrupts the body’s antioxidant defense systems by sticking to and impairing the function of antioxidative enzymes

In particular, oxidative stress promotes atherosclerosis—the narrowing and hardening of blood vessels—in people with insulin resistance. Atherosclerosis can lead to serious health complications, including heart attack, stroke, and even death [more on that in #6 below].

Many of the vascular and multi-organ complications seen in diabetes appear to be directly caused by hyperglycemia-induced free radicals. There’s evidence to suggest that wild swings in glucose levels pose even more of a risk than constant high glucose because none of the body’s adaptive responses have a chance to kick in. Even brief episodes of hyperglycemia cause oxidative stress when we have repeated glucose spikes.

3. Mitochondrial Dysfunction: Disrupting Our Energy Processes

Mitochondria drive the metabolic processes of every cell in our bodies. Their main job is to produce adenosine triphosphate (ATP), the energy currency of cells. As we age, the energy output of our mitochondria slowly declines. Mitochondrial dysfunction is a hallmark of many diseases of aging, and hyperglycemia can accelerate these changes. 

Mitochondria generate ATP via a complex process known as an electron transport chain. When we bombard our cells with sugar, we boost the number of electrons available to fuel that transport chain. If there is minimal demand for energy (ATP), let’s say to power a workout, the mismatch disturbs the balance of charge across the mitochondria’s inner membrane and generates a proliferation of damaging free radicals. Many other things can create mitochondrial dysfunction, including environmental toxins like cigarettes and pesticides, nutrient deficiencies, medications like acetaminophen and ibuprofen, and possibly acute and chronic psychological stress

Compounding the problem, impaired mitochondrial function means we’re less able to fully metabolize fatty acids for energy. This can lead to toxic by-products of lipid metabolism in our cells, such as ceramides and diacylglycerols, which some studies suggest ultimately interferes with insulin’s ability to buffer blood glucose levels. (Other research suggests that it’s not too little but rather too much fatty acid oxidation that leads to insulin resistance within muscle tissue.)

Problems with the body’s energy-generating equipment are bad news for almost every bodily system and process; if our cells can’t produce enough energy to function correctly, things inevitably go awry. Take the retina. It contains five different types of neurons and is one of the most energy-hungry parts of the human body. Mitochondria in these neurons are particularly susceptible to age-related oxidative damage, leading to age-related eye problems, including glaucoma and macular degeneration.

Another less obvious link that researchers are just beginning to understand is the role of mitochondrial dysfunction in depression and degenerative brain diseases. Neurogenesis—the process by which new brain cells form—appears to be impaired by diabetes. In a series of studies involving diabetic rats, researchers found that insulin resistance in the brain may disrupt neurogenesis by stunting mitochondrial function. When the rats took drugs to boost their insulin sensitivity, it enhanced their mitochondrial function. When a similar drug was later given to rats with Parkinson’s disease, it promoted neurogenesis and improved their depressive symptoms.

4. Inflammation: The Quiet Driver Behind Chronic Conditions

Inflammation is a crucial player in the body’s defensive arsenal. When something damages your cells—be it an injury, a pathogen, environmental toxins, or even stress—your body releases pro-inflammatory chemicals, such as cytokines and histamine, that spur the immune system into action. The blood vessels dilate, and white blood cells flood the affected area to battle invaders. 

If you’ve ever sprained an ankle or been stung by a bee, you’ve seen this inflammatory response in action. Classic symptoms include redness, swelling, pain, warmth, and a temporary loss of function that forces you to rest and protect the injured area.

Acute bursts of inflammation such as these help your body defend and heal itself. But when inflammation persists and becomes chronic, it can permanently damage cells and tissues and up the risk of heart attack, cancer, diabetes, and other life-threatening conditions.

High blood glucose can kick the immune system into overdrive through a variety of mechanisms. For starters, we know that a high sugar diet leads to weight gain over time. Excess fat—especially at the waist—activates immune cells and secretes large quantities of pro-inflammatory cytokines.

Similarly, we know that chronic high blood sugar and a rollercoaster of post-meal glucose spikes lead to insulin resistance. People with diabetes and people with insulin resistance both show elevated levels of cytokines and inflammatory blood biomarker C-reactive protein. Indeed, diabetes is a severe proinflammatory state.

And the inflammatory response to sugar isn’t limited to those with metabolic disorders. In one study, researchers gave 10 lean young people without diabetes 50 grams of carbs in the form of glucose, white bread, or pasta. In just an hour, the master inflammatory protein complex NF-kB accumulated in large amounts in the nuclei of immune cells in people who ate glucose or bread. Increased NF-kB activity, in turn, activates immune cells and correlates with significant increases in cytokine release in some cells.

These results suggest that post-meal glucose spikes can aggravate inflammatory processes even in young, healthy people.

Over time, a high sugar diet that forces the body to exist in a state of chronic inflammation dramatically increases the risk of dying from an inflammatory disease such as cardiovascular disease, diabetes, or COVID-19. One study that followed nearly 1,500 postmenopausal women for 13 years found that those who ate a high glycemic index (GI) diet—high in sugar and refined starches, low in fiber and non-starchy vegetables—had a 2.9-fold increased risk of death from inflammatory disease compared to women who ate a low GI diet.

5. Changes in Transcriptional Pathways: Altering How Our Genes Function

The components of the NF-kB master inflammatory complex aren’t the only genes that respond to changes in blood sugar. Others—including several strongly tied to longevity—are expressed most robustly when keeping blood sugar low.

One example, the human telomerase reverse transcriptase (hTERT) gene, helps protect DNA integrity when cells divide. Nearly two trillion cells divide every day in our bodies. Each time that happens, the end caps that protect the DNA, called telomeres, shorten just a little. Eventually, they become so short that the DNA they bookend becomes exposed and unstable—at which point the cell dies. 

The hTERT gene produces an enzyme that helps prevent telomeres from shortening when cells divide, extending the cell’s life. Studies in cell cultures show that glucose restriction for just four weeks activates the hTERT gene.

Another set of genes that responds to the glucose environment are the forkhead box class O (FOXO) family. This group of related proteins plays a pivotal role in controlling how and when many other genes are expressed in the body and impacts several parts of the metabolic chain, from beta cells to glucose production in the liver. Research suggests that some FOXO proteins contribute to longevity and healthy aging by supporting stem cell function and bolstering cells’ antioxidant defense capabilities, as well as being one of the molecular switches involved in meta.

FOXO genes activate during fasting and exercise. This helps facilitate the switch from using carbohydrates for energy to using fat for energy—a key feature of metabolic flexibility, which is a hallmark of longevity.   

Finally, glucose restriction also seems to stall age-related mitochondrial deterioration by increasing sirtuin 3 (SIRT3). SIRT3 is part of a family of genes that stimulate the production of new mitochondria, helping to bolster and refresh the body’s energy-production capacity and put the brakes on age-related diseases.

6. Endothelial Dysfunction: Impairing Our Blood Vessels

The final link between sugar and reduced longevity connects to several of the mechanisms already discussed: dysfunction of the lining of the blood vessels.

Our tissues depend on the vascular system to deliver the oxygen, nutrients, electrolytes, and hormones they need to function. A key mediator in that process is a single layer of flat cells, called the endothelium, which lines the blood vessels. The endothelium performs several critical roles, including modulating blood flow, regulating clotting, and controlling the exchange of molecules between the blood and the surrounding tissues.

When the endothelium is compromised, nearly every major body system can be affected, including the heart, brain, eyes, nerves, and kidneys. 

Chronic high blood sugar and insulin resistance damage the blood vessel walls in several ways, including generating oxidative stress and AGEs, damaging endothelial mitochondria, and causing the endothelium to secrete pro-inflammatory and pro-clotting chemicals. 

A damaged and dysfunctional endothelium is less able to generate and use nitric oxide (NO), the primary signaling molecule it uses to dilate the blood vessels and increase blood flow to the tissues. At the same time, excess glucose may oxidize low-density lipoprotein (LDL—the “bad” cholesterol) in the blood, causing it to clump together and adhere to the vessel walls as plaque—also known as atherosclerosis.

There is also evidence suggesting that post-meal insulin spikes can be a significant risk factor for developing vascular diseases like coronary artery disease. Excess circulating insulin can stimulate a “beefing up” of smooth muscle cells in the arteries, causing them to narrow. It can also increase LDL cholesterol transport in these same cells, leading to inflammation and eventually causing the arteries to harden.

Many of the complications of diabetes stem from dysfunction in either the small or large blood vessels because of poorly controlled blood glucose.

What Can We Do to Support Longevity?

The good news for anyone hoping to improve their longevity is that we can mitigate many of the destructive processes outlined here through diet and lifestyle choices that promote stable glucose.

The more sobering reality for the U.S is that the way we currently screen for glucose disorders doesn’t catch these problems early. The earlier we see them, the better the prognosis and the healthier the population.

Today, most of us have our fasting glucose—the amount circulating in the blood after eight or more hours consuming zero calories—checked every year at a routine physical. In addition, doctors use an oral glucose tolerance test (OGTT), which involves drinking 75g of glucose and monitoring the blood glucose response to confirm suspected cases of diabetes. The U.S. Preventive Services Task Force currently recommends measuring fasting plasma glucose, oral glucose tolerance, or levels of hemoglobin A1c— which reveals a three-month blood glucose average—in adults aged 40 to 70 who do not have symptoms of diabetes but are overweight or obese. 

There are a few limitations to these standard diagnostic measures. First, fasting glucose and the OGTT each capture just a snapshot in time. Mounting evidence suggests that even if we score in the normal range on both of these tests, we may still be developing metabolic dysfunction that is not showing up.  The A1c test offers a longer lens, but it doesn’t capture variability in glucose levels, which can be an independent predictor of future diabetes risk. For this reason and others, its power for diagnosing diabetes is limited.

Indeed, the latest research suggests that glycemic variability—the peaks and troughs of blood glucose levels—may be a stronger predictor of metabolic dysfunction than hyperglycemia alone. The current measures fail to completely capture that risk, meaning that many people with dysregulated glucose are likely going undiagnosed. One study, which fitted 57 seemingly healthy people without prior diabetes diagnoses with continuous glucose monitors, sought to categorize people into “glucotypes” based on their glucose variability. They found that a quarter of people with normal glucose (as defined by standard tests) had severe glycemic variability and spent 15 percent of their time in prediabetic zones.   

Finally, studies show that metabolic problems may begin more than a decade before their effects show up in rising blood glucose levels. Damage starts accumulating during the period where insulin resistance is developing and causing compensatory high insulin levels, which keeps glucose levels in the “normal” range, despite dysfunction progressing. Unfortunately, since we don’t test for fasting insulin levels nor insulin levels after an oral glucose tolerance test, we’re blind to this early marker of developing dysfunction. When researchers analyzed data from more than 6,500 British civil servants, they found that those who developed diabetes showed red flags in their insulin secretion and sensitivity levels at least 13 years before diagnosis.

The upshot: Today, an excessive number of people may be walking around unaware of their compromised metabolic health and snoozing on their chance to improve their longevity. Fortunately, by staying educated on metabolic health and how to optimize our glucose and insulin levels, support our mitochondrial function, and enhance our metabolic flexibility, we can take a significant step towards improving our healthy lifespan.