Mother Nature sometimes shares her secrets in the form of fun facts. For example, mammals usually have roughly the same number of heartbeats in a lifetime, approximately one billion. With a heart rate of 550 beats per minute, a mouse exhausts its supply in 2 to 2.5 years. At the other extreme, a whale lives about 30 years with a resting heart rate of only 30 to 35 beats per minute. Is this observation an oddity or the key to an important physiological principle? A straightforward interpretation of these observations is that death occurs when an important component of the cardiovascular system wears out around the time of the one-billionth heartbeat. This is consistent with the fact that cardiovascular diseases of old age such as heart attack and stroke are the leading causes of death worldwide
Only two mammals routinely have more than one billion heartbeats in a lifetime. One is the human, whose heart will beat around 2.5 billion times in 80 years at rate of 60 beats per minute. The other is the naked mole-rat, a small burrowing rodent native to Africa. It is the longest-lived rodent, with a maximum life expectancy of more than 31 years despite a heart rate of 220 beats per minute. Thus, a naked mole-rat’s heart will beat almost 3.6 billion times.
This unique animal does not experience a significant decline in any physical function until late in life, and its risk of dying is stable throughout most of its life, rather than increasing with age. This is described in the scientific literature as “successful aging.” Consequently, it most commonly dies from bite trauma inflicted by other mole-rats, not the end stage of slow physiological decline or disease. In contrast, humans experience gradual declines in physical functions beginning in the third decade, and their risk of death increases with age.
Another way Mother Nature shares her secrets is through “experiments of nature.” These are unexpected or rare phenomena that provide an opportunity to learn a bigger truth. They can be viewed as experiments in which Mother Nature is the inventor and the outcome of the experiment has already been revealed. Recognizing a rare phenomenon is an achievement, but science only truly advances when it explains how or why the phenomenon occurs. For example, the observation that cattle often bled to death after eating moldy fodder led to the discovery of the anticoagulant drug warfarin. Years of dedicated investigation eventually revealed that certain fungi convert a compound normally found in feed into the molecule which is used medicinally.
From a scientific standpoint, the naked mole-rat is an experiment of nature. This experiment shows that physical decline can be delayed and lifespan extended. Slowing the aging process is not a pipe dream sold on a late night infomercial but a legitimate area of scientific inquiry and a realistic possibility. The task is to identify the crucial difference between the naked mole-rat and all other mammals.
A unique feature of the naked mole-rat’s cardiovascular system is that its arteries do no lose elasticity or stiffen with age, which is commonly called “hardening of the arteries.” This deterioration most seriously affects the function of the aorta, the extremely large artery through which all blood pumped by the heart flows en route to the rest of the body. The elasticity of the aorta dampens the velocity of blood propelled by the heart, preventing the development of the biological equivalent of Class III whitewater downstream. Disordered blood flow causes clots and obstructions called atherosclerotic plaques to form in arteries. When these obstruct blood to the heart or brain, they cause heart attacks or strokes, respectively. Thus, aortic elasticity prevents cardiovascular disease.
Because it is elastic, the aorta bulges slightly to accommodate the volume of blood pumped with every contraction, stretching its elastic elements. Like every other material, repetitive stretching causes fatigue and eventual fragmentation of these elements, causing the aorta to progressively stiffen. An aorta in mint condition is like a rubber band, while that of a sixty-year-old is like the rubber from an old toilet plunger. Elastin, a protein which is an important contributor to aortic elasticity, is not produced in humans after growth ceases, causing the aorta to progressively stiffen as these molecules fragment. Our research shows that the earliest evidence of decreased aortic function is detectable at age 23. That can be considered the beginning of the aging process.
The degree of aortic stiffness correlates with the risk of death, not just from cardiovascular disease but from all causes. This is because aortic stiffening decreases the amount of blood pumped by the heart with every beat, just as a stiff rubber hose can be filled with less air than a balloon at the same pressure. Decreased cardiac output reduces the delivery of oxygen, glucose, and every other nutrient to the entire body, decreasing bodily functions and the ability to recover from an insult. Blood flow determines how much power a muscle, including the heart, can generate, how well the kidneys cleanse the blood, and how much energy the liver can release. By slowly stiffening and reducing cardiac output, the loss of aortic function fundamentally drives the aging process. Thus, the component of the cardiovascular system which wears out and limits lifespan is the aorta.
Loss of elasticity in the skin of the face allows it to sag from the inexorable tug of gravity. The purpose of a facelift is to remove these sags. An aged appearance correlates with an increased risk of death because both are caused by lost elasticity, skin elasticity in the former and aortic elasticity in the latter. Because these key features of aging are linked, the first assessment in the physical examination of an adult is whether a patient’s appearance is older, younger or consistent with the patient’s chronological age.
In 1921, Sir William Osler, perhaps the greatest physician of all time, wrote “arterio-sclerosis [i.e., stiffening of the arteries] is an accompaniment of old age, and is the expression of the natural wear and tear to which the tubes are subjected. Longevity is a vascular question, which has been well expressed in the axiom ‘a man is only as old as his arteries.’ To a majority of men death comes primarily or secondarily through this portal….a man of thirty may have arteries of a man of sixty, and a man of forty may present vessels as much degenerated as they should be at eighty.…commonly the arterio-sclerosis results from bad use of good vessels.” Dr. Osler’s ideas were prescient because heart attacks and strokes were minor causes of death at that time, only becoming the most common causes of death in the mid-twentieth century.
Dr. Osler was describing the difference between physiological or biological age and chronological age. A healthy lifestyle including good dietary, exercise, and sleeping habits, maintaining hydration, quitting smoking, and drinking alcohol sensibly are all recognized to contribute to a longer, healthier life. However, there has been little appreciation, except by Dr. Osler, of the basic role of aortic elasticity and stiffness in determining lifespan, or how a healthy lifestyle preserves aortic elasticity. Dr. Osler can be considered the originator of the vascular elasticity theory of aging
As Dr. Osler understood, it is possible to wear out the aorta prematurely. High blood pressure and its associated conditions, obesity, smoking and drinking alcohol stiffen the aorta, which may not be reversible with blood pressure-lowering drugs. It is also possible to exhaust one’s allotment of heartbeats prematurely. Prolonged elevation of the heart rate, as in chronic over-exercise, will wear out the aorta prematurely and decrease lifespan. Plotting the amount of exercise versus the risk of dying reveals a U-shaped curve. At one extreme are people with a sedentary lifestyle, which elevates the resting heart rate and increases the chances of having many other abnormalities. At the other extreme are athletes like ultramarathoners.
If the goal of exercise is to maximize health and lifespan, the aim should be to minimize the resting heart rate and preserve aortic elasticity for as long as possible. Aortic elasticity is a precious commodity and should be not be wasted. A large study shows that the optimal amount of jogging is one to 2.4 hours per week, the optimal frequency is two to three times per week, and the optimal pace is slow. This is the amount of exercise which decreases the risk of death the most, i.e., the bottom of the U-shaped curve. Once again, the wisdom of Paracelsus, the father of toxicology, is confirmed: “All things are poison, for there is nothing without poisonous qualities. It is only the dose which makes a thing poison.”
Another example of the central role of aortic elasticity in aging is seen in the ultra-rare syndrome Hutchinson-Gilford progeria. People with this condition prematurely develop features of old age and die on average at age fifteen. Their death is usually caused by the same cardiovascular diseases of old age as the general population, heart attack and stroke, even though these teenagers don’t usually have predisposing conditions such as hypercholesterolemia, obesity, or, most importantly, advanced chronological age, the strongest risk factor for these diseases.
Loss of elasticity occurs prematurely in both the aorta and skin in people with Hutchinson-Gilford progeria. The aorta of a seven-year-old with this syndrome is typically as stiff as the aorta of an ordinary person aged 60 to 69, explaining their predisposition to cardiovascular disease. The heart of someone with Hutchinson-Gilford progeria will have beaten only around 2.5 million times by age 15. The naked mole-rat must have an ability to repair or protect elastin molecules in the same way that all organisms have enzymes that repair defects in DNA. This activity must be present to a lesser degree in humans and other mammals, and absent in Hutchinson-Gilford progeria.
Since 2015, the American Heart Association, European Society of Hypertension, and European Society of Cardiology have recognized that measuring arterial stiffness provides a unique measure of the risk of cardiovascular disease, unrelated to the risk determined by blood pressure, cholesterol levels, weight, or any other characteristic. Once the role of aortic stiffening in the development of cardiovascular disease and aging is more widely known, it could be recognized as the second most powerful determinant, behind genetics or family history, of the risk of developing cardiovascular disease. As a marker of physiological or biological age, the degree of arterial stiffening will be more important than chronological age in determining risk. Increased awareness of arterial stiffening will also inform lifestyle choices, especially those involving exercise.