Does physical activity provide a molecular key to longevity?

Fitness and physical exercise are among the most neglected means to improve prognosis. They are the healthiest cardiovascular intervention. Even cardiologists focus on pharmacological treatment and evaluate classical risk factors without asking about daily exercise or objective measures of physical capacity. It is surprising considering the strong data that underscores the survival benefit of regular exercise training.

Exercise works for everybody!
Years ago, Ralph Paffenbarger (1) published on a huge observational study, involving 17,000 male alumni from Harvard University. Men, who spend more than 2000 kcal’s on exercise a week, saw their death rate reduced with one third to one quarter as compared to less active men after a follow-up period of 12 to 16 years. More recently, Jonathan Myers (2) demonstrated the independent predictive value of exercise capacity in 6200 men referred for exercise testing. Remarkably, the largest reduction in mortality was observed between the least fit and the next quintile, suggesting that even a limited improvement in fitness has significant results. The “no pain-no gain” principle seems no longer valid. Exercise capacity mattered in both healthy subjects and cardiovascular patients. This finding has been confirmed in several patient groups, such as those with coronary artery disease and high-risk patients with chronic heart failure.

But how does it work?
Is it just a matter of healthier lifestyle? Apparently not, since the observed benefits occur independent of the modulation of coronary risk factors.

Numerous studies have shown that reversal of abnormal function of blood vessels in cardiovascular patients is one of the important mechanisms that link exercise training with improved outcome. In order to allow increased blood flow during exercise, both coronary arteries and arteries supplying working muscles have to increase in size. This dynamic process, called vasodilation, is severely impaired in patients with coronary artery disease and chronic heart failure.

There is a whole body of evidence suggesting that exercise elicits molecular changes at the level of endothelial cells. These cells cover the inner site of blood vessels. Nitric oxide (NO) is the key biological messenger produced by these endothelial cells. It regulates vascular tone, it prevents blood cells from sticking to the vascular wall and it reduces the likelihood of atherosclerotic plaques to develop. Simply stated, improved regulation of blood flow through exercise might be the mechanism.

During exercise, higher pulse rate and contraction of the heart increase the rate of flow in blood vessels. This phenomenon is sensed by endothelial cells and translated into a very complicated process that finally leads to increased production of NO. First of all, this occurs through increased levels and activity of the enzyme that synthesises the molecule (the endothelial nitric oxide synthase or eNOS). Secondly, the production of highly reactive and toxic oxygen radicals, that are capable of NO inactivation, is reduced. In addition, anti-oxidant enzymes that neutralize oxygen radicals are activated through exercise training. Finally, exercise training increases the diameter of large blood vessels, but it also leads to a higher number of small vessels (capillaries) via a process called angiogenesis.

Cells from the bone marrow; here they come again.
The formation of new blood vessels in areas of limited blood supply has been put forward to explain some of the changes that occur with exercise training. The mobilisation and integration of so-called endothelial progenitor cells (EPC) has recently received enormous attention. These cells are derived from stem cells that reside in the bone marrow. Upon specific signals, they appear in the circulating blood and find their way to areas of injury or oxygen deprivation. EPC contribute to the formation of new small blood vessels, but also aid in the repair of damaged endothelium. It has been shown that low numbers of EPC in the blood stream correlates with dysfunction of blood vessels and impaired prognosis in cardiovascular patients. Animal experiments, as well as human data, show that exercise training leads to higher numbers of circulating EPC. It also enhances the capacity of the cells to contribute to angiogenesis (3). In patients with narrowed arteries of the lower limbs (peripheral arterial occlusive disease) and in patients with coronary artery disease, 4 weeks of exercise training significantly increases the number of circulating EPC and the ability of these cells to integrate into pre-existing vascular networks (4).

To realize these changes, the generation of NO again seems imperative. This issue was addressed in a study by Laufs and colleagues (3). These investigators demonstrated that the effect of exercise on the number of circulating EPC was inhibited in mice that lack eNOS.

Closing the circle.
There is a strong rationale to support the idea that regular exercise training is of benefit for a very broad range of both healthy people and cardiovascular patients. The advantages of exercise outreach the benefits on quality of life and the control of classical cardiovascular risk factors. Physical training reduces hard endpoints, which nowadays is a conditio sine qua non to receive attention in the world of evidence-based medicine. The progressive disclosure of molecular pathways helps to explain how exercise training works and puts blood vessels and their function right at the centre of our attention.

Reference:

1.Paffenbarger RS, et al. N Engl J Med 1986; 314:605.
2.Myers J, et al. N Engl J Med 2002; 346:739.
3.Laufs U, et al. Circulation 2004; 109:220.
4.Sandri M, et al. Circulation 2005; 111:3391.

Notes:
This study was presented at the ESC Congress 2007 in Vienna.

The European Society of Cardiology (ESC):

The ESC represents nearly 53,000 cardiology professionals across Europe and the Mediterranean. Its mission is to reduce the burden of cardiovascular disease in Europe.

The ESC achieves this through a variety of scientific and educational activities including the coordination of: clinical practice guidelines, education courses and initiatives, pan-European surveys on specific disease areas and the ESC Annual Congress, the largest medical meeting in Europe. The ESC also works closely with the European Commission and WHO to improve health policy in the EU.

The ESC comprises 3 Councils, 5 Associations, 19 Working Groups, 50 National Cardiac Societies and an ESC Fellowship Community (Fellow, FESC; Nurse Fellow, NFESC).