**2. Prevention and Protective Factors: The Risk-Reduction Approach**

#### *2.1. Moderate Physical Exercise*

Cross-sectional and longitudinal trials indicate that aerobic exercise can prevent and reverse age-associated arterial stiffness [45]. Moderate exercise tends to be a stimulator of NO• release and favors endothelial function, which in turn reduces the cardiovascular risk profile in patients affected by DM [46]. Recently, a clinical trial was conducted on 33 healthy middle-aged and older subjects (67 ± 1 years), randomly divided into two groups, of which one had aerobic exercise training (AT), while the second was a sedentary control [19]. Circulating apelin and adropin levels gradually increased during the AT intervention and significantly increased from baseline at weeks 4, 6 and 8. Furthermore, plasma ADMA levels significantly decreased during the 8-week AT intervention. Therefore, this study suggested that exercise training induces favorable changes in the time course of NO• production, participating in AT-induced improvements of central arterial stiffening with advancing age [19]. The data indicate that exercise training can increase endotheliumderived nitric oxide activity in patients with an impaired endothelial function [45], and positively modulates inflammation and the atherosclerotic process; consequently, these facts can attenuate the progression of lower-limb myopathy, with subsequent improvements in the patients' functional capacity and health-related quality of life [47,48].

A multicenter observational prospective cohort study on 500 PAD patients (53% of them also affected by DM) who underwent endovascular treatment showed that the implementation of home-based exercise, monitored by pedometers, significantly decreased the risk of major adverse events, including death and the amputation of the target limb [49]. Supervised exercise therapy (SET), implemented several times a week and gradually, is, to date, an approach that should be offered to patients affected by symptomatic PAD [50], and is considered a class IA (highest level) recommendation, according to the 2016 AHA/ACC Guideline on the Management of Patients with PAD [51]. Unfortunately, the long-term participation in these programs is low and, therefore, this approach is underused.

A recent study conducted on PAD patients showed that exercise induces an exaggerated increase in arterial mean pressure compared to controls, but popliteal artery blood flow remains impaired, and concomitantly inflammatory and oxidative stress markers increase [52]. These observations, although derived from a small group of subjects (8 PAD patients), suggest that the improvement of exercise tolerance should be considered as a therapeutic target for people affected by PAD and, furthermore, suggest that the use of anti-inflammatory and antioxidant agents may be a promising approach.
