**4. Interventions to extend longevity**

In the absence of the genetic predisposition to become centenarian, there are several potential ways to extend longevity and eventually surpass 100 years. The potential tools that can be proposed to extend longevity include lifestyle, reduction of several life-threatening diseases and disabilities, hormonal replacement or blockade, antioxidants, autophagy inducers, senolytic drugs, stem cell therapy, and gene therapy [8–24, 26, 33–35, 39, 41, 42, 51, 53, 65, 66].

#### **4.1 Lifestyle**

Diet rich in vegetables, fruits, fibers, and poor in saturated fat and red meat, even if associated with sarcopenia, may extend longevity [26, 65]. Antiinflammatory diets like Mediterranean diet are associated with reduced mortality from cardiovascular disease. Drinks containing sugar and alcohol consumption should be limited, and smoking avoided.

Based on animal data, it has been proposed that even in normal weight individuals, caloric restriction (cutting approximately 500 calories/day) without causing malnutrition and subsequent sarcopenia and osteopenia may improve health and extend longevity [8–11, 21, 26, 33, 35, 39, 66]. However, long-term prospective studies in humans are needed to confirm the benefits of this approach. Hypocaloric diet should be implemented in case of overweight or obesity.

Regular exercise can add few more years to life expectancy. Physical fitness is an important predictor of mortality and being able to live an independent life at old age. Potentiation of physical fitness is a valuable anti-aging therapy [11, 51].

In addition, living in a clean and stress-free environment, being mentally active with positive attitude, having daily objectives, and involved in social interactions further contribute to extended longevity.

#### **4.2 Reduction of life-threatening diseases and disabilities**

Overweight and obesity should be prevented or managed with appropriate tools (e.g., diet, exercise, drugs, medical devices, and surgery) to decrease comorbidities and mortality [33, 34, 41].

Reduction of other life-threatening diseases and disabilities that can affect longevity (e.g., ischemic heart disease, stroke, chronic obstructive pulmonary disease, cancer, respiratory infection, type 2 diabetes, osteoporosis, and dementia) with lifestyle, drugs, and surgery can improve the quality of life and extend longevity [14, 15, 42].
