In the industrialized countries, chronic obstructive pulmonary disease (COPD) is the fourth cause of death. Current therapy does not change prognosis and health related cost. New therapeutic options are therefore needed. Recent evidence shows that COPD pathogenesis is associated with an early pulmonary senescence process, which may explain the insufficient regenerative response to apoptosis and reduced extracellular matrix synthesis which characterize emphysema. Longo et al. have demonstrated bone marrow activation and reduction of cardiovascular and neoplastic risk factors, which can extend lifespan, in mice treated with fasting mimicking diet (FMD).Similar results were shown in humans. Longo et al. have recently demonstrated a correlation between regenerative effect and inhibition of the mTOR dependent nutrient sensing pathways. The demonstration of an up regulation of mTOR in lung homogenate and peripheral blood monocytes of COPD patients, suggests a possible benefit of FMD in COPD. The aim of the study is to evaluate the effects of FMD on bone marrow response and pulmonary function in COPD patients. Patients in GOLD II class will be enrolled and they will be divided into two groups.The FMD group will receive standard of care therapy + 3 FMD cycles (one per month), while the control group will only receive standard of care therapy. Patients will undergo cardiopulmonary exercise test (CPET) and respiratory function tests at the beginning and at the end of the study. Sytoslic blood pressure,diastolic blood pressure, heart rate, circulating stem cell, IGF-1 and GDF11/15, C-reactive protein, insulin, glucose, total and HDL Cholesterol and tryglicerides will be dosed at the beginning and at the end of the study.
Dietary composition and calorie level are key factors affecting aging and age-related diseases. In rodents intermittent fasting promotes protection against diabetes, cancer, heart disease and neurodegeneration; in human models, reduces cardiovascular risk factors (Harvie NM et al, Int J Obes 2011). A key point is the reduction of insulin-like growth factor (IGF-1), which play a role in metabolism, growth and development. IGF-1 in also associated with aging and cancer (Cheng C-W et al, Cell Stem Cell 2014). Despite its potential for disease prevention and treatment, prolonged fasting is difficult to implement in human subjects. For this reason, Longo has developed FMD, a low-fat, carbohydrate and proteic diet that mimics the protective effects of fasting. Using FMD, in a murine model, Longo demonstrated the activation of hepatic, muscular and cerebral regeneration, and a marked increase in mesenchymal stem cells (BrdU+)during the refeeding; he also observed a reduction of IGF-1 and an extension of longevity without disease. He attributed these results to hematopoietic and mesenchymal stem cell activation. In a randomized human pilot study, the FMD group showed an increase in circulating BM-MSCs (lin-CD184+CD45- ), a reduction in blood glucose level, C-reactive protein (CRP) and IGF-1, without side effects (Brandhorst et al, Cell Metabolism 2015). Choi IY et al (Cell Rep 2016) used FMD in a murine experimental autoimmune encephalomyelitis. The FMD reduced clinical severity in all mice, and completely reversed symptoms in 20% of the animals. These improvements were associated with increased corticosterone levels and Treg cell number, reduced levels of pro-inflammatory cytokines (TNF-¿, IL-1 e IL-17), TH1 and TH17 cells, and antigen presenting cells (APCs). Spinal cord histology has shown a significant reduction in inflammation and demyelination and an active regeneration and differentiation process of oligodendrocytes with reduction of apoptosi.These results demonstrate the efficacy of FMD in modulating autoimmune organ specific inflammation and in the stimulation of regeneration of progenitor cells. Cheng CW et al (Cell 2017) recently demonstrated that in an advanced murine diabetic model, intensive treatment with FMD (4 days of FMD per week) resulted in a transient ß-cell growth with high expression of proliferative marker PCNA, a significant expression of the Ngn3 endocrine progenitor line marker, and that the repopulation of ß-cells, coincident with glycemic homeostasis, is Ngn3 dependent. FMD promotes a sophisticated cellular reprogramming process through nutrient sensing, with PKA and mTOR / S6K dependent mode. Akihisha M et al (Am J Respir Crit Care Med 2016) demonstrated hyperactivity of mTOR in pulmonary homogenate and peripheral blood mononuclear cells (PBMNC) of COPD patients. They also demonstrated that PBMNC cortisone resistance, measured as the dexamethasone concentration necessary to inhibit the production of TNF-¿ induced CXCL8 by at least 30%, is secondary to the mTOR / S6K up regulation.By inhibiting mTOR with rapamycin, they restored dexamethasone sensitivity of PBMNCs. The mTOR / S6K pathway is therefore a possible therapeutic target for COPD. In consideration of these data, in our opinion, a study on the effects of FMD in COPD could yield important results. The aim of our study is to observe the effects of FMD on the number of circulating stem cells. The already available evidence show that targeting the nutrient sensing via FMD is an innovative therapeutic approach so far never tested in humans. Moreover, FMD has been demontrated in healthy individuals to improve cardiovascular risk factors, and cardiovascular disease is among the main causes of death in COPD patients.