Aging: Thromboembolic Disease, Metabolic Syndrome, Type 2 Diabetes Mellitus, and Alzheimer’s Disease

Abstract

Aging can be interpreted as an unavoidable process whose end point is the death. Aging entails, in the hemostasis field, some changes that favour blood hypercoagulability. Both the plasminogen activator inhibitor (PAI-1), specific inhibitor of the tissue plasminogen activator (t-PA), accompanied by the oxidative stress and the marked decrease of the main antioxidant-glutathione are fundamental in the bases of elderly pathologies which can cause death. There is some scientific evidence of the relationship between aging, neuro-degenerative diseases, an excessive production of reactive oxygen species and the decrease of proteolysis in brain. The cerebral plasminogen/plasmin system represents the essential proteolytic mechanism that degrades amyloid peptides (βamyloidosis) for action of plasmin with effectiveness. This physiologic process is being considered as a preventive neurodegenerative mechanism. At the same time, the decrease of glutathione levels in aging entails a decrease of cerebral plasmin activity and a progressive descent of t-PA activity due to a descent in t-PA expression and an increase in PAI production. All of them entail an increment of amyloid beta peptides (Aβ) production and a lower level of their clearance. Both mechanisms, oxidative stress, direct consequence of the oxygenate metabolism of aerobics cells, and changes in the systemic fibrinolysis and cerebral b-amyloidolytic activity, play a very important role in thromboembolic disease, metabolic syndrome-obesity, insulin resistance, hyperglycemia-, type 2 Diabetes Mellitus and Alzheimer's disease, clinical processes that accompany the aging. In this revision we show the importance of the interaction between glutathione, proteolytic t-PA/plasminogen/plasmin system, and the inhibitor PAI-1 in aging physiopathology, whose results suggest the hypothesis of the importance of a therapeutic strategy using the inhibition of

Sulodexide and Alzheimer’s Disease: A Preliminary Prospective Study

“…Deficiency of GSH is found in neurodegenerative diseases, mainly Alzheimer's and Parkinson's diseases, [146] [153]- [159] in patients with obesity, metabolic syndrome, resistance to insulin, hyperglycemia and diabetes, clinical conditions very related with AD [160]- [165]. In fact, an important decrease of fibrinolytic activity, with a depletion of t-PA activity, an increase of PAI-1 and an enhanced production of ROS has been found in these metabolic diseases [166]- [177].…”

“…The normalization of the concentration of GSH after the suspension of the effect of BSO is accompanied by normal t-PA and plasmin activities [127]. There are elevated serum concentrations of TGF-β1 in obesity, metabolic syndrome, type 2 Diabetes mellitus and AD [180]- [183] which are pathogenic processes entailing increase of PAI-1 and decrease of the level of GSH [166]- [168]. In addition to this, an improvement of the fibrinolytic activity and a decrease of PAI-1 have been observed with the administration of GSH to patients with non-insulin-dependent diabetes mellitus (NIDDM) [184] [185].…”

The Physiopathological Crossroads of Aging

“…[60].GSH is the most important antioxidant agent used by each of our cells and, among other actions, regulates the functions of the immune system, protects the DNA from mutations and helps inhibit viral replication, being the most important component of the antioxidant mechanism of the brain[61] [62]. However, throughout the development of aging, GSH levels tend to decrease[58] [63]-[68] in the pathogenic entities that accompany aging[62]. This favors the action ofcell damage in neurodegenerative diseases and cerebrovascular accidents [69] [70].…”

Stress/inflammation and pai-1 as stellar processes in the aging and associated pathologies

“…Besides, it is of great interest the pathophysiological function developed by PAI-1 in aging and the multiple pathology associated: obesity, metabolic syndrome, type 2 diabetes, neurodegenerative pathology (mainly in Alzheimer's Disease and Parkinson's Disease), cancer (PAI-1 can be involved in the onset, progression and metastasis of some neoplasia), cardiovascular processes and thromboembolic complications. These clinical entities clearly show increased levels of PAI-1, leading some researchers to suggest the use of PAI-1 inhibitors with therapeutic purposes in those risk processes where reduction to physiological levels could be of interest [32][33][34][35][36][37][38][39].…”