Increased longevity and improved health can be achieved in mammals by two feeding regimens, caloric restriction (CR), which limits the amount of daily calorie intake, and intermittent fasting (IF), which allows the food to be availablead libitum every other day. The precise mechanisms mediating these beneficial effects are still unresolved. Resetting the circadian clock is another intervention that can lead to increased life span and well being, while clock disruption is associated with aging and morbidity. Currently, a large body of evidence links circadian rhythms with metabolism and feeding regimens. In particular, CR, and possibly also IF, can entrain the master clock located in the suprachiasmatic nuclei (SCN) of the brain hypothalamus. These findings raise the hypothesis that the beneficial effects exerted by these feeding regimens could be mediated, at least in part, through resetting of the circadian clock, thus leading to synchrony in metabolism and physiology. This hypothesis is reinforced by a transgenic mouse model showing spontaneously reduced eating alongside robust circadian rhythms and increased life span. This review will summarize recent findings concerning the relationships between feeding regimens, circadian rhythms, and metabolism with implications for ageing attenuation and life span extension.
Transgenic mice designated alpha MUPA overproduce in many brain sites the urokinase-type plasminogen activator (uPA), a protease implicated in fibrinolysis and extracellular proteolysis. Here we report that, compared to their parental wild-type control, alpha MUPA mice spontaneously consumed less food (approximately 20%), exhibited reduced body weight (approximately 20%) and length (approximately 6%), and also prolonged life span (approximately 20%). The alpha MUPA phenotype is thus reminiscent of experimental animals in which dietary restriction enhances longevity. Reduced eating and body weight were observed in alpha MUPA mice shortly after weaning, and these levels were maintained virtually throughout their lifetime. alpha MUPA mice also exhibited lower levels of blood sugar (approximately 9%), smaller litter size (approximately 14%), and lower birth frequency (approximately 10%). In the adult alpha MUPA brain, uPA mRNA has been localized through in situ hybridization also in neuronal cells of the hypothalamic paraventricular nucleus, a region implicated in feeding behavior. No signals of uPA mRNA could be detected in the paraventricular nucleus of control mice. It is suggested that in alpha MUPA mice, overproduction of uPA in brain sites controlling feeding leads to reduced food consumption that, in turn, results in retardation of growth and body weight and also in increased longevity. The alpha MUPA experimental model may have implications for normal mice.
The gene transfer technique was used to examine the role of plasminogen activator (PA) Tumor cell invasion and metastasis are complex processes affected by a multiplicity of factors whose molecular nature is scarcely defined (13,24,44). Hydrolytic enzymes, including proteinases, were long ago implicated in tumor metastasis to account in part for the ability of tumor cells to detach from the primary lesion, to penetrate through basement membrane surrounding blood vessels, and finally to implant themselves into a remote organ (for reviews, see references 8 and 33). One of the enzymes whose role in metastasis is most controversial is plasminogen activator (PA), a serine proteinase that converts the ubiquitous extracellular zymogen plasminogen into the trypsinlike proteinase plasmin. Plasmin, in turn, dissolves the fibrin network of the blood clot, degrades interstitial glycoproteins such as fibronectin and laminin, and converts procollagenases into collagenases necessary for degradation of basement membrane collagen (8). Such a spectrum of activities renders the plasminogen activation system an ideal candidate to participate in tumor invasion and metastasis, since high levels of PA are closely associated with neoplasia-related phenomena (8, 41). The hypothesis concerning the role of the plasminogen activation system in tumor invasion has recently been supported by studies measuring cellular invasion in vitro in assay systems designed to simplify study of tumor cell invasion and metastasis (30,42). These studies have demonstrated that the passage of tumor cells through a barrier of basement membrane in vitro requires a proteolytic cascade of which the final proteinase collagenase is generated by PA-activated plasmin. That PA may also be involved in tumor invasion under physiological conditions is suggested by the immunocytochemical localization of urokinase-type PA (uPA) in areas of invasive growth of the Lewis lung carcinoma (47). Furthermore, the metastatic spread of the Hep-3 human carcinoma in an avian system was significantly inhibited by antibodies specifically blocking the activity of human uPA without affecting either the local growth of the tumor or the avian uPA activity (37,38). Similarly, inhibition by antibod-* Corresponding author.ies of surface-localized uPA on B16 melanoma cells reduced the capacity of the cells to generate experimental metastasis in mice (20). In contrast to the latter cases, in numerous other studies the role of PA in tumor metastasis was inferred from circumstantial rather than direct evidence (for reviews and detailed lists of references, see references 6, 8, 14, 22, 26, 34, 40, and 43). For example, in sublines derived from transplanted tumors, such as the B16 melanoma and the Lewis lung carcinoma, comparison was made between PA production and metastatic capacity (6,9,14,40,54). Comparison was also made between PA levels of spontaneously arising human tumors of the colon, breast, and prostate and PA produced by their invasive and metastatic derivatives (5,22,26,27,36
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