Lysosomes in iron metabolism, ageing and apoptosis

The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ∼4 to 5) that constantly fuse and divide. It receives a large number of hydrolases (∼50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place

Structural and functional features of skeletal muscle cell nuclei are modulated by physical exercise in old mice

The work describes the structural and functional features of skeletal muscle cell nuclei after physical exercise in old mic

Long-term object recognition memory in aged rats

Rats show spontaneous preference for exploring novel rather than familiar objects. Thus, exploratory activity can be used to evaluate recognition memory. To date, the spontaneous novelty-preference test of object recognition has been used to study long-term recognition memory formation in adult rats (Mumby et al., 2002 Behav Brain Res 132:215-26), but not in aged rats. In the present study we used this behavioral test with 25-27 month-old Wistar rats (n=9), but we found that it was not able to elicit recognition memory. Thus, we developed a new experimental protocol and we tested a second group of rats of the same age (n=18). Each animal received 5 training sessions (1 per day on days 1 and 2, and 1 on day 3) lasting 5 min in a small box (48x26,5x21 cm) containing two identical plastic cubes (8 cm high). We found that the time spent in exploring this pair of objects significantly (P<0.01) decreased on the third session. Twenty-four h after the training 8 rats were tested in the same box, in which one of the two cubes (familiar object) was replaced by a plastic pyramid (8 cm high, novel object). The animals displayed a significantly (P<0.05) longer exploration time of the novel object in comparison with the familiar one. When we applied the new protocol to adult animals (4-6 month-old, n=19), we found that the time spent in exploring the pair of familiar objects significantly (P<0.01) decreased on the second training session, and the time spent in exploring the novel object in comparison with the familiar one was significantly (P<0.05, n=10) longer after 24 h. These findings indicate that the new protocol is able to induce long-term recognition memory formation in aged animals, and allows the evaluation of age-related differences in learning ability

Physical training modulates structural and functional features of cell nuclei in type II myofibers of old mice.

Aging is associated with a progressive loss of muscle mass, strength, and function, a condition known as sarcopenia, which represents an important risk factor for physical disability in elderly. The mechanisms leading to sarcopenia are still largely unknown, and no specific therapy is presently available to counteract its onset or progress. Many studies have stressed the importance of physical exercise as an effective approach to prevent/limit the age-related muscle mass loss. This study investigated the effects of physical training on pre-mRNA pathways in quadriceps and gastrocnemius muscles of old mice by ultrastructural cytochemistry: Structural and in situ molecular features of myonuclei and satellite cell nuclei of type II fibers were compared in exercised versus sedentary old mice, using adult individuals as control. Our results demonstrated that in myonuclei of old mice physical exercise stimulates pre-mRNA transcription, splicing, and export to the cytoplasm, likely increasing muscle protein turnover. In satellite cells, the effect of physical exercise seems to be limited to the reactivation of some factors involved in the transcriptional and splicing apparatus without increasing RNA production, probably making these quiescent cells more responsive to activating stimuli