Long-term treatment with spermidine increases health span of middle-aged Sprague-Dawley male rats.

Let alone calorie restriction, life span extension in higher organisms has proven to be difficult to achieve using simple drugs. Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. However, younger subjects (< 40 years of age) are infrequently prescribed nor self-medicating with antiaging drugs. Therefore, in the present study, we aimed at assessing the effect of long-term treatment with spermidine given in the drinking water on behavioral performance and longevity of male, middle-aged Sprague-Dawley rats. We report that spermidine given in the drinking water did not extend neither the median nor the maximum life span of the middle-aged male Sprague-Dawley rats. However, spermidine treatment had a beneficial effect on the body weight and the kidney tubules, liver, and heart morphology. Behaviorally, spermidine led to a reduction in anxiety and an increase in curiosity, as assessed by exploratory behavior. Moreover, long-term treatment with spermidine enhanced autophagy in the brain and led to a diminished expression of the inflammatory markers, Tgfb, CD11b, Fcgr1, Stat1, CR3, and GFAP mRNAs in several cortical region and hippocampus of the treated rats suggesting that one beneficial effect of the long-term treatment with spermidine is an attenuated proinflammatory state in the aged brain. Our results suggest that long-term treatment with spermidine increases health span of middle-aged rats by attenuating neuroinflammation and improving anxiety and exploratory behavior.

Autophagy in aging and disease.

Autophagy is a catabolic degradation system used to destroy and recycle the unnecessary or damaged components of a cell. Autophagy is present at a basal level in all mammals and is regulated by some conditions, such as oxidative stress, starvation or hypoxia. In aged tissues, increased but also decreased expression of autophagy-specific proteins, Beclin 1, LC3, Atg5 and Atg7 has been reported. Likewise, it could be shown that the lifespan of yeast, nematodes and flies is prolonged by pharmacologically stimulated autophagy using exogenous administered spermidine. Autophagy is potentially implicated in acute lung injury and sepsis, two main causes of morbidity and mortality worldwide. Finally, a quite recent study supports the hypothesis that autophagy might be useful in vascular disease prevention by stimulating cholesterol efflux, which leads to inhibition of necrotic core formation and lipid accumulation. Since autophagy is also implicated in neuro-protection, in Alzheimer's and Huntington's disease animal models and many others normal and pathological states, including immunity, diabetes mellitus, different kind of tumors, colorectal cancer, different inflammations, lung diseases, neurodegenerative diseases, autophagy is of interest to many biomedical researchers.

Molecular mechanisms underlying neurodevelopmental disorders, ADHD and autism.

Neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism represent a significant economic burden, which justify vigorous research to uncover its genetics and developmental clinics for a diagnostic workup. The urgency of addressing attention deficit hyperactivity disorder comorbidities is seen in the chilling fact that attention deficit hyperactivity disorder (ADHD), mood disorders, substance use disorders and obesity each increase the risk for mortality. However, data about comorbidity is mainly descriptive, with mechanistic studies limited to genetic epidemiological studies that document shared genetic risk factors among these conditions. Autism and intellectual disability affects 1.5 to 2% of the population in Western countries with many individuals displaying social-emotional agnosia and having difficulty in forming attachments and relationships. Underlying mechanisms include: (i) dysfunctions of neuronal miRNAs; (ii) deletions in the chromosome 21, subtelomeric deletions, duplications and a maternally inherited duplication of the chromosomal region 15q11-q13; (iii) microdeletions in on the long (q) arm of the chromosome in a region designated q21.1 increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems associated with autism, schizophrenia, and epilepsy and weak muscle tone (hypotonia); (iv) interstitial duplications encompassing 16p13.11.

Age-related hypoxia in CNS pathology.

Although neuropathological conditions differ in the etiology of the inflammatory response, cellular and molecular mechanisms of neuroinflammation are probably similar in aging, hypertension, depression and cognitive impairment. Moreover, a number of common risk factors such as obesity, hypertension, diabetes and atherosclerosis are increasingly understood to act as "silent contributors" to neuroinflammation and can underlie the development of disorders such as cerebral small vessel disease (cSVD) and subsequent dementia. On the other hand, acute neuroinflammation, such as in response to traumatic or cerebral ischemia, aggravates the acute damage and can lead to a number of pathological such as depression, post-stroke dementia and potentially neurodegeneration. All of those sequelae impair recovery and most of them provide the ground for further cerebrovascular events and a vicious cycle develops. Therefore, understanding the mechanisms associated with vascular dementia, stroke and related complications is of paramount importance in improving current preventive and therapeutic interventions. Likewise, understanding of molecular factors and pathways associated with neuroinflammation will eventually enable the discovery and implementation of new diagnostic and therapeutic strategies indicated in a wide range of neurological conditions.

Poststroke Cell Therapy of the Aged Brain.

During aging, many neurodegenerative disorders are associated with reduced neurogenesis and a decline in the proliferation of stem/progenitor cells. The development of the stem cell (SC), the regenerative therapy field, gained tremendous expectations in the diseases that suffer from the lack of treatment options. Stem cell based therapy is a promising approach to promote neuroregeneration after brain injury and can be potentiated when combined with supportive pharmacological drug treatment, especially in the aged. However, the mechanism of action for a particular grafted cell type, the optimal delivery route, doses, or time window of administration after lesion is still under debate. Today, it is proved that these protections are most likely due to modulatory mechanisms rather than the expected cell replacement. Our group proved that important differences appear in the aged brain compared with young one, that is, the accelerated progression of ischemic area, or the delayed initiation of neurological recovery. In this light, these age-related aspects should be carefully evaluated in the clinical translation of neurorestorative therapies. This review is focused on the current perspectives and suitable sources of stem cells (SCs), mechanisms of action, and the most efficient delivery routes in neurorestoration therapies in the poststroke aged environment.