Biogerontology

Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions Abstract Nicotinamide adenine dinucleotide (NAD+) has been described as central coenzyme of redox reactions and is a key regulator of stress resistance and longevity. Aging is a multifactorial and irreversible process that is characterized by a gradual diminution in physiological functions in an organism over time, leading to development of age-associated pathologies and eventually increasing the probability of death. Ischemia is the lack of nutritive blood flow that causes damage and mortality that mostly occurs in various organs during aging. During the process of aging and related ischemic conditions, NAD+ levels decline and lead to nuclear and mitochondrial dysfunctions, resulting in age-related pathologies. The majority of studies have shown that restoring of NAD+ using supplementation with intermediates such as nicotinamide mononucleotide and nicotinamide riboside can be a valuable strategy for recovery of ischemic injury and age-associated defects. This review summarizes the molecular mechanisms responsible for the reduction in NAD+ levels during ischemic disorders and aging, as well as a particular focus is given to the recent progress in the understanding of NAD+ precursor's effects on aging and ischemia.

Oxidative stress resistance as a factor in aging: evidence from an extended longevity phenotype of Drosophila melanogaster Abstract Longevity of a species is a multifactorial quantitative trait influenced by genetic background, sex, age and environment of the organism. Extended longevity phenotypes (ELP) from experimental evolution in the laboratory can be used as model systems to investigate the mechanisms underlying aging and senescence. ELPs of Drosophila are correlated with various life history attributes such as resistance to environmental stressors (starvation, desiccation, cold and paraquat), developmental time, biochemical defenses, etc. The association between oxidative stress resistance and longevity is not clear and ELPs offer an opportunity to examine the role of oxidative stress resistance in longevity. Here, we have investigated the hypothesis that enhanced oxidative stress resistance and elevated antioxidant defense system play a positive role in longevity using an ELP of Drosophila melanogaster. An ELP of D. melanogaster isolated and characterized in our laboratory through artificial selection (inbred laboratory strain of Oregon K) is employed in this study. Our ELP, named as long lifespan (LLS) flies, shows marked extension in lifespan when compared to the progenitor population (normal lifespan, NLS) and makes a suitable model to study the role of mitochondrial genome in longevity because of its least heterogeneity. In this study, sensitivity to ethanol with age was employed as a measure of resistance to oxidative stress in NLS and LLS flies. Effect of age and oxidative stress on longevity was examined by employing NLS and LLS flies of different age groups against ethanol-induced oxidative stress. Results show that the lower mortality against ethanol was associated with enhanced oxidative stress resistance, higher antioxidant defenses, lower reactive oxygen species (ROS) levels, enhanced alcohol dehydrogenase activity and better locomotor ability attributes of LLS flies. In addition, age-related changes like locomotor impairments, decreased antioxidant defenses, higher ROS levels and sensitivity to oxidative stress were delayed in LLS flies when compared to NLS. Our study supports the hypothesis that higher oxidative stress resistance and enhanced antioxidant defenses are significant factors in extending longevity.

N -Acetylcysteine extends lifespan of Drosophila via modulating ROS scavenger gene expression Abstract N-Acetylcysteine (NAc) has been shown to play a diversity of favorable health-related roles (e.g., antioxidant, paracetamol antidote, mucolytics, neuroprotective agent). Having said that, here in this study, we evaluate the health-promoting properties of NAc, particularly its ability to modulate organismal longevity. We note that 1 mg/ml NAc prolonged the lifespan of Drosophila. Furthermore, it was observed that NAc increased the capability of these flies to resist environmental stresses measured by starvation and paraquat stress assays. In an effort to reveal cellular mechanisms behind this interesting phenomenon, qPCR was performed, uncovering that transcript levels of catalase and phospholipid hydroperoxide glutathione peroxidase—key enzymes to fend off reactive oxygen species (ROS) assaults, were up-regulated. Correspondingly, enzyme activities of catalase and glutathione peroxidase were increased as well. Combined, we hope our research helps broaden the spectrum of clinical application for NAc so that one may eventually determine if NAc is a potentially useful anti-aging agent by encouraging others to scrutinize the hidden health benefits of NAc.

Administration of rGDF11 retards the aging process in male mice via action of anti-oxidant system Abstract One of the most studied and widely accepted conjectures of aging process is the oxidative stress theory. Current studies have generated disputes on the effects of GDF11 and GDF8, a closely related member of GDF11, on rejuvenation and anti-aging properties. In this study, we first demonstrated that when recombinant GDF8 (rGDF8) and GDF11 (rGDF11) of the fish Nothobranchius guentheri were injected into 20-month-old male mice, their serum GDF8 and GDF11 levels were clearly increased. We also showed that injection of rGDF8 and rGDF11 had little influences on the body weight and serological parameters of the mice, indicating their general condition and physiology were not affected. Based on these findings, we started to test the effects of administration of piscine rGDF11 and rGDF8 on the aging process of male mice and to explore the underlying mechanisms. It was found that rGDF11 was able to reduce the levels of AGEs, protein oxidation and lipid peroxidation, and to slow down the accumulation of age-related histological markers, while rGDF8 was not. Moreover, rGDF11 significantly prevented the decrease in CAT, GPX and SOD activities, but rGDF8 did not. Collectively, these results suggest that it is GDF11 but not GDF8 that can exert rejuvenation and anti-aging activities via the action of antioxidant system. It is also the first report that shows the activity of GDF11 is not species-specific, implicating potential usefulness of piscine GDF11 in prolonging the lifespan of the elderly.

Fecundity for free? Enhanced oviposition in longevous populations of Drosophila melanogaster Abstract Artificial selection for increased life span in experimental populations of Drosophila melanogaster sometimes produces long-lived populations that exhibit greater fecundity than unselected controls. The absence of a trade-off between survival and reproduction in these cases might be an artefact of the rich diet of typical lab culture; if nutritional resources are not limiting then there may be no need to trade off. Here I test the rich diet hypothesis by estimating genetic correlations between survival and age-specific fecundity in three nutritional environments. Experimental material consists of 58 recombinant inbred lines derived from an artificial selection experiment. Reducing the yeast content of medium causes substantial reductions in fecundity but does not alter patterns of genetic correlation. The correlation between life span and early fecundity is non-significant in all environments, while the life span correlations with mid-life fecundity are positive and statistically significant in all environments. The rich diet hypothesis is rejected. Qualitative features of fecundity trajectories are conserved across environments, with long-lived lines exhibiting a secondary peak of oviposition in mid-life. The micro-evolution of extended life span is not a monolithic process and does not necessarily involve direct trade-offs between survival and reproduction.

Toxin-induced hormesis may restrain aging Abstract Mild environmental stress might have beneficial effects in aging by activating maintenance and repair processes in cells and organs. These beneficial stress effects fit to the concept of hormesis. Prominent stressors acting in a hormetic way are physical exercises, fasting, cold and heat. This review will introduce some toxins, which have been found to induce hormetic responses in animal models of aging research. To highlight the molecular signature of these hormetic effects we will depict signaling pathways affected by low doses of toxins on cellular and organismic level. As prominent examples for signaling pathways involved in both aging processes as well as toxin responses, PI3K/Akt/mTOR- and AMPK-signal transduction will be described in more detail. Due to the striking overlap of signaling pathways mediating toxin induced responses and aging processes we propose considering the ability of low doses of toxins to slow down the rate of aging.

Aging renders desynchronization between clock and immune genes in male Wistar rat kidney: chronobiotic role of curcumin Abstract Suprachiasmatic nucleus (SCN) contains the central clock that orchestrate circadian rhythms in physiology and behavior in mammals. Tightly interlocked transcriptional and translational feedback loops (TTFLs) comprising of various clock genes such as Clock, Bmal1, Periods, Cryptochromes etc. in the SCN, send the timing signals to peripheral clocks that governs local metabolism with similar TTFLs. Peripheral clocks in kidney regulates several circadian rhythms like blood pressure, immunity etc. However, aging leads to circadian and inflammatory disorders in kidney. Though there are increasing evidences on age associated perturbations, studies elucidating the rhythmic expression of clock and immune genes across aging in kidney are obscure. We therefore studied changes in daily rhythms of clock and immune genes in kidney. In this study we measured mRNA expression of clock genes rBmal1, rPer1, rPer2, rCry1, rCry2, rRev-erbα, rRorα, and inflammatory genes rNfκb1, rTnfα, rIl6, rTlr4 and rTlr9 in 3, 12 and 24 months male Wistar rat kidney using qRT-PCR. From our study, we did not observe significant changes in clock genes expression except rRorα, but immune genes showed significant phase alterations as well as increase in mean 24 h levels. Pearson correlation analysis of data showed desynchronization between immune and clock genes expression. We further studied the effect of administration of curcumin which has anti-aging, anti-inflammatory, anti-oxidant etc. properties, and evaluated its chronobiotic properties. We here report differential effects of curcumin administration on daily rhythms of clock and immune genes expression.

Submandibular gland-specific inflammaging-induced hyposalivation in the male senescence-accelerated mouse prone -1 line (SAM-P1) Abstract Aging has pronounced effects on mammalian tissues and cells, but the impacts of aging on salivary gland function are relatively unknown. This study aims to evaluate the effects of aging on submandibular gland (SMG) and parotid gland (PG) functions in the male senescence-accelerated mouse. In vivo analysis at the systemic level revealed that salivary secretion induced by pilocarpine, a muscarinic agonist, from the SMG was significantly decreased in aged mice, whereas salivary secretion from the PG was not affected. To evaluate organ-level function, the SMG was perfused with the muscarinic agonists carbachol and calcium ionophore A23187 ex vivo to induce salivary secretion, and decreased saliva production was also observed in the aged SMG. Histological analysis revealed the presence of CD4-positive lymphocytes infiltrating the aged SMG. Furthermore, real-time PCR revealed that the aged SMG exhibited accelerated cell aging, increased levels of the inflammatory cytokine interleukin-6, and decreased mRNA levels of the water channel protein aquaporin-5 (AQP5). In summary, these results demonstrate that SMG function in aged mice was diminished, and that cell senescence, chronic inflammation, and the decreased gene expression of AQP5 are the likely causes of hyposalivation in the SMG of aged mice.

Activation of transposable elements and genetic instability during long-term culture of the human fungal pathogen Candida albicans Abstract It has been repeatedly reported that transposable elements (TE) become active and/or mobile in the genomes of replicatively and stress-induced senescent mammalian cells. However, the biological role of senescence-associated transposon activation and its occurrence and relevance in other eukaryotic cells remain to be elucidated. In the present study, Candida albicans, a prevalent opportunistic fungal pathogen in humans, was used to analyze changes in gene copy number of selected TE, namely Cirt2, Moa and Cmut1 during long-term culture (up to 90 days). The effects of stress stimuli (fluconazole, hydrogen peroxide, hypochlorite) and ploidy state (haploid, diploid, tetraploid cells) were also considered. An increase in copy number of Cirt2 and Moa was the most accented in tetraploid cells after 90 days of culture that was accompanied by changes in karyotype patterns and slightly more limited growth rate compared to haploid and diploid cells. Stress stimuli did not potentiate TE activity. Elevation in chromosomal DNA breaks was also observed during long-term culture of cells of different ploidy, however this was not correlated with increased TE activity. Our results suggest that increased TE activity may promote genomic diversity and plasticity, and cellular heterogeneity during long-term culture of C. albicans cells.

Therapeutic effects of curcumin on age-induced alterations in daily rhythms of clock genes and Sirt1 expression in the SCN of male Wistar rats Abstract The aging brain is linked to accumulation of oxidative stress and increase in damage to biomolecules which in turn may cause or promote circadian dysfunction by disruption of biological clock, the suprachiasmatic nucleus (SCN). Age associated alterations in clock gene expression in the SCN has been reported earlier. In the present study we have examined therapeutic effects of the antioxidant curcumin on age induced alterations in daily rhythms and levels of core clock genes in SCN of young [3 months (m)], middle (12 months) and old (24 months) male Wistar rats. Curcumin was administered orally at ZT-11, 1 hour (h) before the onset of darkness. The effect of curcumin administration on daily rhythms and levels of expression of clock genes such as rBmal1, rPer1, rPer2, rCry1, rCry2 and rRev-erbα as well as on the clock modulator rSirt1 were studied. There was restoration of phase of rPer1, rPer2, rCry1, rCry2 and daily pulse of rPer2 in middle aged animals. However, in old aged rats the phase and daily pulse of rPer1 were restored with curcumin treatment. rSirt1 did not show age related alterations in its transcript levels though the rhythms were abolished in old aged rat SCN. Pearson correlation analysis showed that curcumin administration to 12 and 24 months animals had resulted in restorations of several correlations among clock genes which were found to be altered/abolished in age matched control groups. In addition, strong interlocking interactions between rSirt1 and clock genes were observed in young age which were disrupted with aging and curcumin administration resulted in partial restoration.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com