Rejuvenation Research

Maillard reactions are an unavoidable feature of life that appear to be damaging to cell and organisms. Consequently, all living systems must have ways to protect themselves against this process. As of 2012, several such defense mechanisms have been identified. They are all enzymatic and were found in mesophilic organisms. To date, no systematic study of Maillard reactions and the relevant defense mechanisms has been conducted in thermophiles (50°C–80°C) or hyperthermophiles (80°C–120°C). This is surprisingly because Maillard reactions become significantly faster and potent with increasing temperatures. This review examines this neglected issue in two well-defined sets of hyperthermophiles. My analysis suggests that hyperthermophiles cope with glycation stress by several mechanisms:

• Absence of glycation-prone head groups (such as ethanoalamine) from hyperthermophilic phospholipids

Disruption of the Maillard process at its early stages, rather than repair of damage caused by it at later stages, appears to be the preferred strategy in the organisms examined. The most unique among these mechanisms appears to be a polyamine-based scavenging system. Undertaking research of the Maillard process in hyperthermophiles is important in its own right and is also likely to provide new insights for the control of these reactions in humans, especially in diseases such as diabetes mellitus.

The pineal hormone melatonin plays a major role in circadian sleep–wake rhythm in many mammals, including humans. Patients with acute confusional state or delirium, especially those with underlying cognitive impairment, frequently suffer from sleep disturbances and disturbed circadian rhythm. In this review, an overview is given of delirium and delirium symptoms that correspond with symptoms in dementia, such as sundowning, followed by a presentation of the circadian rhythm disorders in delirium in relation to melatonin deficiency. Finally, this review examines the therapeutic benefit of melatonin treatment in disorders related to delirium and dementia, including the placebo-controlled randomized clinical trials addressing this topic.

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant steroids in humans. DHEA levels fall with age in men and women, reaching values sometimes as low as 10%–20% of those encountered in young individuals. This age-related decrease suggests an “adrenopause” phenomenon. Studies point toward several potential roles of DHEA, mainly through its hormonal end products, making this decline clinically relevant. Unfortunately, even if positive effects of DHEA on muscle, bone, cardiovascular disease, and sexual function seem rather robust, extremely few studies are large enough and/or long enough for conclusions regarding its effects on aging. Moreover, because it has been publically presented as a “fountain of youth” equivalent, over-the-counter preparations lacking pharmacokinetic and pharmacodynamic data are widely used worldwide. Conceptually, supplementing a pre-hormone is extremely interesting, because it would permit the human organism to adequately use it throughout long periods, increasing or decreasing end products according to his needs. Nevertheless, data on the safety profile of long-term DHEA supplementation are still lacking. In this article, we examine the potential relation between low DHEA levels and well-known age-related diseases, such as sarcopenia, osteoporosis, dementia, sexual disorders, and cardiovascular disease. We also review risks and benefits of existing protocols of DHEA supplementation.

Trophocytes and fat cells of queen honeybees have been used for delayed cellular senescence studies, but their oxidative stress and anti-oxidant enzyme activities with advancing age are unknown. In this study, we assayed reactive oxygen species (ROS) and anti-oxidant enzymes in the trophocytes and fat cells of young and old queens. Young queens had lower ROS levels, lower superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, and higher thioredoxin reductase (TR) activity compared to old queens. These results show that oxidative stress and anti-oxidant enzyme activities in trophocytes and fat cells increase with advancing age in queens and suggest that an increase in oxidative stress and a consequent increase in stress defense mechanisms are associated with the longevity of queen honeybees.

Discovering the genetic origin of aging-related traits could greatly advance strategies aiming to extend health span. The results of genome-wide association studies (GWAS) addressing this problem are controversial, and new genetic concepts have been fostered to advance the progress in the field. A limitation of GWAS and new genetic concepts is that they do not thoroughly address specifics of aging-related traits. Integration of theoretical concepts in genetics and aging research with empirical evidence from different disciplines highlights the conceptual problems in studies of genetic origin of aging-related traits. To address these problems, novel approaches of systemic nature are required. These approaches should adopt the non-deterministic nature of linkage of genes with aging-related traits and, consequently, reinforce research strategies for improving our understanding of mechanisms shaping genetic effects on these traits. Investigation of mechanisms will help determine conditions that activate specific genetic variants or profiles and explore to what extent these conditions that shape genetic effects are conserved across human lives and generations.

This review synthesizes behavioral research with neuromolecular mechanisms putatively involved with the low-toxicity cognitive enhancing action of Bacopa monnieri (BM), a medicinal Ayurvedic herb. BM is traditionally used for various ailments, but is best known as a neural tonic and memory enhancer. Numerous animal and in vitro studies have been conducted, with many evidencing potential medicinal properties. Several randomized, double-blind, placebo-controlled trials have substantiated BM's nootropic utility in humans. There is also evidence for potential attenuation of dementia, Parkinson's disease, and epilepsy. Current evidence suggests BM acts via the following mechanisms—anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]). BM appears to exhibit low toxicity in model organisms and humans; however, long-term studies of toxicity in humans have yet to be conducted. This review will integrate molecular neuroscience with behavioral research.

Age-related functional alterations in the perforant path projection from the entorhinal cortex to the dentate gyrus (DG) of the hippocampus play a major role in age-related memory impairments, but little is known about the molecular mechanisms responsible for these changes. In a recent interesting study, Hara and colleagues (J Neurosci 2012;32:7336–7344) tested young and aged monkeys on the visual recognition memory test “delayed nonmatching-to-sample” (DNMS). Then they performed electron microscopy immunocytochemistry in the hippocampal DG to determine the subcellular localization of the GluA2 subunit of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) and protein kinase Mζ (PKMζ), which promotes memory storage by regulating GluA2-containing AMPAR trafficking. The results obtained suggest that age-related deficits in visual recognition memory are coupled with impairment in PKMζ-dependent maintenance of GluA2 at the synapse. Together with previous evidence of the critical role of PKMζ in memory consolidation, these data render this enzyme an attractive potential therapeutic target for preventing or treating age-related memory decline, and support the view that the pharmacological manipulation of AMPAR trafficking in the synapses may provide new insights in the search of memory enhancers for aged individuals, including those affected by Alzheimer disease.

Specific subtle changes in regulation or activity of factors that maintain homeostasis and cell differentiation may play significant roles in mammalian aging. Drift resulting from reaching the end of an organism's developmental program might involve a specific ordered set of changes. Several studies have suggested that dysfunctional changes associated with aging in skeletal muscle, neurons, and hematopoietic stem cells may be caused by specific changes either in the extracellular environment or in intracellular regulatory networks and that such dysfunction may be reversible. On the basis these data, Loffredo et al. hypothesized that extrinsic circulating factors in young mice might reverse cardiac aging. Parabiosis, the surgical linking of circulations between old and young mice, was employed to identify an anti-hypertrophic factor (growth differentiation factor 11 [GDF-11]) that appears to rejuvenate aging murine hearts, raising exciting prospects for the development of anti-aging therapeutics. However, much work remains to be done to evaluate the utility of GDF-11 as a therapeutic rejuvenation factor. Similar rejuvenating factors for diverse tissues may exist as well and will hopefully be identified in the near future.