Current Aging Science - Volume 3, Issue 1, 2010

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The accumulation of DNA damage has been widely implicated in premature aging and neurodegeneration. Progeroid syndromes with defects in the cellular response to DNA damage suggest that progressive genome instability represents an important aspect of the aging process. Moreover, most of the major neurodegenerative diseases are characterized by the accumulation of neuronal DNA damage, suggesting that impaired DNA repair mechanisms might be relevant to both premature aging and neurodegeneration. Two progeroid syndromes, Hutchinson-Gilford progeria syndrome and Werner's syndrome, are characterized by clinical features mimicking physiological aging at an early age and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases. Defects in nucleotide excision repair cause three distinct human diseases: xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy; each of them is characterized by premature onset of pathologies that overlap with those associated with old age in humans. Increasing evidence also suggests that an impaired DNA repair, particularly the base excision repair pathway, might play a fundamental role in the development of age-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington' s disease. Here, we review the current knowledge on the role of DNA repair in premature aging and neurodegenerative diseases.

Age-related hearing loss (AHL), also known as presbycusis, is a universal feature of mammalian aging and is the most frequently occurring sensory disorder in the elderly population. AHL is characterized by a decline of auditory function and loss of hair cells and spiral ganglion neurons in the cochlea of the inner ear. It has been postulated that AHL occurs gradually as a result of the cumulative effect with aging of exposure to noise, diet, oxidative damage, and mitochondrial DNA mutations. However, the molecular mechanisms of AHL remain unclear and no preventative or therapeutic interventions have been developed. A growing body of evidence suggests increased oxidative damage with aging to macromolecules such as DNA, proteins, and lipids may play a causal role in aging and age-related diseases. Caloric restriction (CR) extends the lifespan of most mammalian species, delays the onset of multiple age-related diseases, and attenuates both the degree of oxidative damage and the associated decline in physiological function. Here, we review studies on CR's ability to prevent cochlear pathology and AHL in laboratory animals and discuss potential molecular mechanisms of CR's actions.

In cartilage regenerative medicine, which is highly expected in the face of our aging society, insulin is the potent factor for culture media. To secure the safety of culture media, we attempted to use medical insulin formulations, and compared their effects on human articular or auricular chondrocytes between regular human insulin (R) and neutral protamine hagedorn insulin (N). In monolayer culture with the media containing either R or N, the cell growth reached approximately 15-fold-increase in 6 days, which showed no significant difference between them. These cells showed the equivalent ability to produce cartilage matrices, both in vitro and in vivo. Also, in the 3D culture of the dedifferentiated chondrocytes, either R or N increased gene expression of type II collagen at 3-4 folds in the combination with other growth factors, compared with basal medium, while insulin could similarly enhance both the redifferentiation and cartilage maturation. The in vitro half-life of each insulin in the presence of chondrocytes neither decreased within 3 days, suggesting little degradation in the culture media, unlike in the body. Although both R and N showed similar biological effects on cultured chondrocytes, we may choose the R for clinical practice because of its pure composition.

Age-associated changes within an individual are inherently complex and occur at multiple levels of organismal function. The overall decline in function of various tissues is known to play a key role in both aging and the complex etiology of certain age-associated diseases such as Alzheimer's disease (AD) and cancer. Continuing research highlights the dynamic capacity of polyphenols to protect against age-associated disorders through a variety of important mechanisms. Numerous lines of evidence suggest that dietary polyphenols such as resveratrol, (-)-epigallocatechin-3-gallate (EGCG), and curcumin have the capacity to mitigate age-associated cellular damage induced via metabolic production of reactive oxygen species (ROS). However, recently acquired evidence also demonstrates a likely role for these polyphenols as anticancer agents capable of preventing formation of new vasculature in neoplastic tissues. Polyphenols have also been shown to possess other anticancer properties such as specific cell-signaling actions that may stimulate the activity of the regulatory protein SIRT1. Additionally, polyphenolic compounds have demonstrated their inhibitory effects against chronic vascular inflammation associated with atherosclerosis. These increasingly well-documented results have begun to provide a basis for considering the use of polyphenols in the development of novel therapies for certain human diseases. And while the mechanisms by which these effects occur are yet to be fully understood, it is evident that further investigation may yield a potential use for polyphenols as pharmacological interventions against specific age-associated diseases.

The zebrafish (Danio rerio) has recently become a mainstream model system for genetic studies of human diseases, such as neurological degenerative diseases, heart diseases, immuno-system disorders, etc. In this article, we will review some recent findings of the usefulness of zebrafish as a model vertebrate for behavioral screening of mutations in vertebrate visual system, for example, genes involved in age-related retinal degeneration.

The two major neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular Amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). A number of additional pathogenic mechanisms, possibly overlapping with Aβ plaques and NFTs formation, have been described, including inflammation, oxidative damage, iron disregulation, cholesterol metabolism. The first drugs developed for AD, anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed “disease modifying” drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms. In this review, current treatment will be summarized and new perspectives discussed. In particular, several approaches will be described, including Aβ deposition interference by Anti-Aβ aggregation agents, vaccination, β- secretase inhibition or Selective Aβ42-lowering agents (SALAs); tau deposition interference by methyl thioninium chloride (MTC); reduction of inflammation and oxidative damage.

The relationship between diet and cognitive function has been a topic of increasing interest, as numerous studies have shown that variations in dietary practices and nutrient intake may protect against age-related cognitive decline, as well as the development of dementia and Alzheimer's Disease (AD). Various dietary practices and specific nutrient components of these diets have been examined in relation to cognitive performance including 1) dietary fatty acids (including fish oil) and the Mediterranean diet, 2) antioxidants (including vitamins E and C) and fruits and vegetables, 3) vitamins B6, B12 (cobolamine), and folate, and, more recently, 4) caloric restriction. Although observational studies have generally reported significant associations between dietary practices and reduced incidence of cognitive dysfunction, randomized trials of dietary interventions have yielded mixed findings, with many trials yielding small gains or equivocal findings. In addition, findings appear to vary based on sample characteristics, methods of dietary assessment, and length of study follow-up. The influence of dietary practices on cognitive function in middle aged and older adults remains uncertain, and further research is needed to clarify the nature of this relationship and identify mechanisms by which diet may affect neurocognition.

Background: The aim of the study was to evaluate correlation of breath holding index (BHI) as functional parameter for intracranial subclinical atherosclerotic changes - we have shown in our previous works and arterial stiffness (AS-functional parameter for extracranial subclinical atherosclerotic changes) in normal population. Patients and Methods: We included 120 healthy volunteers (conventional risk factors for cerebrovascular disease were excluded) who were examined at our Neurology Department. They were divided into 6 age groups-(25-35, 36-45, 46-55, 56-65, 66-75, 76+ years). We performed standard laboratory workup, body weight and height measurements, Color Doppler and Power Doppler of the main head and neck vessels and Transcranial Doppler, (measured by means of e-Tracking software). Results: There was decline of BHI, and increase in AS - in correlation with age increase (p<0.01). There was statistically significant negative correlation between BHI and AS (r= -0,931, p<0.01 right and r = -0,938, p<0.01 left). Conclusion: These results show that decline in BHI as parameter for intracranial microvessel dysfunction is in good correlation with increase of AS as functional parameter of extracranial vascular aging.

This paper offers a conceptual framework that focuses on “care-getting”, a proactive means of insuring responsive and high quality care that is necessary for maintenance of good quality of life during the final years of life. Unlike traditional formulations and empirical studies that consider end of life issues among the terminally ill, we call for a broader consideration of the final years of life among older adults experiencing different health trajectories. We expect frail older adults' dispositions, proactive adaptations, and responsiveness of their informal and formal social resources, to play key roles in achieving good quality of life close to the end of life. Such positive outcomes near the end of life help preserve the integrity of the person and contribute to a sense of being cared for [1]. The conceptual framework we propose is a necessary next step for social gerontology, in order to incorporate preparation for dying into the life course. This important final life stage has been previously neglected in gerontological life course theory. Cross-cultural considerations in getting responsive care close to the end of life are discussed.

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