Biological aging and the etiology of aneuploidy

A prevalent hypothesis concerning the cause of the rise in aneuploid conceptions with maternal age is that the changes that accompany normal ovarian aging increase the rate of meiotic errors in the oocyte. Biological aging of the ovary is accompanied by a decline in both the total oocyte pool and the number of antral follicles maturing per cycle, as well as changes in the levels of circulating reproductive hormones. The biological aging hypothesis predicts that aneuploidy rates should be higher in women with a prematurely reduced oocyte pool, and that women with trisomic conceptions should show signs of earlier ovarian aging than women of the same chronological age without trisomic conceptions. Comprehensive studies of aneuploidy in groups of women with known causes of premature ovarian failure remain to be done, though anecdotal evidence does suggest increased rates of pregnancy loss and aneuploidy. Smoking, which is a well-documented cause of earlier ovarian aging, is not associated with an increase in aneuploid conceptions. Evidence from women with unilateral ovariectomies is inconsistent. Support for the biological aging hypothesis was provided by one study showing that menopause occurred about a year earlier in women with a trisomic spontaneous abortion compared to women with chromosomally normal conceptions. Associations between high FSH and pregnancies with Down syndrome and chromosomally abnormal spontaneous abortions have also been reported. However, the most direct test of the hypothesis, which compared antral follicle counts and hormonal levels in women with trisomic pregnancies and those with chromosomally normal pregnancies, failed to find a difference in the expected direction. A prospective study of FSH levels in women with subfertility also failed to find an association with the rate of pregnancy loss. The bulk of evidence thus suggests that, if the processes of biological aging are indeed related to aneuploidy, they probably involve factors other than those measured by oocyte or antral follicle pool size and reproductive hormone levels.     

On the etiology of interproximal grooves

The recent suggestion by Brown and Molnar (1990) that the common etiology of sinew processing is responsible for the production of interproximal tooth grooves is contested. Based on a review of the Australian evidence and presentation of a previously undescribed dentition from Central Europe, it is argued toothpicks are a likely cause of many artificial grooves in human teeth.     

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.     

On the evolutionary origin of aging

It is generally believed that the first organisms did not age, and that aging thus evolved at some point in the history of life. When and why this transition occurred is a fundamental question in evolutionary biology. Recent reports of aging in bacteria suggest that aging predates the emergence of eukaryotes and originated in simple unicellular organisms. Here we use simple models to study why such organisms would evolve aging. These models show that the differentiation between an aging parent and a rejuvenated offspring readily evolves as a strategy to cope with damage that accumulates due to vital activities. We use measurements of the age-specific performance of individual bacteria to test the assumptions of the model, and find evidence that they are fulfilled. The mechanism that leads to aging is expected to operate in a wide range of organisms, suggesting that aging evolved early and repeatedly in the history of life. Aging might thus be a more fundamental aspect of cellular organisms than assumed so far.     

On the etiology of contact/occupational vitiligo

Vitiligo is an acquired depigmentary disorder of the skin that results from the selective destruction of melanocytes, generally during the second decade of life and affecting approximately 1% of the population worldwide. Loss of cutaneous pigment appears to render the skin susceptible to premature aging and cancer. In addition this disease can be socially devastating for afflicted individuals. The etiology of vitiligo is poorly understood. The present dogma suggests that genetic factors render the melanocyte fragile thus predisposing individuals to developing vitiligo. When subjected to instigating factors, these susceptible, fragile melanocytes undergo apoptosis. Autoimmune factors then perpetuate the removal of the melanocyte component from the skin. In the majority of cases the instigating factors are not known (idiopathic vitiligo), however a small sub-set of individuals develop contact/occupational vitiligo following exposure to particular chemicals. Many of these chemicals have been implicated in both contact/occupational vitiligo and chemical leukoderma. Both conditions present with well-defined, depigmented skin lesions that develop following exposure. Only in the case of vitiligo does the depigmentation spread beyond the areas of contact, probably via an immune-mediated mechanism. The largest class of chemicals known to trigger contact/occupational vitiligo is the phenolic/catecholic derivatives. Many have been demonstrated to be preferentially cytotoxic to melanocytes, with high-dose exposure resulting in the initiation of apoptosis. Phenolic/catecholic derivatives are structurally similar to the melanin precursor tyrosine, and therefore tyrosinase was originally implicated as a mediator of cytotoxicity. However, our data suggests that tyrosinase-related protein-1, rather than tyrosinase, facilitates toxicity, possibly by catalytic conversion of the compounds, which results in the generation of radical oxygen species. The ensuing oxidative stress then triggers activation of cellular free radical scavenging pathways to prevent cell death. Genetic inability of melanocytes to tolerate and/or respond to the oxidative stress may underlie the etiology of contact/occupational vitiligo.     

On the epidemiology and etiology of pneumonia in adults

In a group of 74 hospitalized patients with the diagnosis of acute infectious pneumonia, the etiological contribution of viral and bacterial agents is analyzed in cases of clarified etiology and an assessment is made of the relationship between the explained etiology and the overall epidemiological situation. Etiology was clarified in 36 patients (48.6%). Viral and bacterial etiology was confirmed in 13.3% and 39.8% of the entire group respectively. In three cases, mixed viral and bacterial infection was reported. Most prominent among the viral agents were herpes simplex, parainfluenza, respiratory syncytial and influenza type B viruses. As far as the bacterial agents were concerned, the species most frequently isolated were Staphylococcus aureus, Streptococcus pneumoniae and a variety of Enterobacteriaceae. The relationship between the overall epidemiological situation and pneumonia etiology is discussed as well as the relevance of the diagnostic methods employed.     

On the mechanism of aging in soybean seeds

Changes in seeds of soybeans (Glycine max [L.] Merr. var. Wayne) which occur during accelerated aging (41 C, 100% relative humidity) showed subsequent loss of vigor, a decline in early respiratory activity, increased leakage of electrolytes, losses of as much as 10% dry weight from imbibing cotyledons, and a decrease in the swelling response of the imbibing system (seed plus H₂O). Each of these changes with aging is interpreted as resulting from deteriorative changes in membranes.     

On the programmed/non-programmed aging controversy

The programmed vs. non-programmed aging controversy has now existed in some form for at least 150 years. For much of the XX century, it was almost universally believed that evolution theory prohibited programmed (adaptive) aging in mammals and there was little direct experimental or observational evidence favoring it. More recently, multiple new evolutionary mechanics concepts that support programmed aging and steadily increasing direct evidence favoring it overwhelmingly support the existence of programmed aging in humans and other organisms. This issue is important because the different theories suggest very different mechanisms for the aging process that in turn suggest very different paths toward treating and preventing age-related diseases.     

On the role of aging in cancer incidence

All tumors classified by the Connecticut Tumor Registry which had a single peak incidence at age greater than 50 were found to have similar patterns of incidence as a function of age. The average of all such patterns was described by an equation of the form log incidence = m(age) + b, where m and b are constants. This equation suggests that the tumors in this study could all be related to a common physiological property such that the number of tumors in the population described the status of this property and the status of this property determined the number of tumors. A similar equation describes the incidence of death from all causes as a function of age. We suggest that the incidence of both cancer and death in general are related to a common physiological property and that this property is the integrity of the genome.     

On the cause of aging and control of lifespan

What the causes of aging are and which factors define lifespan are key questions in the understanding of aging. Here, it is argued that cellular life involves (i) inevitable accumulation of damage resulting from imperfectness and heterogeneity of every cellular process, and (ii) dilution of damage when cells divide. While severe damage is cleared by protective systems, milder damage can only be diluted. This is due to the high cost of accuracy, the greater number of damage forms compared to protective systems, and the constraints on cellular life inherited from the prokaryotic world. This strategy also applies to cancer cells, which are particularly dependent on damage dilution. Imposing restriction on cell division necessarily leads to aging. Interventions that extend lifespan act through metabolic reprogramming, thereby changing both damage composition and the rate of damage accumulation. Thus, heterogeneity leading to myriad mild damage forms represents the cause of aging, whereas the processes that affect the damage landscape and damage accumulation are lifespan regulators.     

On the nature and function of yellow aging pigment lipofuscin

A comparison of lipofuscin granules from warm-blooded animals and carotenoid-containing granules (cytosomes) from molluscoid neurons was carried out. It was confirmed that the carotenoids are a component of the lipofuscin granules. Data in literature and the experimental data obtained showed that the lipofuscin granules contained carotenoids, myoglobin and some respiratory enzymes.On the basis of identification of the properties of carotenoid-containing granules (cytosomes) of molluscoid neurones and the lipofuscin granules, it is proposed that the functions of the lipofuscin are those of forming the intracellular oxygen stock and providing the energy requirements of the cells under the conditions of low rate oxygen penetration into tissues.     

On the importance of fatty acid composition of membranes for aging

The membrane pacemaker theory of aging is an extension of the oxidative stress theory of aging. It emphasises variation in the fatty acid composition of membranes as an important influence on lipid peroxidation and consequently on the rate of aging and determination of lifespan. The products of lipid peroxidation are reactive molecules and thus potent damagers of other cellular molecules. It is suggested that the feedback effects of these peroxidation products on the oxidative stress experienced by cells is an important part of the aging process. The large variation in the chemical susceptibility of individual fatty acids to peroxidation coupled with the known differences in membrane composition between species can explain the different lifespans of species, especially the difference between mammals and birds as well as the body-size-related variation in lifespan within mammals and birds. Lifespan extension by calorie-restriction can also be explained by changes in membrane fatty acid composition which result in membranes more resistant to peroxidation. It is suggested that lifespan extension by reduced insulin/IGF signalling may also be mediated by changes in membrane fatty acid composition.