Does the road to muscle rejuvenation go through Notch?

The capacity of skeletal muscles to repair and regenerate declines during aging in humans, and this decline may lead to muscle loss and frailty. Conboy et al. show that injured muscles of aging mice are defective in Notch signaling, because up-regulation of the Notch ligand, Delta-1, is impaired. Delta-1 promotes proliferation of the satellite cells that repair damaged muscles, and Conboy et al. show that experimental activation of Notch signaling is sufficient to reverse the age-related decline in muscle regenerative capacity. Extension of these important findings to humans could lead to the development of new therapeutic approaches to maintain muscle function during aging.     

Olfactory loss in aging

Olfactory loss is a common age-related complaint that may be caused by changes in the anatomy of the structures required for olfaction (for example, loss of olfactory receptor cells) or in the environment surrounding the receptor cell (for example, altered nasal mucus composition). However, aging, as well as age-related diseases and medications, may also alter the distribution, density, or function of specific receptor proteins, ion channels, or signaling molecules that affect the ability of neural elements throughout the olfactory pathway to signal and process odorant information. Although a great deal has been learned about the prevalence and nature of age-related olfactory loss, we are just beginning to explore avenues to prevent or alleviate this sensory deficit. Some studies suggest that, rather than being a necessary outcome of aging, age-associated factors such as chronic diseases, medications, and dental and sinus problems are the primary culprits in causing olfactory impairment. This idea suggests optimism in that, as we address these other age-related health issues, the prevalence of olfactory loss will lessen as well.     

Age-related effects on the zona glomerulosa cells of the rat adrenal cortex

Zona glomerulosa cells of the rat adrenal cortex were studied at 2, 6, 12, 18 and 24 months. Adrenals from unstimulated rats were processed for light and electron microscopy and trunk blood was obtained for the assay of plasma renin activity and aldosterone. Similar assays were made in rats stimulated with adrenocorticotropic hormone (ACTH), 30 min before sacrifice. At light microscopy, no major structural changes were observed; the ultrastructure of most organelles was well preserved and the presence of lipofuscin granules in older animals was remarkable. Acid phosphatase activity was observed in lysosomes and some lipofuscin granules. The quantitative study showed an age-related decrease in cell and nuclear volume (p < 0.01 and p < 0.001 respectively) and an increase in volume density of lipid droplets, lipofuscin granules (p < 0.001), lysosomes and Golgi complex; a decrease in volume density of mitochondria and smooth endoplasmic reticulum (p = 0.052) was also observed. Plasma renin activity and aldosterone level were both reduced (p < 0.001). In stimulated animals, an enhanced aldosterone level was obtained which was higher at 12 months and decreased thereafter. These results show an age-related decrease of aldosterone secretion, consistent with structural and ultrastructural data and related to plasma renin decrement. They also show a decline in the response to aldosterone stimulation by ACTH, indicating a lesser functional ability of zona glomerulosa cells in old animals.     

Gonadal steroids and visuo-spatial abilities in adult males: Implications for generalized age-related cognitive decline

The relationship between the gonadal steroids, testosterone and estrogen, and individual and group differences in performance on some cognitive tasks remains unclear but sex differences favoring males on some tests of visuo-spatial ability are large and robust. This aim of this review is to assess evidence for both organizational and activational effects of gonadal steroids as the principle cause of sex difference in visuo-spatial ability. Additionally, the implications of this relationship are discussed in the context of decreasing levels of gonadal steroids in aging males and psychological theories of generalized age-related cognitive decline. Based upon human and non-human research gonadal steroids have organizational effects on visuo-spatial ability in adulthood. Activational effects of gonadal steroids on visuo-spatial ability appear most dominant in older men and are necessary for maintaining optimal visuo-spatial ability; randomized clinical trials show that testosterone supplementation improves performance. Additionally, decreasing gonadal steroid levels in aging males may contribute to generalized age-related cognitive decline. Future supplementation studies in men should attempt to control for constituent abilities related to visuo-spatial task performance, and investigate interactions between dosage levels and baseline gonadal status. Further future animal research is required to investigate changes in gonadal steroid levels and their relationship to neurotransmitter systems, neural plasticity, and behavioral correlates.     

Aging effects on joint proprioception: the role of physical activity in proprioception preservation

Throughout the human life span the functions of several physiological systems dramatically change, including proprioception. Impaired proprioception leads to less accurate detection of body position changes increasing the risk of fall, and to abnormal joint biomechanics during functional activities so, over a period of time, degenerative joint disease may result. Altered neuromuscular control of the lower limb and consequently poor balance resulting from changes in the proprioceptive function could be related to the high incidence of harmful falls that occur in old age subjects. There is evidence of proprioception deterioration with aging. Regular physical activity seems to be a beneficial strategy to preserve proprioception and prevent falls among older subjects. Some studies have demonstrated that the regular physical activity can attenuate age-related decline in proprioception. This paper reviews the evidence of age effects on joint proprioception. We will discuss the possible mechanisms behind these effects and the role of regular physical activity in the attenuation of age-related decline in proprioception.     

Hematopoietic stem cells and aging

Hematopoiesis is a process by which a single cell--called a hematopoietic stem cell (HSC)--has the proliferative potential to give rise to all of the major lineages of blood and immune cells. Stem cells can undergo both symmetric division, which results in two copies of the parent stem cell, and asymmetric division, which results in self-renewal of the parent stem cell as well as production of a daughter cell that is capable of differentiating along a specific lineage. A number of different elements of HSC replication change with age, even though these transformations do not appear to result in hematopoietic deficiencies under normal circumstances. In this Perspective, the author discusses these age-related alterations.     

State ideology and the status of Iranian war widows

Imbedded in widowhood are emotional loss and change in personal life. For women, depending on social constructions of gender relations, widowhood can also lead to identity change, role adjustment and change in social status. Socio-economic and emotional supports rendered by family, community and society at large can highly impact widows in coping with change and making adjustments. These changes and the corresponding societal supports find new dimensions for ‘war widows’. The political nature of their widowhood may provide them with some benefits not enjoyed by non-war widows. As a token of public gratitude, political regimes compensate war widows and their children for their losses. Some political regimes weave political ideology into their compensatory programs, and through these programs they simultaneously raise widows' self-sufficiency and control their lives and thoughts. The specific case of the Islamic Republic of Iran will be examined here.     

Exploiting proteomics in the discovery of drugs that target mitochondrial oxidative damage

To understand how oxidative stress contributes to aging and age-related diseases and to better evaluate the therapeutic effect of antioxidant drugs, it would be highly desirable to have a comprehensive and detailed readout of the types of oxidative damage that occur to proteins at a global or proteome level. In this Perspective, I examine how proteomics, defined here as the science of examining all proteins in an organelle, cell, or tissue in the context of biological phenomena, can be used to provide molecular details of mitochondrial protein oxidative damage. Specifically, I discuss approaches that combine knowledge of the mitochondrial proteome with newer mass spectrometry-based techniques that are capable of identifying proteins and sites of oxidative modification in a high-throughput manner.     

The ageless question--what accounts for age-related cognitive decline?

Recent studies have provided partial insight into mechanisms underlying age-related declines in brain function. However, precisely where in the brain these changes occur is not entirely clear. A new report suggests that the hippocampal dentate gyrus may be the earliest locus of age-related memory decline.     

Mouse and human cells versus oxygen

Mice and humans are at opposite ends of the mammalian spectrum of longevity. A major question in biology is whether this difference can be accounted for by differences in the properties of cells from these two species. A new publication from Judith Campisi's lab reports that human cells in culture are more resistant than mouse cells to the damaging effects of 20% oxygen. The greater burden of DNA damage sustained by mouse cells causes them to rapidly enter a phase of culture in which most cells enter permanent growth arrest (replicative senescence). However, some mouse cells usually escape from senescence and then grow into an immortal cell line. This never happens in human fibroblast cell cultures. Human cells also eventually enter replicative senescence in culture, but this phenomenon is caused by shortening of telomeres and not by DNA damage of the type responsible for mouse cell senescence. Human fibroblasts never spontaneously escape from senescence. This Perspective reviews differences between mouse and human cells that could account for these differences in behavior. Some evidence indicates that human cells are generally more resistant than mouse cells to oxidative damage to DNA, but more needs to be done to confirm this finding and to understand the underlying mechanisms. Whether or not there are differences in the amount of DNA damage caused by oxygen or in the early phase of repair, there may be important differences in the later consequences of DNA damage. Mouse cells appear to be able to continue to divide with DNA damage that has not been repaired or has been misrepaired, and becomes fixed in the form of chromosomal abnormalities. The checkpoints that cause cells to stop dividing when chromosomes develop abnormalities (aberrations or shortened telomeres) appear to operate more efficiently in human cells. Much more work is needed to understand the basis for these differences and the implications for aging and cancer.     

Age-related slowing of movement as basal ganglia dysfunction

Attributions of age-related deficits in motor function to structural changes are compromised once the elderly exhibit lower error rates. This is because performance decrements observed in older adults are attributed to inferred strategic preferences for accuracy over speed. To understand genuine age differences in performance, we argue in the following theoretical paper that research needs to resolve methodological shortcomings and account for them within theoretical models of aging. Accounts of aging need to directly manipulate or control strategic differences in performance while assessing structural deficits. When this is done, age-related changes in motor control resemble the intermittencies of control seen in basal ganglia disorders. Given homologous circuitry in the basal ganglia, such observations could generalize to age-related changes in cognitive and emotional processes.     

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25?mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while β-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment.

The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and β-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain.

In conclusion, the present study demonstrates that 25?mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.     

Neuropathology in Alzheimer's disease: awaking from a hundred-year-old dream

For one hundred years after Alois Alzheimer's first report of Alzheimer's disease (AD) in 1906, the pathological hallmarks of the disease, senile plaques and neurofibrillary tangles (NFTs), have been attractive targets for researchers. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the cell biology of amyloid-beta (Abeta) deposition as senile plaques or on the phosphorylation and aggregation of tau as NFTs. However, it now appears that this focus on pathology as a central contributor to disease may be misguided. Indeed, neurons associated with Abeta and NFTs in AD brain show a decrease in oxidative damage relative to those in vulnerable but morphologically intact areas of the brain, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. That Abeta and tau accumulations indicate an age-related physiological reaction to chronic stress calls into question the rationale of current therapeutic efforts targeted toward lesion removal. Moreover, if this concept holds true for pathology in other neurodegenerative diseases, we may need to restructure our thinking and undergo a paradigm shift before substantial progress can be made in therapeutic intervention.     

Hypertension in aging: physical activity as primary prevention

In most physiologic systems, there is considerable evidence that the normal aging processes do not result in significant impairment or dysfunction in the absence of pathology and under resting conditions. However, in response to a stress, the age-related reduction in physiologic reserves causes a loss of regulatory or homeostatic balance. This happens before an individual notices that something is wrong. An additional consequence of age-related changes is an increased perception of effort associated with submaximal work. Thus, a vicious cycle is set up, leading to decreasing exercise capacity, resulting in an elevated perception of effort, subsequently causing avoidance of activity, and finally feeding back to exacerbation of the age-related declines secondary to disuse. Sedentary behavior is an important risk factor for chronic disease morbidity and mortality in aging. However, there is a limited amount of information on the type and amount of activity needed to promote optimal health and function in older people [19]. The purpose of this review is to discuss the important role of exercise training as a primary prevention tool to hypertension. In addition, this review will address the topic of the recommended amount of physical activity required for health promotion along with the current exercise guidelines.     

Not All Laws are Created Equal: Legal Differences in State Non-Discrimination Laws and the Impact of LGBT Employment Protections

In this paper, I study the impact of legal differences in state employment nondiscrimination acts (ENDAs) for gay men and lesbian women on labor market outcomes. Employing a DDD approach, I show that enacting an employment non-discrimination act is associated with increased wages of gay men and decreased employment of lesbian women. If all employment non-discrimination acts are treated as identical, these laws increased the hourly wages of gay men by 2.7% and decreased the employment of lesbian women by 1.7% and their hours worked by 0.7 hours. The results show that the strength of the law can result in heteroge-neous effects of the laws for gay men, but not for lesbian women. ENDAs with both punitive and compensatory damage provisions resulted in smaller wage increases for gay men than ENDAs with only compensatory damage provisions. ENDAs with longer statutes of limitations for complaints increased the employment of gay men, whereas laws with shorter statutes of limitations decreased employment. Based on the estimates from the state-level employment non-discrimination acts, I argue that extending federal protections under Title VII would lead to a small increase in the wages of gay men, but would significantly reduce the employment of lesbian women.     

Alterations in IGF-I affect elderly: role of physical activity

The growth hormone–insulin-like growth factor I (IGF-I) axis is an important physiological regulator muscle for development. Although there is evidence that aging muscle retains the ability to synthesize IGF-I, there is also evidence that aging may be associated with attenuation of the ability of exercise to induce an isoform of IGF-I that promotes satellite cell proliferation. However, it is clear that overexpression of IGF-I in the muscle can protect against age-related sarcopenia. Strength training appears to be the intervention of choice for the prevention and treatment of sarcopenia. IGF-I has been implicated in the loss of the muscle with age, and IGF-I expression levels change as a consequence of strength training in older adults. However, it seems that advancing age, rather than declining serum levels of IGF-I, appears to be a major determinant of life-time changes in body composition in women and men. We concluded that resistive exercise is a significant determinant of muscle mass and function. Elevated levels of IGF-I have been found in physically active compared to sedentary individuals. Recent work suggests that IGF-I as a mediator plays an important role in muscle hypertrophy and angiogenesis, both of which characterize the anabolic adaptation of muscles to exercise.     

STATUS CHANGE AND PERSISTENCE IN CHICAGO SUBURBS: MULTIPLE PATTERNS OF CAUSATION*

An examination of 1970–1980 census data for suburban Chicago indicates that, within the context of persisting inequities, causal links between community characteristics and status change vary by initial status. Individual change in the relative rankings of initially affluent communities is a direct function of housing age and location; residential development and changes in population size have little or no effect on this process. In contrast, cyclical growth is the primary determinant of status change among places of lesser initial affluence. Within the larger context of centrifugal drift and age-related growth cycles, stronger growth and resulting status improvements occur in accessible, underdeveloped newer places that, due to recent suburbanization, have already attained somewhat higher rankings.     

Functions of eukaryotic DNA polymerases

A major function of DNA polymerases is to accurately replicate the six billion nucleotides that constitute the human genome. This task is complicated by the fact that the genome is constantly challenged by a variety of endogenous and exogenous DNA-damaging agents. DNA damage can block DNA replication or alter base coding potential, resulting in mutations. In addition, the accumulation of damage in nonreplicating DNA can affect gene expression, which leads to the malfunction of many cellular processes. A number of DNA repair systems operate in cells to remove DNA lesions, and several DNA polymerases are known to be the key components of these repair systems. In the past few years, a number of novel DNA polymerases have been discovered that likely function in replicative bypass of DNA damage missed by DNA repair enzymes or in specialized forms of repair. Furthermore, DNA polymerases can act as sensors in cell cycle checkpoint pathways that prevent entry into mitosis until damaged DNA is repaired and replication is completed. The list of DNA template-dependent eukaryotic DNA polymerases now consists of 14 enzymes with amazingly different properties. In this review, we discuss the possible functions of these polymerases in DNA damage repair, the replication of intact and damaged chromosomes, and cell cycle checkpoints.     

Mapping Prefrontal Cortex Functions in Human Infancy

It has long been thought that the prefrontal cortex, as the seat of most higher brain functions, is functionally silent during most of infancy. This review highlights recent work concerned with the precise mapping (localization) of brain activation in human infants, providing evidence that prefrontal cortex exhibits functional activation much earlier than previously thought. A systematic evaluation of the activation patterns in these neuroimaging studies mainly based on functional near‐infrared spectroscopy reveals that prefrontal cortex function can be broadly divided into two distinct anatomical clusters with different functional properties. One cluster of activations falls within the region of the medial prefrontal cortex and is mainly involved in affective processes; another cluster is located in lateral aspects of the prefrontal cortex and shows sensitivity to cognitive processes such as memory and attention. This distinction is in line with adult data and evolutionary models and may represent a developmentally continuous organization principle of prefrontal cortex function. All in all, this review is aimed at providing a synthesis of new findings that are emerging from the use of neuroimaging techniques with infants as well as at encouraging further theory‐driven research to understand the developmental origins of prefrontal cortex function.     

Age-related variations in the growth hormone response to growth hormone secretagogues

Growth hormone (GH) secretagogues are synthetic peptidyl and non-peptidyl molecules which possess a strong, dose-dependent and reproducible GH-releasing effect after intravenous and even oral administration in humans. This effect is probably mediated via the activation of specific receptors, mainly present at the pituitary and hypothalamic level; a human pituitary GH secretogogue receptor has already been cloned, pointing to the existence of an endogenous GH secretagogue-like ligand. The GH-releasing effect of GH secretagogues is gender-independent but undergoes marked age-related variations. In fact, the effect is low at birth, increases markedly at puberty, persists at a similar level in adulthood and decreases thereafter, being already similar in middle age to that in elderly subjects. It is likely that the reduced activity of GH secretagogues in aging reflects the age-related changes in the neural control of somatotrope function. These could include the hypothetical impairment in the activity of the putative natural GH secretagogue-like ligand. Prolonged treatment with non-peptidyl GH secretagogues has been shown to restore spontaneous GH pulsatility and insulin-like growth factor I (IGF-I) levels in aged humans as well as in animals. The possibility that chronic treatment with GH secretagogues in aging rejuvenates the activity of the GH/IGF-I axis and counteracts the age-related changes in body composition, structure functions and metabolism seems very attractive.