Songbirds: A novel perspective on estrogens and the aging brain

Songbirds perform some remarkable feats of memory, including forming memories for songs and for complex spatial features of their environments. Research into the neural and hormonal control of these behaviors reveals discrete circuits that can retain considerable plasticity in adulthood. The songbird brain is also a prominent site of estrogen synthesis and a target of estrogen action. Estrogens contribute to the plasticity of the adult songbird brain and contribute to the bird's capacity to form and retrieve some memories. We describe the brain, behavior and endocrinology of songbirds and discuss these findings within the context of the neurology of the aging brain.     

Cell aging in vitro: a historical perspective

This article describes the historical background to the demonstration by Hayflick and Moorhead that human diploid cell strains in culture have limited life-spans. I suggest that the recognition of cell aging in vitro is an example from the biological sciences of a Kuhnian scientific revolution.     

The biology of cancer stem cells and its clinical implication in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumor with limited treatment options in its advanced state. The molecular mechanisms underlying HCC remain unclear because of the complexity of its multi-step development process. Cancer stem cells (CSCs) are defined as a small population of cells within a tumor that possess the capability for self-renewal and the generation of heterogeneous lineages of cancer cells. To date, there have been two theories concerning the mechanism of carcinogenesis, i.e., the stochastic (clonal evolution) model and the hierarchical (cancer stem cell-driven) model. The concept of the CSC has been established over the past decade, and the roles of CSCs in the carcinogenic processes of various cancers, including HCC, have been emphasized. Previous experimental and clinical evidence indicated the existence of liver CSCs; however, the potential mechanistic links between liver CSCs and the development of HCC in humans are not fully understood. Although definitive cell surface markers for liver CSCs have not yet been found, several putative markers have been identified, which allow the prospective isolation of CSCs from HCC. The identification and characterization of CSCs in HCC is essential for a better understanding of tumor initiation or progression in relation to signaling pathways. These markers could be used along with clinical parameters for the prediction of chemoresistance, radioresistance, metastasis and survival and may represent potential targets for the development of new molecular therapies against HCC. This review describes the current evidence for the existence and function of liver CSCs and discuss the clinical implications of CSCs in patients demonstrating resistance to conventional anti-cancer therapies, as well as clinical outcomes. Such data may provide a future perspective for targeted therapy in HCC.     

Mechanical factors in arterial aging: a clinical perspective

The human arterial system in youth is beautifully designed for its role of receiving spurts of blood from the left ventricle and distributing this as steady flow through peripheral capillaries. Central to such design is "tuning" of the heart to arterial tree; this minimizes aortic pressure fluctuations and confines flow pulsations to the larger arteries. With aging, repetitive pulsations (some 30 million/year) cause fatigue and fracture of elastin lamellae of central arteries, causing them to stiffen (and dilate), so that reflections return earlier to the heart; in consequence, aortic systolic pressure rises, diastolic pressure falls, and pulsations of flow extend further into smaller vessels of vasodilated organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased stresses on small arterial vessels, particularly of brain and kidney. Clinical manifestations are a result of diastolic LV dysfunction with dyspnea, predisposition to angina, and heart failure, and small vessel degeneration in brain and kidney with intellectual deterioration and renal failure. While aortic stiffening is the principal cause of cardiovascular disease with age in persons who escape atherosclerotic complications, it is not a specific target for therapy. The principal target is the smooth muscle in distributing arteries, whose relaxation has little effect on peripheral resistance but causes substantial reduction in the magnitude of wave reflection. Such relaxation is achieved through regular exercise and with the vasodilating drugs that are used in modern treatment of hypertension and cardiac failure.     

Oxidative stress,antioxidants, hormesis and calorie restriction: The current perspective in the biology of aging

Aging, in a large measure, has long been defined as the resultant of oxidative stress acting on the cells. The cellular machinery eventually malfunctions at the basic level by the damage from the processes of oxidation and the system starts slowing down because of intrinsic eroding. To understand the initial destruction at the cellular level spreading outward to affect tissues, organs and the organism, the relationship between molecular damage and oxidative stress is required to understand. Retarding the aging process is a matter of cumulatively decreasing the rate of oxidative damage to the cellular machinery. Along with the genetic reasons, the decrease of oxidative stress is somehow a matter of lifestyle and importantly of diet. In the current review, the theories of aging and the understanding of various levels of molecular damage by oxidative stress have been emphasized. A broader understanding of mechanisms of aging have been elaborated in terms of effects of oxidative at molecular, mitochondrial, cellular and organ levels. The antioxidants supplementation, hormesis and calorie restriction as the prominent anti-aging strategies have also been discussed. The relevance and the efficacy of the antiaging strategies at system level have also been presented.     

A historical perspective of research on the biology of aging from Nathan W. Shock.

This article describes some of the thoughts and the conceptual framework from which Nathan W. Shock prepared his last major presentation. This paper, written some 8 months following Dr. Shock's death on November 12, 1989, is based upon his extensive notes and discussions with one of the authors (George T. Baker). This presentation in no way is meant to encapsulate the long and distinguished career of Nathan Shock, but rather to provide a glimpse of his perspectives on the development of the field of aging. Furthermore, we believe that the scientific principles concerning aging research laid out by Dr. Shock in this publication are still valid today and may provide valuable insights for researchers in the field.     

Targeting Wnt signaling pathway by polyphenols: implication for aging and age-related diseases

Biogerontology - Age is an important risk factor for different diseases. The same mechanisms that promote aging are involved in the development and progression of age-associated diseases....     

Quantifying dense bodies and lipofuscin during aging: a morphologist's perspective

Secondary lysosomes, residual or dense bodies containing lipofuscin or age pigment accumulate in post-mitotic and inter-mitotic cells during aging. The consensus is that the accumulation of this auto-fluorescent material is an index of cellular senescence. Biochemical and morphological studies have independently demonstrated marked age-related increases in the cell and tissue contents of lipofuscin. Most morphological studies on aging have been qualitative, have included only two or three age groups and have not yielded data that are easily correlated with biochemical analyses. One of the best documented age-related changes in hepatocytes and cardiac myocytes is the accumulation of dense bodies and lipofuscin inclusions. Independent stereologic studies reported two- to eightfold age-related increases in the dense body volume fraction of rat hepatocytes. Furthermore, we reported a fourfold increase in the dense body volume fraction of cardiac myocytes in rats between 6 and 30 months of age. These and other studies confirm the use of quantitative morphology to estimate the increases in dense body and lipofuscin inclusions as indices of age. Whether or not the accumulated lipofuscin compromises cell functions in senescent animals has not been adequately addressed. On the one hand, there is little evidence that several-fold increases in this subcellular compartment impair the functional capacities of either hepatocytes or cardiac myocytes. On the other hand, the age-related accumulation of immunoprecipitable, but catalytically inactive, lysosomal enzymes in both liver and heart muscle may be a reflection of increased lipofuscin deposits in the dense bodies.     

The menopause transition and the aging process: a population perspective

The menopause transition period, extending from active reproductive capacity with well-characterized hormone profiles through reproductive senescence, has been less well studied than any other period of the life span except extreme old age. Yet, for the gerontologist, this is an important period to understand for at least two reasons. First, during this period changes in the neuroendocrine system and ovary may provide a model for the study of other aging-related processes. Second, specific characteristics of this transitional period (including duration, intensity, and age at menopause) may be considered "aging", and influence short-term health and quality-of-life status, as well as life expectancy. In addition to discussing the menopause transition in terms of age and culture, we include some of the theories and conceptual models that can influence the nature and interpretation of information from this time period, and its ultimate impact on health and health practice.     

The molecular biology of pituitary tumors: a personal perspective

Oncogenes and tumor suppressor genes involved in most common cancers are not involved in the great majority of pituitary adenomas. Similarly, there is little evidence to suggest that the mutations involved in genetic syndromes associated with pituitary tumors (such as the gsp, MEN1, PKAR1A or AIP mutations) are common in sporadic tumors. A novel pituitary tumor transforming gene (PTTG, securin) has been identified which is over-expressed in most tumors—but it is unclear as to its causal role in oncogenesis. Cell signaling abnormalities have been identified in pituitary tumors but their genetic basis is unknown. However, both the Akt pathway and the MAPK pathway are over-expressed in many pituitary tumors, which results in the inhibition of cell cycle inhibitors. These pathways share a common root in the tyrosine kinase receptor, and a change to these receptors or their relationship to membrane matrix-related proteins may be an early event in tumorigenesis.     

Metabolic biology of 3-methylglutaconic acid-uria: a new perspective

Over the past 25 years a growing number of distinct syndromes/mutations associated with compromised mitochondrial function have been identified that share a common feature: urinary excretion of 3-methylglutaconic acid (3MGA). In the leucine degradation pathway, carboxylation of 3-methylcrotonyl CoA leads to formation of 3-methylglutaconyl CoA while 3-methylglutaconyl CoA hydratase converts this metabolite to 3-hydroxy-3-methylglutaryl CoA (HMG CoA). In “primary” 3MGA-uria, mutations in the hydratase are directly responsible for the accumulation of 3MGA. On the other hand, in all “secondary” 3MGA-urias, no defect in leucine catabolism exists and the metabolic origin of 3MGA is unknown. Herein, a path to 3MGA from mitochondrial acetyl CoA is proposed. The pathway is initiated when syndrome-associated mutations/DNA deletions result in decreased Krebs cycle flux. When this occurs, acetoacetyl CoA thiolase condenses two acetyl CoA into acetoacetyl CoA plus CoASH. Subsequently, HMG CoA synthase 2 converts acetoacetyl CoA and acetyl CoA to HMG CoA. Under syndrome-specific metabolic conditions, 3-methylglutaconyl CoA hydratase converts HMG CoA into 3-methylglutaconyl CoA in a reverse reaction of the leucine degradation pathway. This metabolite fails to proceed further up the leucine degradation pathway owing to the kinetic properties of 3-methylcrotonyl CoA carboxylase. Instead, hydrolysis of the CoA moiety of 3-methylglutaconyl CoA generates 3MGA, which appears in urine. If experimentally confirmed, this pathway provides an explanation for the occurrence of 3MGA in multiple disorders associated with compromised mitochondrial function.     

Mechanical factors in arterial aging: a clinical perspective.

The human arterial system in youth is beautifully designed for its role of receiving spurts of blood from the left ventricle and distributing this as steady flow through peripheral capillaries. Central to such design is "tuning" of the heart to arterial tree; this minimizes aortic pressure fluctuations and confines flow pulsations to the larger arteries. With aging, repetitive pulsations (some 30 million/year) cause fatigue and fracture of elastin lamellae of central arteries, causing them to stiffen (and dilate), so that reflections return earlier to the heart; in consequence, aortic systolic pressure rises, diastolic pressure falls, and pulsations of flow extend further into smaller vessels of vasodilated organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased stresses on small arterial vessels, particularly of brain and kidney. Clinical manifestations are a result of diastolic LV dysfunction with dyspnea, predisposition to angina, and heart failure, and small vessel degeneration in brain and kidney with intellectual deterioration and renal failure. While aortic stiffening is the principal cause of cardiovascular disease with age in persons who escape atherosclerotic complications, it is not a specific target for therapy. The principal target is the smooth muscle in distributing arteries, whose relaxation has little effect on peripheral resistance but causes substantial reduction in the magnitude of wave reflection. Such relaxation is achieved through regular exercise and with the vasodilating drugs that are used in modern treatment of hypertension and cardiac failure.     

The interdependence of skin aging, skin cancer, and DNA repair capacity: a novel perspective with therapeutic implications

The human body is constantly exposed to exogenous and endogenous insults that threaten its genomic integrity and that lead to changes at the molecular, biochemical, and cellular levels. As a major interface between the environment and the internal milieu, our skin is especially subject to such events. Common insults include but are not limited to infectious agents, environmental pollutions and toxins, carcinogens, and ultraviolet (UV) irradiation. It is estimated that there are thousands of DNA alterations in each cell daily. Therefore, if not efficiently repaired, our genome would rapidly be destroyed. This review focuses predominantly on UV-induced DNA damage in human skin, protective molecular responses to UV damage, and the consequences of these opposing forces for aging and photocarcinogenesis.