Cellular senescence: A reflection of normal growth control,differentiation, or aging?

Normal cells, with few exceptions, cannot proliferate indefinitely. Cell populations--in vivo and in culture--generally undergo only a limited number of doublings before proliferation invariably and irreversibly ceases. This process has been termed the finite lifespan phenotype or cellular senescence. There is long-standing, albeit indirect, evidence that cellular senescence plays an important role in complex biological processes as diverse as normal growth control, differentiation, development, aging, and tumorigenesis. In recent years, it has been possible to develop a molecular framework for understanding some of the fundamental features of cellular senescence. This framework derives primarily from the physiology, genetics, and molecular biology of cells undergoing senescence in culture. Our understanding of senescence, and the mechanisms that control it, is still in its infancy. Nonetheless, recent data raise some intriguing possibilities regarding potential molecular bases for the links between senescence in culture and normal and abnormal growth control, differentiation, and aging.     

Liver diseases and aging: friends or foes?

The liver is the only internal human organ capable of natural regeneration of lost tissue, as little as 25% of a liver can regenerate into a whole liver. The process of aging predisposes to hepatic functional and structural impairment and metabolic risk. Therefore, understanding how aging could affect the molecular pathology of liver diseases is particularly important, and few studies to date have tackled this complex process. The most common liver disease, affecting one‐third of the overall population, is nonalcoholic fatty liver disease (NAFLD), characterized by an intrahepatic accumulation of lipids. NAFLD can evolve into nonalcoholic steatohepatitis (NASH) in the presence of oxidative stress and inflammation. NASH is a serious risk factor for disabling and deadly liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Old age seems to favor NAFLD, NASH, and ultimately HCC, in agreement with the inflamm‐aging theory, according to which aging accrues inflammation. However, the incidence of HCC drops significantly in the very elderly (individuals aged more than 70) and the relationship between the progression of NAFLD/NASH/HCC and very old age is obscure. In this review, we discuss the literature and we argue that there might be an age window in which the liver becomes resistant to the development of injury; this needs to be studied to understand fully the interaction between age and liver diseases from a therapeutic perspective.     

Short telomeres: cause or consequence of aging?

Questions about mechanisms, about the direction of causality, and about cellular heterogeneity complicate interpretation of claims associating short telomeres with adverse health outcomes.     

Mitochondria and aging: innocent bystanders or guilty parties?

There are many theories of aging and a number ofthem encompass the role of mitochondria in this process. Mitochondrial DNA mutations and deletions have been shown to accumulate in many tissues in mammals during aging. However, there is little evidence that these mutations could affect the functioning of aging tissues.     

The mitochondrial theory of aging: dead or alive?

The mitochondrial theory of aging is based around the idea of a vicious cycle, in which somatic mutation of mtDNA engenders respiratory chain dysfunction, enhancing the production of DNA-damaging oxygen radicals. In turn, this is proposed to result in the accumulation of further mtDNA mutations. Finally, a bioenergetic crisis leads to overt tissue dysfunction and degeneration. A substantial body of circumstantial evidence seems to support this idea. However, the extent of detectable mtDNA mutation is far less than can easily be reconciled to this hypothesis, unless it is assumed that a subset of cells with much higher than average mtDNA mutation load is systematically lost by apoptosis. A rigorous test of the hypothesis remains to be undertaken, but would require a direct manipulation of the rate of mtDNA mutagenesis, to test whether this could alter the kinetics of aging.     

Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging?

The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an “antiaging” action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging.     

Genetic assessment of the red squirrel in Illinois: Immigrants or Exotics?

Novel populations pose unusual challenges for wildlife managers because knowledge regarding the source of these populations is essential to develop sound management approaches. One example that illustrates the complexity of this issue is the small population of red squirrels (Tamiasciurus hudsonicus) identified in northeastern Illinois in the 1970s. To elucidate the source of the red squirrel population in Illinois, we examined both contemporary and less recent patterns of genetic structure using nuclear microsatellite loci and mitochondrial DNA. Analyses revealed the Illinois subpopulation was primarily comprised of descendents of immigrants from Indiana, but there was also evidence of a translocation of squirrels from Minnesota. We recommend continued protection for the red squirrel in Illinois due to its restricted geographic range, small population size, and status as a native population. © 2011 The Wildlife Society.     

Stem cell aging: Survival of the laziest?

The question whether stem cells age remains an enigma. Traditionally, aging was thought to change the properties of hematopoietic stem cell (HSC). We discuss here a new model of stem cell aging that challenges this view. It is now well-established that the HSC compartment is heterogeneous, consisting of epigenetically fixed subpopulations of HSC that differ in self-renewal and differentiation capacity. New data show that the representation of these HSC subsets changes during ageing. HSC that generate lymphocyte-rich progeny are depleted, while myeloid-biased HSC are enriched in the aged HSC compartment. Myeloid-biased HSC, even when isolated from young donors, have most of the characteristics that had been attributed to aged HSC. Thus, the distinct behavior of the HSC isolated from aged hosts is due to the accumulation of myeloid-biased HSC. By extension this means that the properties of individual HSC are not substantially changed during the lifespan of the organism and that aged hosts do not contain many aged HSC. Myeloid-biased HSC give rise to mature cells slowly but contribute for a long time to peripheral hematopoiesis. We propose that such slow, “lazy” HSC are less likely to be transformed and therefore may safely sustain hematopoiesis for a long time.     

Hydrostatic pressure and cellular respiration: are the values observed post-decompression representative of the reality under pressure?

The goal of this article was to assess whether a pressure change can constitute a bias of interpretation of pressure effects on pressure-acclimatized fishes. This work consisted first in a study of the recompression effects of mitochondrial extracts from eels pressure-acclimatized; and then in a study of red muscle fibre compression/decompression. The first experimental series shows a decrease of mitochondrial performances after recompression when compared with the decompressed group. It is concluded that recompression does not allow to get rid of decompression effects. This is confirmed by the second experimental series which show that a decompression induces a stronger reduction of MO2 than the previous compression.     

Hormesis and ecological risk assessment: Fact or fantasy?

Hormesis is a widespread phenomenon across occurring many taxa and chemicals, and, at the single species level, issues regarding the application of hormesis to human health and ecological risk assessment are similar. However, interpreting the significance of hormesis for even a single species in an ecological risk assessment can be complicated by competition with other species, predation effects, etc. In addition, ecological risk assessments may involve communities of hundreds or thousands of species as well as a range of ecological processes. Applying hormetic adjustments to threshold effect levels for chemicals derived from sensitivity distributions for a large number of species is impractical. For ecological risks, chemical stressors are frequently of lessor concern than physical stressors (e.g., habitat alteration) or biological stressors (e.g., introduced species), but the relevance of hormesis to non‐chemical stressors is unclear. Although ecological theories such as the intermediate disturbance hypothesis offer some intriguing similarities between chemical hormesis and hormetic‐like responses resulting from physical disturbances, mechanistic explanations are lacking. While further exploration of the relevance of hormesis to ecological risk assessment is desirable, it is unlikely that hormesis is a critical factor in most ecological risk assessments, given the magnitude of other uncertainties inherent in the process.     

Ethno-religious minorities and labour market integration: generational advancement or decline?

Abstract

This paper examines the generational progress of ethnic minorities in Britain by analysing four labour market outcomes: economic inactivity, unemployment, access to salaried jobs and self-employment. An important contribution of this paper is the possibility to examine the impact of a range of cultural and social resources on employment outcomes, namely language fluency, co-ethnic spouse, co-ethnic employer, bridging and bonding social capital. Controlling for ethnic and religious identities, individual, social and human capital characteristics, it finds clear advantages of language proficiency in obtaining employment and salaried jobs. However, the second generation shows little advancement in all the outcomes examined and a particularly strong religious penalty is found among Muslim women. It concludes that persistent ethno-religious penalty experienced by the second generation poses a serious policy challenge and does little to strengthen our economy or in building a cohesive society.     

Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease?

Endometriosis is a chronic inflammatory disease, characterized by implantation and growth of endometrial tissue outside the uterine cavity. This disabling condition is considered one of the most frequent diseases in gynecology, affecting 15-20% of women in their reproductive life. Pelvic endometriosis, the most common form of the disease, is associated with increased secretion of pro-inflammatory cytokines, neo-angiogenesis, intrinsic anomalies of the refluxed endometrium and impaired function of cell-mediated natural immunity. Recently, endometriosis has also been considered to be an autoimmune disease, owing to the presence of autoantibodies, the association with other autoimmune diseases and recurrent immune-mediated abortion. These findings are in apparent contradiction with the reduced cell-mediated natural immunity observed during the disease. In this review, we focus on the multiple processes underlying the complex pathogenesis of endometriosis, with particular emphasis on the role played by the immune system with the induction of autoimmunity.     

Cell senescence and human aging: where's the link?

Normal human cells will not divide forever in culture. After a defined number of passages, every culture enters a viable non-dividing state termed senescence. This led to the proposal that the progressive accumulation of senescent cells contributes to (but does not exclusively cause) the aging process. Data now suggest that cell senescence, like apoptosis, occurs as an anti-cancer mechanism. In vivo, extremely low rates of division occur over very long periods of time. Thus, by the end of its lifespan, an organism has performed a surprisingly large amount of cell turnover. In a normal culture the fraction of senescent cells increases smoothly with proliferation in vitro. This process can be accurately modelled by the progressive loss of telomeric sequence (proposed as a counting mechanism for senescence). Telomere length is usually maintained by the enzyme telomerase (repressed in many human tissues). Re-introduction of telomerase prevents the onset of senescence. However, data suggest that a separate telomere-independent pathway exists. Evidence that this pathway is present in humans is now emerging.     

Antioxidant defense and aging in C. elegans: Is the oxidative damage theory of aging wrong?

The oxidative damage theory of aging once seemed almost proven. Yet recently the buzzards have been assembling in the blue skies above it. New challenges to the theory from work using nematode worms seem set to bring them down to peck at its bones. But is the theory really dead, or does it just need to be modified?     

The ‘chicken or the egg’: which comes first,forest tree decline or loss of mycorrhizae?

Forest trees are experiencing massive declines globally caused by a multitude of stressors, both abiotic (pollution, fragmentation and climate change) and biotic (fungi, bacteria, viruses and insects). Mycorrhizal fungi aid plants in the requisition of nutrients through their mutualistic relationship with plant roots and are integral to tree health. Stresses affecting tree health will also influence mycorrhizal fungi directly or indirectly, and thus alter the pathways responsible for nutrient absorption. Such an intimate association is a true chicken or egg quandary; do external stressors cause a loss of mycorrhizae which leads to tree decline, does tree decline result in a loss of mycorrhizae, or is it a combination of both? A review of literature has identified six stressors known to contribute to tree decline and to impact directly on mycorrhizae; global climate change, pesticides, heavy metals, excess fertilizer, pathogens and habitat fragmentation. A few review papers have highlighted the link; however, what is missing is irrefutable empirical research. This review documents the known direct impacts of the six stressors on mycorrhizal communities and places this in the context of decline syndromes in long-lived forest trees. We also discuss methodologies available to identify fungi and future research needed to unravel the complex relationships between forest tree declines and their associated mycorrhizal fungi.