SciCombinator

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Concept: Senescence

218

Research into the microbiome-the indigenous microbial communities (microbiota) and the host environment that they inhabit-has changed clinicians' ideas about microbes in human health and disease. Perhaps the most radical change is the realization that most of the microbes that inhabit our body supply crucial ecosystem services that benefit the entire host-microbe system. These services include the production of important resources, bioconversion of nutrients, and protection against pathogenic microbes. Thus disease can result from a loss of beneficial functions or the introduction of maladaptive functions by invading microbes. This review will show how an understanding of the dynamics and function of the indigenous microbiota has altered our view of microbes in maintaining homeostasis and causing disease. It will discuss how disruption of the beneficial functions of the microbiota can lead to disease. Methods for studying the microbiota will be introduced as part of a conceptual framework for using these methods to delineate novel roles for microbes in health. Key associations between specific changes in the microbiome and disease will be discussed. This will lead to an explanation of how the intentional manipulation of the microbiota, either by restoring missing functions or eliminating harmful functions, may lead to novel methods to prevent or treat a variety of diseases. With the explosion of studies relating the microbiome to health and disease, this review aims to provide a foundation for clinicians to follow this developing area of biomedical research.

Concepts: Change, Senescence, Introduction, Disease, Bacteria, Microbiology, Medicine, Epidemiology

209

Life stress resulting from early-life experiences and domestic stress is linked with shorter leukocyte telomere length (LTL), but evidence on employment-related stress is scarce. We explored whether unemployment in early adulthood is associated with shorter LTL, a potential biomarker of premature aging.

Concepts: Cell division, Death, Biology, Immortality, Telomerase, Senescence, Telomere

205

Aging is the main risk factor for Alzheimer’s disease (AD); however, the aspects of the aging process that predispose the brain to the development of AD are largely unknown. Astrocytes perform a myriad of functions in the central nervous system to maintain homeostasis and support neuronal function. In vitro, human astrocytes are highly sensitive to oxidative stress and trigger a senescence program when faced with multiple types of stress. In order to determine whether senescent astrocytes appear in vivo, brain tissue from aged individuals and patients with AD was examined for the presence of senescent astrocytes using p16(INK4a) and matrix metalloproteinase-1 (MMP-1) expression as markers of senescence. Compared with fetal tissue samples (n = 4), a significant increase in p16(INK4a)-positive astrocytes was observed in subjects aged 35 to 50 years (n = 6; P = 0.02) and 78 to 90 years (n = 11; P<10(-6)). In addition, the frontal cortex of AD patients (n = 15) harbored a significantly greater burden of p16(INK4a)-positive astrocytes compared with non-AD adult control subjects of similar ages (n = 25; P = 0.02) and fetal controls (n = 4; P<10(-7)). Consistent with the senescent nature of the p16(INK4a)-positive astrocytes, increased metalloproteinase MMP-1 correlated with p16(INK4a). In vitro, beta-amyloid 1-42 (Aβ(1-42)) triggered senescence, driving the expression of p16(INK4a) and senescence-associated beta-galactosidase. In addition, we found that senescent astrocytes produce a number of inflammatory cytokines including interleukin-6 (IL-6), which seems to be regulated by p38MAPK. We propose that an accumulation of p16(INK4a)-positive senescent astrocytes may link increased age and increased risk for sporadic AD.

Concepts: Central nervous system, Death, Gerontology, Ageing, Neuron, Brain, Senescence, Nervous system

199

The purpose of this article is to review the association of the obesity pandemic with appearance of cancers in young adults under age 50 and to define potential mechanisms by which obesity may accelerate the development of malignancy.

Concepts: Senescence, Oncology, Obesity, Cancer

196

Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity. Telomeres are protective nucleotide repeats on chromosome tips that shorten with cell division, potentially limiting life span. Bats are the longest-lived mammals for their size, but it is unknown whether their telomeres shorten. Using >60 years of cumulative mark-recapture field data, we show that telomeres shorten with age inRhinolophus ferrumequinumandMiniopterus schreibersii, but not in the bat genus with greatest longevity,Myotis. As in humans, telomerase is not expressed inMyotis myotisblood or fibroblasts. Selection tests on telomere maintenance genes show thatATMandSETX, which repair and prevent DNA damage, potentially mediate telomere dynamics inMyotisbats. Twenty-one telomere maintenance genes are differentially expressed inMyotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity inMyotisbats, advancing our understanding of healthy aging.

Concepts: Cell, Histone, Gerontology, DNA repair, Evolution, Gene, Senescence, DNA

189

Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.

Concepts: Death, Cancer, Radical, Ageing, Senescence, DNA, Gerontology, Gene expression

182

Leucocyte telomere length (LTL) shortening is associated with cardiovascular ischemic events and mortality in humans, but data on its association with subclinical atherosclerosis are scarce. Whether the incidence and severity of subclinical atherosclerosis are associated with the abundance of critically short telomeres, a major trigger of cellular senescence, remains unknown.

Concepts: Death, Radical, Maximum life span, Cell division, Immortality, Telomerase, Senescence, Telomere

181

It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer’s disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in the APP-SwDI mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.

Concepts: Amyloid, Memory, Inclusion body myositis, Pathology, Senescence, Cognition, Beta amyloid, Alzheimer's disease

178

The reproductive-cell cycle theory of aging posits that reproductive hormone changes associated with menopause and andropause drive senescence via altered cell cycle signaling. Using data from the Wisconsin Longitudinal Study (n = 5,034), we analyzed the relationship between longevity and menopause, including other factors that impact “ovarian lifespan” such as births, oophorectomy, and hormone replacement therapy. We found that later onset of menopause was associated with lower mortality, with and without adjusting for additional factors (years of education, smoking status, body mass index, and marital status). Each year of delayed menopause resulted in a 2.9% reduction in mortality; after including a number of additional controls, the effect was attenuated modestly but remained statistically significant (2.6% reduction in mortality). We also found that no other reproductive parameters assessed added to the prediction of longevity, suggesting that reproductive factors shown to affect longevity elsewhere may be mediated by age of menopause. Thus, surgical and natural menopause at age 40, for example, resulted in identical survival probabilities. These results support the maintenance of the hypothalamic-pituitary-gonadal axis in homeostasis in prolonging human longevity, which provides a coherent framework for understanding the relationship between reproduction and longevity.

Concepts: Oophorectomy, Life expectancy, Gerontology, Organism, Hormone, Senescence, Ageing, Menopause

177

The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure.

Concepts: Biomarker, Senescence