Genetic modifications during cellular aging

Summary We review evidence that biological aging is a genetic process related to development and cytodifferentiation and thus may involve alterations of DNA structure and gene expression. We conclude that although determined to a high degree aging also involves stochastic features which lead to progressive somatic cell diversification during the life span. These considerations may help to explain the unevenness of physiological decline and the clonal emergence of certain age-dependent diseases such as cancer.     

Novel effects of diosgenin on skin aging

Extracts of Dioscorea coomposita or Dioscorea villosa are consumed as supplemental health foods at the time of climacteric. The extracts contain large amounts of the plant steroid, diosgenin. Here, we studied the safety and efficacy of diosgenin against skin aging at the time of climacteric. In vitro, diosgenin enhanced DNA synthesis in a human 3D skin equivalent model, and increased bromodeoxyuridine uptake and intracellular cAMP level in adult human keratinocytes. The increase of bromodeoxyuridine uptake by diosgenin was blocked by an adenylate cyclase inhibitor, but not by antisense oligonucleotides against estrogen receptor α, estrogen receptor β or an orphan G-protein-coupled receptor, GPR30, indicating the involvement of cAMP but not estrogen receptor α, estrogen receptor β or GPR30. In vivo, administration of diosgenin improved the epidermal thickness in the ovariectomized mice, a climacteric model, without altering the degree of fat accumulation. In order to examine the safety of diosgenin, diosgenin and 17β-estradiol were administered to breast cancer-burdened mice. The results revealed that while 17β-estradiol accelerated the tumor growth, diosgenin did not show this effect. Our finding, a restoration of keratinocyte proliferation in aged skin, suggests that diosgenin may have potential as a safe health food for climacteric.     

阿托伐他汀治疗对肾脏衰老的影响

目的：观察长期应用不同剂量的阿托伐他汀对老年大鼠肾脏的影响。方法：正常20月龄Wistar雌性大鼠分为3组（n=9）：①给予大剂量阿托伐他汀10 mg/（kg.d）灌胃;②给予小剂量阿托伐他汀1 mg/（kg.d）灌胃;③给予等剂量生理盐水灌胃,三组均连续灌胃4个月后处死大鼠,以3月龄大鼠（n=9）为对照。测定肾重指数,血清肌酐及血清脂蛋白,行PAS染色、天狼猩红染色观察肾脏病理,计算肾小球硬化指数。结果：三组老年大鼠的肾脏重量均显著减轻。老年大鼠小剂量阿托伐他汀组显著降低老年大鼠的血清肌酐（P〈0.01）。老年大鼠血脂水平显著高于青年大鼠,大剂量阿托伐他汀组显著降低老年大鼠的总胆固醇（CH）和低密度脂蛋白胆固醇（LDL-C,P均〈0.05）,小剂量阿托伐他汀组显著降低老年大鼠的LDL-C（P〈0.05）。大剂量阿托伐他汀组降低血脂的作用强于小剂量阿托伐他汀组。老年大鼠肾脏病理改变为显著的肾小球局灶节段性硬化,肾小球硬化指数显著增高（P〈0.05）,肾间质内大量炎性细胞浸润,肾内小动脉明显硬化。阿托伐他汀组显著减轻肾小球的局灶节段性硬化的程度,减少肾间质内炎性细胞浸润,显著改善肾内小动脉粥样硬化的病变程度。大剂量阿托伐他汀改善肾组织异常病理表现的作用更为明显。结论：长期应用阿托伐他汀可以显著改善老年大鼠肾脏衰老的异常病理改变,这些作用可能是通过阿托伐他汀的降脂作用、显著减轻肾内小动脉硬化及显著减少肾间质内炎性细胞浸润而综合起效的。     

Genetic and evolutionary aspects of aging.

Four questions of fundamental importance to gerontology are considered. 1) The number of genes involved in aging--in the case of man, an analysis of the phenotypes of relevant spontaneous mutants indicates that aging is highly polygenic. 2) General categories of genes--regulator genes may be more relevant than structural genes: a) three aneuploid disorders, Down's, Turner's and Klinefelter's syndromes, ranked among the top 10 candidates as "segmental progeroid syndromes" when compared with 162 single gene disorders of relevance to the pathobiology of aging; b) the rates at which maximum life spans have been increasing, especially among hominids, have probably been too rapid to be accounted for by changes in the amino acid sequences of proteins; c) a preliminary analysis of the variance of maximum life spans among a few orders of mammals is suggestive of a linear correlation with the indexes of rates of chromosomal evolution, as estimated by Bush et al. (Proc. Natl. Acad. Sci. USA 74: 3942-3946, 1977). 3) Nature of gene action--although there are reasons for invoking genes that modulate the rates of accumulation of somatic mutations, differential regulation of development is likely to be a major setting for gene action. 4) New approaches to formal genetic analysis of aging--advances in experimental embryology and somatic cell genetics offer such opportunities.     

Genetic control of circadian rhythms and aging

The review establishes a link between a group of genes which are conserved in evolution and form a molecular oscillator responsible for generation of circadian rhythms and genetic determinants of aging including associated pathways of intracellular signaling. An analysis of mechanisms of development of agedependent pathologies is conducted from the viewpoint of circadian genetics. Systematic data of circadian gene expression studies in animals demonstrating different rates of aging from accelerated to negligible are presented.     

Global and tissue-specific aging effects on murine proteomes

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The effects of reactive oxygen species on amphibian aging

To clarify the role of reactive oxygen species (ROS) in the aging process of amphibians, antioxidant enzyme activity and indexes of ROS damage were investigated biochemically using the livers of 3- and 10-year-old Rana nigromaculata frog males and females. Findings revealed no significant difference in survival rate between males and females. Antioxidant enzyme activity displayed an age-related decline. Superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) activity in 10-year-old liver decreased 40-80% from 3-year-old liver levels. In contrast, urate oxidase activity in the 10-year-old liver increased more than 200% from 3-year-old liver levels. At the same time levels of ROS damage, including the concentration of inorganic peroxide and thiobarbituric acid reactive substances (TBARS), greatly increased with age. Liver catalase from 10-year-old frogs proved to be more susceptible to aminotriazole and urea, losing approximately 80% of its original activity after 30 min of treatment. It seems likely that liver catalase in older frogs has diverged from liver catalase in younger frogs through oxidative modification. These findings suggest that a decrease in the activity of antioxidant enzymes over time results in increased levels of ROS damage in the livers of older frogs.     

Differential effects of aging on EEG after baclofen administration

Baclofen is a selective gamma-aminobutyric acid (GABA) type B agonist that may have important medicinal uses, such as in analgesics and drug addiction treatment. In addition, evidence is accumulating that suggests GABAergic-mediated neurotransmission is altered during aging. This study investigated whether baclofen administration (5 mg kg⁻¹) induces differential effects on cortical electrical activity with age. Electroencephalograms (EEGs) were recorded from young (3–4 months) and aged (15–17 months) rats, and both the absolute and relative powers in five frequency bands (delta: 2–4 Hz; theta: 4–8 Hz; alpha: 8–12 Hz; beta: 12–20 Hz; gamma: 20–100 Hz) were analyzed. Before administration of baclofen, we found that the EEG relative power in the beta band was higher in the aged than that in the young rats. After administration of baclofen, there was a slower increase in the relative power in the delta band in the aged than that in the young rats. Moreover, there was no significant difference between the two age groups in absolute power in any frequency band. These findings indicate that baclofen treatment appears to differentially modify cortical EEG activity as a function of age. Our data further elucidate the relationship between GABA_B receptor-mediated neurotransmission and aging.     

Genetic and epigenetic effects on centromere establishment

Chromosoma - Endogenous chromosomes contain centromeres to direct equal chromosomal segregation in mitosis and meiosis. The location and function of existing centromeres is usually maintained...     

Genetic analysis of mutagenesis in aging Escherichia coli colonies

Bacteria live in unstructured and structured environments, experiencing feast and famine lifestyles. Bacterial colonies can be viewed as model structured environments. SOS induction and mutagenesis have been observed in aging Escherichia coli colonies, in the absence of exogenous sources of DNA damage. This cAMP-dependent mutagenesis occurring in Resting Organisms in a Structured Environment (ROSE) is unaffected by a umuC mutation and therefore differs from both targeted UV mutagenesis and recA730 (SOS constitutive) untargeted mutagenesis. As a recB mutation has only a minor effect on ROSE mutagenesis it also differs from both adaptive reversion of the lacI33 allele and from iSDR (inducible Stable DNA Replication) mutagenesis. Besides its recA and lexA dependence, ROSE mutagenesis is also uvrB and polA dependent. These genetic requirements are reminiscent of the untargeted mutagenesis in λ phage observed when unirradiated λ infects UV-irradiated E. coli. These mutations, which are not observed in aging liquid cultures, accumulate linearly with the age of the colonies. ROSE mutagenesis might offer a good model for bacterial mutagenesis in structured environments such as biofilms and for mutagenesis of quiescent eukaryotic cells.     

Genetic control of retroviral disease in aging wild mice

Different populations of wild mice (Mus musculus domesticus) in Los Angeles and Ventura Counties were observed over their lifespan in captivity for expression of infectious murine leukemia virus (MuLV) and murine mammary tumor virus (MMTV) and for the occurrence of cancer and other diseases. In most populations of feral mice these indigenous retroviruses were infrequently expressed and cancer seldom occurred until later in life (>2 years old). MMTV was found in the milk of about 50% of wild mice, but was associated with only a low incidence (>1%) of breast cancer after one year of age. By contrast, in several populations, most notably at a squab farm near Lake Casitas (LC), infectious MuLV acquired at birth via milk was highly prevalent, and the infected mice were prone to leukemia and a lower motor neuron paralytic disease after one year of age. These two diseases were both caused by the same infectious (ecotropic)strain of MuLV and were the principal cause of premature death in these aging LC mice. A dominant gene called FV-4^R restricting the infection with ecotropic MuLV was found segregating in LC mice. Mice inheriting this FV-4^R allele were resistant to the ecotropic MuLV associated lymphoma and paralysis. The FV-4^R allele represents a defective endogenous MuLV provirus DNA segment that expresses an ecotropic MuLV envelope-related glycoprotein (gp70) on the cell surface. This FV-4^R encoded gp70 presumably occupies the receptor for ecotropic MuLV and blocks entry of the virus. The FV-4^R gene was probably acquired by the naturally occurring crossbreeding of LC feral mice with another species of feral mice (Mus castaneus) from Southeast Asia. The FV-4^R gp70 does not block entry of the amphotropic MuLV that uses a separate cell surface receptor. Therefore LC mice continued to be susceptible to the highly prevalent but weakly lymphogenic and nonparalytogenic amphotropic strain of MuLV. The study points out the potential of feral populations to reveal genes associated with specific disease resistance.     

Differential effects of aging on limb blood flow in humans

Aging appears to attenuate leg blood flow during exercise; in contrast, such data are scant and do not support this contention in the arm. Therefore, to determine whether aging has differing effects on blood flow in the arm and leg, eight young (22 +/- 6 yr) and six old (71 +/- 15 yr) subjects separately performed dynamic knee extensor [0, 3, 6, 9 W; 20, 40, 60% maximal work rate (WRmax)] and handgrip exercise (3, 6, 9 kg at 0.5 Hz; 20, 40, 60% WRmax). Arterial diameter, blood velocity (Doppler ultrasound), and arterial blood pressure (radial tonometry) were measured simultaneously at each of the submaximal workloads. Quadriceps muscle mass was smaller in the old (1.6 +/- 0.1 kg) than the young (2.1 +/- 0.2 kg). When normalized for this difference in muscle mass, resting seated blood flow was similar in young and old subjects (young, 115 +/- 28; old, 114 +/- 39 ml x g(-1) x min(-1)). During exercise, blood flow and vascular conductance were attenuated in the old whether expressed in absolute terms for a given absolute workload or more appropriately expressed as blood flow per unit muscle mass at a given relative exercise intensity (young, 1,523 +/- 329; old, 1,340 +/- 157 ml x kg(-1) x min(-1) at 40% WRmax). In contrast, aging did not affect forearm muscle mass or attenuate rest or exercise blood flow or vascular conductance in the arm. In conclusion, aging induces limb-specific alterations in exercise blood flow regulation. These alterations result in reductions in leg blood flow during exercise but do not impact forearm blood flow.     

The effects of aging and activity on muscle blood flow

Background

Our purpose was to determine if aging had an influence on muscle blood flow independent of habitual physical activity levels.

Methods

Blood flow was measured in the femoral artery by Doppler ultrasound after cuff occlusion of 10 minutes. Active and inactive older subjects (73 ± 7 years) were compared to active and inactive young subjects (26 ± 6 years).

Results

Peak blood flow capacity when normalized to lean muscle mass was related to activity level (p < 0.001), but not to age. Specifically, the young active group had higher peak blood flows than the young inactive (p = 0.031) or older inactive (p = 0.005) groups. Resting blood flow and conductance were not significantly different between groups. Mean arterial pressure was significantly higher in the older compared to young group (p = 0.002). Conductance was related to both activity (p = 0.002) and age (p = 0.003). A prolonged time for blood flow to recover was found in the older compared to the young group (p = 0.038) independent of activity status.

Conclusions

The prolonged recovery time in the older subjects may suggest a reduced vascular reactivity associated with increased cardiovascular disease risk. Peak blood flow capacity is maintained in older subjects by physical activity. In summary, maximal flow capacity and prolonged recovery of blood flow are influenced by different mechanisms in young and older active and inactive subjects.

     

Differential effects of aging on estrogen negative and positive feedback

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E(2)) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E(2) and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 ± 19.5 vs. 226.8 ± 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E(2) and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging.     

Maturational and aging effects on human brain apparent transverse relaxation

The goal of this study was to address the need for comprehensive reference data regarding maturational and aging effects on regional transverse relaxation rates (R(2)) of the brain in normal humans. Regional R(2)s were measured in twenty-five brain structures from a sample of seventy-seven normal volunteers 9 to 85 years of age. The relationships between regional R(2) and age were determined using generalized additive models, without the constraint of a specified a priori model. Data analysis demonstrated that the brain tissue R(2)-age correlations followed various time courses with both linear and non-linear characteristics depending on the particular brain structure. Most anatomical structures studied exhibited non-linear characteristics, including the amygdala, hippocampus, thalamus, globus pallidus, putamen, caudate nucleus, red nucleus, substantia nigra, orbitofrontal white matter and temporal white matter. Linear trends were detected in occipital white matter and in the genu of corpus callosum. These results indicate the complexity of age-related R(2) changes in the brain while providing normative reference data that can be utilized in clinical examinations and studies utilizing quantitative transverse relaxation.