Ageing adversely affects the migration and function of marginal zone B cells

Marginal zone (MZ) B cells are positioned within the spleen to capture blood‐borne antigen and immune complexes and deliver them to follicular dendritic cells in the B‐cell follicles. We show that within the spleens of aged mice antigen capture by MZ B cells, and their ability to shuttle between the follicle and MZ, were impaired. The ability of aged MZ B cells to migrate towards the MZ chemoattractant sphingosine‐1‐phosphate was increased, suggesting that aged MZ B cells had a greater propensity to be retained within the MZ. An extrinsic impairment in aged B‐cell migration towards the MZ was demonstrated using bone marrow chimeras. The follicular shuttling of MZ B cells derived from either young or aged bone marrow was similarly reduced in aged recipient spleens, showing that ageing effects on splenic stromal cells were responsible for the impaired follicular shuttling of MZ B cells. MZ B cells rapidly mount T‐cell‐independent (TI) antibody‐responses to microbial polysaccharide antigen. In aged mice the ability to produce immunoglobulins in response to the TI type 1 antigen TNP‐LPS was impaired. These ageing‐related changes to the MZ and MZ B cells have implications for the clearance of blood‐borne pathogens. Indeed elderly people have increased susceptibility to Streptococcus pneumoniae, a TI antigen, and decreased responses to vaccination. A thorough analysis of the mechanisms that underpin the ageing‐related decline in the status of the MZ and MZ B cells will help the design of novel treatments to improve immunity in the elderly.     

The effect of ageing in spinal cord injured humans on the blood pressure and heart rate responses during fatiguing isometric exercise

Groups of 50 healthy male controls and 50 subjects suffering from paraplegia (aged 20–65 years) were examined as to the inter-relationships between age, paraplegia and the strength, endurance, blood pressure and heart rate responses to fatiguing isometric exercise. Contractions were maintained in both groups under voluntary effort and through a contraction induced by electrical stimulation in the paraplegic group. All contractions were maintained to fatigue at a tension of 40% of the maximal muscle strength in either the handgrip or quadriceps muscles. Muscle strength of the handgrip was higher in the paraplegic subjects than in the controls, averaging 589 N and 463 N, respectively for the two groups. In contrast, quadriceps leg extension strength averaged 696 N in the controls and 190 N in the paraplegic groups; for both groups, ageing was associated with a reduction in muscle strength. While leg endurance was less in the paraplegic group than the control group, handgrip endurance was similar in the two groups, endurance increasing with ageing in both the controls and paraplegics. Both systolic and diastolic blood pressures increased at rest in paraplegic and control subjects with age. The magnitude of the pressor response to exercise also increased with age. This was true during both voluntary exercise and exercise induced through electrical stimulation in the paraplegic groups. The heart rate response (change in heart rate during exercise) to a fatiguing isometric handgrip contraction decreased by about 50% between the ages of 20 and 60 years in both the controls and paraplegics for isometric handgrip exercise. In contrast, heart rate changed little with age during contractions of the quadriceps muscle in paraplegics which were induced by electrical stimulation. Electronic Publication     

Androgens and the ageing male

Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men with severe primary or secondary hypogonadism. Thus, androgen substitution therapy is warranted in men with true hypogonadism at all ages. Symptoms experienced by otherwise healthy ageing males are non-specific and vague, although some may be similar to symptoms of hypogonadism. Therefore, the term 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial in some elderly males with low-normal testosterone levels. However, at this point in time, widespread use of testosterone in an elderly male population outside controlled clinical trials seems inappropriate.     

Transfer of germinal vesicle to ooplasm of young mice could not rescue ageing-associated chromosome misalignment in meiosis of oocytes from aged mice

BACKGROUD: Transferring a germinal vesicle (GV) from an aged woman's oocyte into ooplasm from a younger woman has been proposed as a possible way to overcome the problem of age-related decline in female fertility. Here we assessed this possibility by determining whether ooplasts derived from young mice could rescue ageing-associated chromosome misalignment in meiosis of oocytes from aged mice. METHODS: Three groups of reconstructed oocytes, young GV-young cytoplast (group YY), aged GV-young cytoplast (group AY), and young GV-aged cytoplast (group YA), were created by micromanipulation and electrofusion. RESULTS: Nuclear transplantation was successful in 89.8-94.4% of GV-ooplast complexes, and maturation rate of the reconstructed oocytes was 93.5-97.9%. Confocal microscopy analysis showed a significantly higher rate (49.2%) of chromosome misalignment in ageing mice than in young mice (16.9%), and 57.1% of oocytes in group AY exhibited chromosome misalignment, while the abnormality rate in groups YY and YA was 16.3 and 16.7% respectively. Calcium imaging showed that the three groups of reconstructed oocytes exhibited a similar pattern of calcium oscillations upon stimulation with bovine sperm extracts. Fertilization rate and developmental capacity to 2-cell embryos were also similar among the three groups of oocytes. CONCLUSIONS: Our findings suggest that: (i) the ooplasm from young mice could not rescue ageing-associated chromosome misalignment in meiosis of GV from aged mice; and (ii) behaviour of chromosome alignment over metaphase spindle is predominantly determined by GV material.     

Hippocampal and medial prefrontal cortical volume is associated with overnight declarative memory consolidation independent of specific sleep oscillations

The current study was designed to further clarify the influence of brain morphology, sleep oscillatory activity and age on memory consolidation. Specifically, we hypothesized, that a smaller volume of hippocampus, parahippocampal and medial prefrontal cortex negatively impacts declarative, but not procedural, memory consolidation. Explorative analyses were conducted to demonstrate whether a decrease in slow‐wave activity negatively impacts declarative memory consolidation, and whether these factors mediate age effects on memory consolidation. Thirty‐eight healthy participants underwent an acquisition session in the evening and a retrieval session in the morning after night‐time sleep with polysomnographic monitoring. Declarative memory was assessed with the paired‐associate word list task, while procedural memory was tested using the mirror‐tracing task. All participants underwent high‐resolution magnetic resonance imaging. Participants with smaller hippocampal, parahippocampal and medial prefrontal cortex volumes displayed a reduced overnight declarative, but not procedural memory consolidation. Mediation analyses showed significant age effects on overnight declarative memory consolidation, but no significant mediation effects of brain morphology on this association. Further mediation analyses showed that the effects of age and brain morphology on overnight declarative memory consolidation were not mediated by polysomnographic variables or sleep electroencephalogram spectral power variables. Thus, the results suggest that the association between age, specific brain area volume and overnight memory consolidation is highly relevant, but does not necessarily depend on slow‐wave sleep as previously conceptualized.     

老化大鼠坐骨神经Fas与FasL的表达及纤维结构变化

为了观察老化对神经纤维组成和结构的影响以及对凋亡相关因子Fas及其配体FasL表达的影响,随机取3月龄(成年组)和24月龄(老年组)正常SD大鼠各16只进行以下实验:采用透射电镜(TEM)观察坐骨神经的超微结构变化;苏木精-伊红(HE)染色计数轴突数与Schwann细胞数的比例;免疫组织化学染色检测大鼠坐骨神经老化时Fas和FasL的表达变化。结果显示:透射电镜下可见老年大鼠坐骨神经轴突直径增加,轴突周围间隙扩大,多数髓鞘分离,部分板层结构排列紊乱、破坏甚至呈气球样变。老年组的轴突数与Schwann细胞数的比例较成年组变大(P<0.01)。两组动物坐骨神经的髓鞘与轴突均可见Fas和FasL免疫组化阳性染色,但老年组大鼠的Fas和Fasl表达量明显增多(P<0.05)。以上结果提示老化大鼠坐骨神经神经纤维的形态结构发生很大的变化,可能与凋亡相关基因产物Fas及其配体FasL的表达增加有关。     

Fertilization and early embryology: Influence of maternal age on meiotic spindle assembly oocytes from naturally cycling women

To examine the effects of maternal ageing on the meiotic apparatus,we obtained oocytes from naturally cyding women in two age groups,including younger (aged 20–25 years) and older (aged 40–45years) women. Using high- resolution confocal microscopy weobtained a detailed picture of the meiotic spindle and chromosomeplacement during various phases of meiosls. Our data revealedthat the meiotic spindle in older women is frequently abnormal,both with regard to chromosome alignment and the micro- tubulematrix that comprise the meiotic spindle. The spindle in 79%of the oocytes from the older group exhibited abnormal tubulinplacement and one or more chromosomes were displaced from themetaphase plate during the second meiotic division. In contrast,only 17% of the oocytes from the younger age group exhibitedaneuploid conditions. The majority of eggs from this group possesseda well ordered, meiotlc spindle containing chromosomes thatwere fully aligned within a distinct metaphase plate in thespindle. Chromosome management during meiosis is directed bymicrotubule assembly within the spindle. These data suggestthat the regulatory mechanisms responsible for assembly of themeiotic spindle are significantly altered in older women, leadingto the high prevalence of aneuploidy.     

Efficacy of oocytes donated by older women in an oocyte donation programme

Population and insemination studies indicate that women experiencedeclining fertility with ageing. The question therefore ariseswhether older women are suitable oocyte donors. This study addressesthis issue by examining the relationship between oocyte donorage and clinical outcome in a large oocyte donation programme.We retrospectively reviewed data from 458 consecutive oocytedonation cycles completed by 164 different designated oocytedonors. Data were divided into two groups: group A, cycles withdonors aged 21–30 years at the time of follicular aspiration(193 cycles, 88 donors); and group B, cycles with donors aged31–40 years at the time of follicular aspiration (265cycles, 86 donors). Five donors, because of ageing during repetitivedonations, contributed data to groups A and B. In a given cycle,all oocytes for a recipient came from only one designated donor.Comparing the two donor groups, there was no difference in theamount of gonadotrophin used to achieve optimal stimulation;however, more oocytes were obtained from group A than groupB donors (16.8 ± 6.9 and 15.1 ± 8.1 respectively,P < 0.05). Similar percentages of oocytes were fertilizedin each group, resulting in the transfer of comparable numbersof embryos (4.5 ± 1.1 and 4.4 ± 13 respectively).Comparable clinical pregnancy rates were achieved (group A,36%; group B, 37%). The spontaneous abortion rates were alsosimilar (group A, 20%; group B, 12%), resulting in comparableongoing and delivered pregnancy rates per cycle (group A, 29%;group B, 32%) and per embryo transferred (group A, 6.4%; groupB, 7.3%). In conclusion, women of proven fertility should notbe excluded from donating oocytes simply because of their age.There exists a cohort of fertile women who resist the decreasingfecundity and increasing spontaneous abortion rates associatedwith ageing. With careful screening, many women of proven fertilitycan donate oocytes until the age of 40 years with an efficacyequal to that of younger women. Given the relative shortageof suitable oocyte donors, and increasing requests from recipientswith previous donor oocyte babies to obtain oocytes from thesame, now older, donor, the findings of this study are of practicalclinical importance.     

Role of L-arginine uptake mechanisms in renal blood flow responses to angiotensin II in rats

Aim: Reduced muscle force greater than expected from loss of muscle mass has been reported in ageing muscles. Impaired sarcoplasmic reticulum (SR) Ca²⁺ release has been implicated as a possible mechanism, and attributed to several factors, including loss of ryanodine receptor (RYR) expression and protein binding. The aim of this study was to evaluate muscle quality and SR Ca²⁺ release in ageing rats that were not so old that major atrophy had occurred. Methods: We collected in situ force data from the plantarflexor muscle group and muscle mass from the constituent muscles to determine muscle quality (force/mass) in adult (6–8 months) and ageing (24 months) rats (n = 8/group). We evaluated SR Ca²⁺ uptake and release, and determined expression of key proteins associated with Ca²⁺ release [RYR and FK506 binding protein (FKBP)] and uptake (SERCA, parvalbumin, calsequestrin). Results: Plantarflexor force and muscle quality were reduced with ageing (approx. 28 and 34%, respectively), but atrophy was limited, and significant only in the medial gastrocnemius (approx. 15%). The fast phase of SR Ca²⁺ release was reduced with ageing in both gastrocnemii, as was FKBP expression and FKBP–RYR binding, but RYR expression was not affected. Similar, but non‐significant changes were present in the plantaris, but the soleus muscle generally showed no ageing‐related changes. Conclusion: These data suggest a possible role for impaired SR Ca²⁺ release in ageing‐related loss of muscle quality, although not through loss of RYR expression.     

Decoding and rejuvenating human ageing genomes: Lessons from mosaic chromosomal alterations

One of the most curious findings emerged from genome-wide studies over the last decade was that genetic mosaicism is a dominant feature of human ageing genomes. The clonal dominance of genetic mosaicism occurs preceding the physiological and physical ageing and associates with propensity for diseases including cancer, Alzheimer’s disease, cardiovascular disease and diabetes. These findings are revolutionizing the ways biologists thinking about health and disease pathogenesis. Among all mosaic mutations in ageing genomes, mosaic chromosomal alterations (mCAs) have the most significant functional consequences because they can produce intercellular genomic variations simultaneously involving dozens to hundreds or even thousands genes, and therefore have most profound effects in human ageing and disease etiology. Here, we provide a comprehensive picture of the landscapes, causes, consequences and rejuvenation of mCAs at multiple scales, from cell to human population, by reviewing data from cytogenetic, genetic and genomic studies in cells, animal models (fly and mouse) and, more frequently, large-cohort populations. A detailed decoding of ageing genomes with a focus on mCAs may yield important insights into the genomic architecture of human ageing, accelerate the risk stratification of age-related diseases (particularly cancers) and development of novel targets and strategies for delaying or rejuvenating human (genome) ageing.