The new biology of ageing

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.     

The effect of isokinetic dynamometer deceleration phase on maximum ankle joint range of motion and plantar flexor mechanical properties tested at different angular velocities

During range of motion (max-ROM) tests performed on an isokinetic dynamometer, the mechanical delay between the button press (by the participant to signal their max-ROM) and the stopping of joint rotation resulting from system inertia induces errors in both max-ROM and maximum passive joint moment. The present study aimed to quantify these errors by comparing data when max-ROM was obtained from the joint position data, as usual (max-ROM_POS), to data where max-ROM was defined as the first point of dynamometer arm deceleration (max-ROM_ACC). Fifteen participants performed isokinetic ankle joint max-ROM tests at 5, 30 and 60° s⁻¹. Max-ROM, peak passive joint moment, end-range musculo-articular (MAC) stiffness and area under the joint moment-position curve were calculated. Greater max-ROM was observed in max-ROM_POS than max-ROM_ACC (P < 0.01) at 5 (0.2 ± 0.15%), 30 (1.8 ± 1.0%) and 60° s⁻¹ (5.9 ± 2.3%), with the greatest error at the fastest velocity. Peak passive moment was greater and end-range MAC stiffness lower in max-ROM_POS than in max-ROM_ACC only at 60° s⁻¹ (P < 0.01), whilst greater elastic energy storage was found at all velocities. Max-ROM and peak passive moment are affected by the delay between button press and eventual stopping of joint rotation in an angular velocity-dependent manner. This affects other variables calculated from the data. When high data accuracy is required, especially at fast joint rotation velocities (≥30° s⁻¹), max-ROM (and associated measures calculated from joint moment data) should be taken at the point of first change in acceleration rather than at the dynamometer’s ultimate joint position.     

Intrauterine programming of ageing

Ageing is an unavoidable corollary to being alive; the most intuitive interpretation of ageing being that it is the consequence of progressive body degeneration. In agreement with this, current models propose that ageing occurs through a stepwise accumulation of DNA damage, which ultimately limits the regenerative capacity of tissues. On the other hand, there is increasing evidence that fetal distress can influence the development of disease in adult life, a phenomenon known as ‘intrauterine programming’. The extent to which an intrauterine exposure to DNA damage can compromise lifespan remains unclear. My group has recently generated a murine model of a human syndrome linked to defective DNA repair and observed that these animals age prematurely, but the accumulation of DNA damage is restricted mostly to the embryonic period. Here, I discuss the implications of this finding and propose that ageing can be influenced by fetal distress.     

The effect of starvation on the ultrastructure of the red and white myotomal muscles of the crucian carp (Carassius carassius)

Summary The effect of 16 weeks total starvation on the ultrastructure of the red and white myotomal muscles of the crucian carp (Carassius Carassius) has been investigated. In the white fibres the amount of myofibrillar material fell from 89.6% to 70.7% of the total fibre volume whilst in the red fibres the fall was from 72.2% to 70.3%. The sarcoplasmic reticulum appeared to have become swollen during starvation in both fibre types. In the white fibres the terminal cisternae of some triads seem to have fused. The volume of the red fibres occupied by mitochondria was reduced from 16.2 % to 5.9 %. The concentration of mitochondria in the white fibres was too low to detect any quantitative changes. A marked reduction in the amount of euchromatin material was observed in most white fibre nuclei and many red fibre nuclei. Many of the ultrastructural changes noted in the present study can be correlated with biochemical changes known to occur in the red and white myotomal muscles of fish during starvation. This work was supported by a grant from the Natural Environmental Research Council.     

B‐cell capacity for differentiation changes with age

BackgroundAge‐related immune deficiencies are thought to be responsible for increased susceptibility to infection in older adults, with alterations in lymphocyte populations becoming more prevalent over time. The loss of humoral immunity in ageing was attributed to the diminished numbers of B cells and the reduced ability to generate immunoglobulin.AimsTo compare the intrinsic B‐cell capacity for differentiation into mature plasma cells (PCs), between young and old donors, using in vitro assays, providing either effective T‐cell help or activation via TLR engagement.MethodsB cells were isolated from healthy individuals, in younger (30–38 years) and older (60–64 years) donors. An in vitro model system of B‐cell differentiation was used, analysing 5 differentiation markers by flow cytometry, under T‐dependent (TD: CD40/BCR stimulation) or T‐independent (TI: TLR7/BCR activation) conditions. Antibody secretion was measured by ELISA and gene expression using qPCR.ResultsTI and TD differentiation resulted in effective proliferation of B cells followed by their differentiation into PC. B‐cell‐executed TI differentiation was faster, all differentiation marker and genes being expressed earlier than under TD differentiation (day 6), although generating less viable cells and lower antibody levels (day 13). Age‐related differences in B‐cell capacity for differentiation were minimal in TD differentiation. In contrast, in TI differentiation age significantly affected proliferation, viability, differentiation, antibody secretion and gene expression, older donors being more efficient.ConclusionAltogether, B‐cell differentiation into PC appeared similar between age groups when provided with T‐cell help, in contrast to TI differentiation, where multiple age‐related changes suggest better capacities in older donors. These new findings may help explain the emergence of autoantibodies in ageing.     

Effect of arm-shoulder fatigue on carpenters at work

The purpose of the study was to analyse the effect of arm-shoulder fatigue on manual performance. Ten experienced carpenters performed three standardized tasks (nailing, sawing and screwing). Electromyographic activity was recorded from six arm-shoulder muscles and the performances were video-filmed. After 45 min of standardized arm-cranking (arm-shoulder-fatiguing exercise of approximately 70%-80% maximal oxygen consumption), the tasks were repeated. The number of work movements and the time taken for each task were recorded and the quality of the work performed was compared. After the fatiguing exercise, only nailing was perceived as being harder and more mistakes were made during nailing and sawing. Movement performance was not influenced during nailing but was slightly slower during sawing and faster during screwing. However, there were increased mean EMG amplitudes in the upper trapezius and biceps muscles during nailing, in the upper trapezius, anterior deltoid and infraspinatus muscles during sawing and in the anterior deltoid muscle during screwing. Of the muscles studied the upper trapezius and anterior deltoid muscles increased their activity most after the arm-shoulder-fatiguing exercise.     

Smooth muscle and myofibroblast-like cells in the perimedullary stromal basket of kidneys from ringed seals (Phoca hispida)

Summary The medullary pyramid of renculi in kidneys of ringed seals (Phoca hispida) is enclosed by a basket composed of ribbons of stromal tissue continuous with the wall of the calyx. Branched smooth muscle cells with well-developed Golgi complexes and rough endoplasmic reticulum and only an incomplete external lamina are the principal cells in sites near the origin of the ribbons from the calycal wall. Deeper in the corticomedullary junctional region, smooth muscle is progressively replaced with stellate or spindle-shaped cells exhibiting structural characteristics intermediate between those of fibroblasts and smooth muscle fibers. These myofibroblast-like cells contain arrays of parallel microfilaments 6–8 nm thick with associated focal densities and subplasmalemmal dense plaques, caveolae, elongate, often deeply wrinkled nuclei, and well-developed Golgi complexes and rough endoplasmic reticulum. Material resembling external lamina is associated with parts of the surfaces of most myofibroblast-like cells and intermediate junctions are present. Fibroblasts lacking arrays of parallel microfilaments are a minority at any level in the stromal ribbons. Interstitial cells in the vicinity of the corticomedullary junction show similar myofibroblast-like characteristics. The smooth muscle and myofibroblast-like cells presumably assist expression of urine from the papilla and calyx, and possibly participate as pacemakers for the urinary tract.     

Cardiac Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase Causes Adverse Myocardial Remodeling following Myocardial Infarction

The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.     

Reduced sexual dimorphism in upper arm muscle circumference associated with protein-deficient diet in a South American population

Animal experiments have demonstrated that individuals exhibit differing tendencies to arrest growth and resorb muscle tissue under nutritional stress. Since placental and adrenocortical hormones are active in promoting muscle tissue resorption, sex differences may exist. In order to identify such sex differences, the upper arm circumferences of 362 individuals, aged one to 60 years, living in an area of chronic protein-calorie malnutrition were compared by age and sex with published data collected from U.S. and highland Peruvian populations. Sexual dimorphism for arm muscle circumference in the malnourished population is less than in U.S. samples of comparable age-categories. The highland population is closer to U.S. samples in the degree of dimorphism. The reduction in muscle circumference of males in the malnourished population appears to be the cause of the comparatively greater similarity of the sexes where protein-calorie malnutrition is experienced from infancy through adolescence. High muscle relief and excellent tonus in these same males indicate that reduced muscle circumference is not the result of flaccidity or higher ratios of compressible fat to muscle tissue. Reduction of muscle tissue in undernourished males is a reduction in total metabolic demand. Such reductions are adaptive in areas of chronic nutritional stress.