Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the Golgi apparatus

It is well recognized that the world population is ageing rapidly. Therefore, it is important to understand ageing processes at the cellular and molecular levels to predict the onset of age‐related diseases and prevent them. Recent research has focused on the identification of ageing biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi‐mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro‐inflammatory cytokines and extracellular matrix–degrading enzymes, is modified during ageing, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi‐related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non‐senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and ageing.     

A genome wide association study identifies new genes potentially associated with eyelid sagging

Sagging eyelid is considered as an outward of skin ageing and may cause medical issues. However, little is known about the factors involved in sagging eyelid. The study, which aims at determining genetic risk factors for eyelid sagging, was conducted in a cohort of 502 unrelated Caucasian women living in the Paris region. All included participants were aged between 44 and 70 years old (mean age, 57.6 years old). The severity of sagging eyelid was graded in 6 categories by a dermatologist using standardized photographs of the face. A genome wide association study adjusted on potential risk factors (including age and smoking habits) was conducted to identify genetic associations. Two single nucleotide polymorphisms in total linkage disequilibrium on chromosome 10, rs16927253 (P = 7.07 × 10^‐10) and rs4746957 (P = 1.06 × 10^‐8), were significantly associated with eyelid sagging severity. The rs16927253‐T and rs4746957‐A alleles showed a dominant protective effect towards eyelid sagging. These polymorphisms are located in intronic parts of the H2AFY2 gene which encodes a member of the H2A histone family and very close to the AIFM2 gene that induces apoptosis. Additionally, single nucleotide polymorphisms with a false discovery rate below 0.25 were located nearby the type XIII collagen COL13A1 gene on chromosome 10 and in the ADAMTS18 gene on chromosome 16. Several relevant genes were identified by the genome wide association study for their potential role in the sagging eyelid severity.     

Multimorbidity and functional impairment–bidirectional interplay,synergistic effects and common pathways

This review discusses the interplay between multimorbidity (i.e. co‐occurrence of more than one chronic health condition in an individual) and functional impairment (i.e. limitations in mobility, strength or cognition that may eventually hamper a person's ability to perform everyday tasks). On the one hand, diseases belonging to common patterns of multimorbidity may interact, curtailing compensatory mechanisms and resulting in physical and cognitive decline. On the other hand, physical and cognitive impairment impact the severity and burden of multimorbidity, contributing to the establishment of a vicious circle. The circle may be further exacerbated by people's reduced ability to cope with treatment and care burden and physicians’ fragmented view of health problems, which cause suboptimal use of health services and reduced quality of life and survival. Thus, the synergistic effects of medical diagnoses and functional status in adults, particularly older adults, emerge as central to assessing their health and care needs. Furthermore, common pathways seem to underlie multimorbidity, functional impairment and their interplay. For example, older age, obesity, involuntary weight loss and sedentarism can accelerate damage accumulation in organs and physiological systems by fostering inflammatory status. Inappropriate use or overuse of specific medications and drug–drug and drug–disease interactions also contribute to the bidirectional association between multimorbidity and functional impairment. Additionally, psychosocial factors such as low socioeconomic status and the direct or indirect effects of negative life events, weak social networks and an external locus of control may underlie the complex interactions between multimorbidity, functional decline and negative outcomes. Identifying modifiable risk factors and pathways common to multimorbidity and functional impairment could aid in the design of interventions to delay, prevent or alleviate age‐related health deterioration; this review provides an overview of knowledge gaps and future directions.     

DIFFERENCES IN ENDOTHELIUM-DEPENDENT RELAXATION IN VARIOUS ARTERIES FROM WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS WITH INCREASING AGE

1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10^?7 to 10^?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery.     

LYSOSOMAL IRON ACCUMULATION AND TUBULAR DAMAGE IN RAT PUROMYCIN NEPHROSIS AND AGEING

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11–12 days rats treated with puromycin (10 mg/100g, i.v.i.) had greater proteinuria (211.6 ± 35.7 mg/day, mean ± s.e.m.) and urinary iron excretion (15.4 ± 2.2 μg/day) than salinetreated controls (14.5 ± 1.4 mg/day and 1.1 ± 0.2 μg/day, respectively, both P<0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 ± 64.5 vs 11.9 ± 8.6 mg%, P<0.001), and proximal tubular cell damage assessed semi-quantitively (1.17 ± 0.10 vs 0.62 ± 0.10, P<0.001) were higher and creatinine clearance (0.15 ± 0.01 vs 0.29 ± 0.02 mL/min perg kidney weight, P<0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.     

The natural history of dementia in ageing people with intellectual disability

In a retrospective follow-up study over 11 years, the incidence and natural history of dementia was assessed in an institutionalized group of 144 people, aged 60 years and over, with mild to profound intellectual disability resulting from causes other than Down's syndrome. Age-related incidences, age at onset, duration and symptoms of dementia were comparable to those in the general population. The frequent and invalidating physical comorbidity (11 /11) hampered the diagnostic process in this group. The high prevalence of episodes of delirium (9/11) and depressive symptoms (8/11) as the first manifestations of dementia and/or during dementia might reflect increased vulnerability as compared to other ageing people.     

Age-related Changes in Excitability and Recurrent Inhibition in the Rat CA1 Hippocampal Region

In hippocampal slices from male Wistar rats aged 1–34 months, we recorded the synaptic field potential responses of the CA1 neurons to stimulation of Schaffer collaterals. Eight electrophysiological indexes were extracted from input/output curves and compared in 11 age groups from 1 to 30 months. Neuronal excitability presented a U-shaped curve of development with a minimum at ˜7–8 months of age. There was a significant continuous increase in neuronal excitability, i.e. a decrease in excitatory postsynaptic potential (EPSP) producing both the threshold and half-maximal population spike from middle age (8–10 months) to senescence (30 months). Synaptic efficiency also increased in old rats to reach a maximum during senescence, i.e. both the current for threshold EPSP and that for half-maximal EPSP reached a minimum in senescence, although the earlier developmental patterns of these two indexes were non-linear. The duration of the field EPSP elicited with maximal stimulation presented an abrupt decay after the first month. Aged animals presented a relatively small maximal population spike. Recurrent inhibition was most prominent on neuronal excitability rather than synaptic strength. Measured as the percentage change in the half-maximal EPSP and half-maximal population spike, recurrent inhibition was found to decrease during the first 7–10 months of life and remained small in later development.     

Orthostatic blood pressure control and ageing*

Reflex haemodynamic responses to orthostatic stress are attenuated with ageing, the extent of attenuation increasing with advancing age. In 15–20% of individuals aged >65 years, the attenuation may be so marked that there is an excessive fall of blood pressure (BP) on assumption of the upright posture, sufficient on occasions to cause symptomatic cerebral hypoperfusion - this is known as ‘ageing-related’ orthostatic hypotension (AOH), a major risk factor for morbidity and mortality. Comparison of the cardiovascular responses to a variety of physiological and pharmacological stresses in healthy young and elderly subjects and in those with AOH suggests that the predominant site of the ageing-related change in cardiovascular reflex function is in the central connections of the arterial baroreflex, affecting particularly the BP buffering response. There is no evidence for ageing-related impairment of the efferent limb of the baroreflex, i. e. there is no significant ageing change in sympathetic vasomotor function or cardiac drive. Ageing-related impairment of baroreflex function also does not appear to result from either attenuation of arterial compliance or the presence of systolic hypertension, despite the epidemiological association between systolic hypertension and AOH. Better understanding of this important problem has the potential to improve the health of all elderly people.